# Radiation Oncology/Head & Neck/Sinonasal/Overview

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Nasal Cavity and Paranasal Sinuses

## Epidemiology

* Tumors of the nasal vestibule are frequently considered separately from nasal cavity and paranasal sinus tumors, because they are essentially skin cancers and as such have a different natural history
* Primary tumors of the nasal cavity and paranasal sinuses are usually grouped together, because they are frequently advanced at presentation and it's not clear from which site they originated
* Annual incidence ~1/100,000
* Occur more often in men, and age >40 (except salivary gland tumors and esthesioneuroblastoma which are seen earlier)

## Anatomy

* Sites
** Nasal vestibule
** Nasal cavity
** Maxillary sinuses
** Frontal sinuses
** Ethmoid sinuses
** Sphenoid sinus
* Lymphatic drainage
** Nasal vestibule: submandibular LNs, usually ipsilateral but may be bilateral
** Nasal cavity: olofactory group and respiratory group with different drainage patterns
*** Olofactory group drains to lateral retropharyngeal LNs, but can also communicate with subarachnoid space and CSF
*** Respiratory group drain lower, in lateral retropharyngeal LNs or in Level II LNs
** Paranasal sinuses have minimal drainage

## Pathology

* Benign: inverting papilloma can be associated with carcinoma in 5-15% of cases
* Squamous cell carcinoma most common
* Minor salivary glands account for 10-15% cases
* Lymphoma accounts for ~5%, and includes NK/T cell variant, which is locally very destructive
* Esthesioneuroblastoma accounts for 3-4%
* Mucosal melanoma accounts for ~1%

## Treatment Overview

* Combination of radical surgery and postop radiation is a frequently used approach
* Surgical approaches depend on location, and include lateral rhinotomy, medial maxillectomy, total maxillectomy, or craniofacial resection
* Extent of surgery correlates with DFS and OS, but not local control if RT is used
* Higher radiation doses are associated with improved local control, but visual toxicity is common
* Conversely, using conformal RT reduced toxicity while keeping survival comparable to conventional RT
* Poor overall survival ~50% at 5 years

## Outcomes

* Ghent, Belgium
** 2005 (1998-2003) PMID 15915466 -- "Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients." (Duthoy W, Cancer. 2005 Jul 1;104(1):71-82.)
*** Retrospective. 39 patients, surgery + postop RT. AdenoCA 79%, SCC 21%. Cribriform plate invasion 28%, orbital invasion 36%. Median IMRT 70 Gy. Median F/U 2.6 years
*** Outcome: 4-year LC 68%, 4-year OS 59%
*** Toxicity: decreased vision 6%, no blindness
*** Conclusion: Postop IMRT good LC, with low acute toxicity
** 2009 (1998-2006) PMID 18755554 -- "Intensity-modulated radiotherapy for sinonasal tumors: ghent university hospital update." (Madani I, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):424-32. Epub 2008 Aug 26.)
*** Retrospective. 84 patients. Postop IMRT in 89%, primary 11%. Median F/U 3.3 years
*** Outcome: 5-year LC 71%, DFS 60%, DMFS 82%, DSS 67%, OS 58%. Invasion of cribriform plate negative predictor
*** Toxicity: No radiation blindness, 1 patient radiation retinopathy, 1 patient lacrimal duct stenosis, 3 patients brain necrosis
*** Conclusion: IMRT low rate of toxicity, with high local control and survival
* Turin, Italy; 2008 (2000-2005) PMID 18705398 -- "Stage III-IV sinonasal and nasal cavity carcinoma treated with three-dimensional conformal radiotherapy." (Gabriele AM, Tumori. 2008 May-Jun;94(3):320-6.)
** Retrospective. 31 patients, locally advanced paranasal sinus and nasal cavity tumors. 3D-CRT. Postop (68%) dose 60 Gy or radical dose 68 Gy (32%). Some use of chemotherapy. Median F/U 3.5 years
** Outcome: Postop: 5-year LC 74%, 5-year OS 72%. Radical RT 20% and 25%. Local recurrence most common site of failure
** Toxicity: No radiation-induced blindness; 4 patients enucleation as part of radical surgery
** Conclusion: Local control remains low; 3D-CRT reduces risk of optical pathways but doesn't modify survival
* UCSF
** IMRT; 2007 (1998-2004) PMID 17189068 -- "Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses." (Daly ME, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):151-7.)
*** Retrospective. 36 patients with PNS cancers, 32 after gross total resection. Sites: 13 ethmoid, 10 maxillary, 7 nasal cavity, 6 other. IMRT 70 Gy to GTV, and 60 Gy to CTV. Median F/U 51 months
*** 5-year outcomes: LC 58%; DFS 55%; OS 45%
*** Toxicity: minimal, no decreased vision, 1 xerophalmia, 1 lacrimal stenosis, 1 cataract
*** Conclusion: IMRT no benefit on disease control, but low incidence of complications
** Historical; 2007 (1960-2005) PMID 17459609 -- "Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement?" (Chen AM, Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):141-7. Epub 2007 Apr 24.)
*** Retrospective. 127 patients, sinonasal carcinoma. Conventional 46%, 3D-CRT 39%, IMRT 18%
*** Outcome: 5-year OS: 1960's 46%, 1970's 56%, 1980's 51%, 1990's 53%, 2000's 49%
*** Toxicity: Grade 3-4 late: 53%, 45%, 39%, 28%, 16% (SS)
*** Conclusion: No improvement in disease control or survival, but decreased incidence of complications
* MSKCC; 2006 (1987-2005) PMID 17161557 -- "Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting-the MSKCC experience." (Hoppe BS, Int J Radiat Oncol Biol Phys. 2006 Dec 7)
** Retrospective. 85 patients with PNS, treated with post-op RT. Median RT 63 Gy. 62% treated with IMRT or 3D-CRT, rest with 2D. Median F/U 60 months
** 5-year outcomes: LC 62%, DM-free 82%, DFS 55%, OS 67%. Bad prognosis: squamous cell and cribriform plate involvement
** Toxicity: 1 blindness (but no Grade 3-4 among patients treated with IMRT/3D-CRT)
** Conclusion: Local recurrence main problem. Modern RT safe.

## Treatment Technique

* Utah; 1991 PMID 1764170 -- "Graduated block technique for the treatment of paranasal sinus tumors." (Tobler M, Med Dosim. 1991 Dec;16(4):199-204.)
** 5-field graduated wedge technique. AP beam heavily weighted, prescribed just beyond lens. Lateral wedge fields posteriorly fill-in dose as anterior contribution decreases

## Proton Therapy
### Clinical Outcomes

* Harvard
** 2008 (1991-2002) PMID 17902164 -- "Extent of surgery in the management of locally advanced sinonasal malignancies." (Resto VA, Head Neck. 2008 Feb;30(2):222-9.)
*** Retrospective. 102 patients, locally advanced, treated with proton therapy with or without surgery (R0 20%, R1 49%, R2/biopsy 31%). Squamous cell 32%, neuroendocrine 29%, adenoid cystic 20%, sarcoma 13%, adenocarcinoma 6%. Median RT dose if R0 resection 67.6 Gy, if R1/R2 resection 75.6 Gy usually given BID. Median proton contribution 57%. Concurrent chemo 33% (typically for neuroendocrine). Median F/U 3.6 years, alive 5.1 years
*** Outcome: 5-year LC R0 95% vs R1 82% vs R2 87% (NS, no difference by histology); 5-year DFMS 95% vs. 69% vs 52% (no difference by histology). 5-year OS 90% vs 49% vs 39% (worst for squamous cell). Regional failure rate 12%
*** Conclusion: High dose proton RT excellent local control regardless of extent of surgery. However, DFS and DMFS depended on extent of surgery. Can consider observation for regional neck
** 2006 (1991-2001) PMID 17050017 -- "Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons." (Weber DC, Radiother Oncol. 2006 Dec;81(3):243-9. Epub 2006 Oct 16.)
*** Retrospective. 36 patients, advanced stage nasal or paranasal malignant tumors. Treated with aggressive surgery and post-op RT (78%) or radical RT (22%). Median dose 69.6 CGE, usually BID or concomitant boost. Proton contribution 20-85% depending on beam availability. No concurrent chemo. Median F/U 4.4 years
*** Outcome: 3-year OS 90%, 5-year OS 81%. 3-year DFS 77%, 5-year DFS 73%
*** Toxicity: late visual/ocular toxicity Grade 2+ (retinopathy, optic neuropathy, cataract, dry-eye syndroma, or nasolacrimal duct blockage) 22% in median 2.6 years after RT)
*** Conclusion: AFRT enables delivery of 70 CGE with acceptable ophthalmologic complications
** 2002 (1992-1998) PMID 12173330 -- "Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy." (Fitzek MM, Cancer. 2002 May 15;94(10):2623-34.)
*** Prospective. 19 patients with olofactory neuroblastoma or neuroendocrine carcinoma. Kadish Stage B 4/19, Kadish Stage C 15/19. Induction cisplatin/etoposide x2 cycles, then proton/photon RT to 69.2 CGE concomitant boost. If response, further 2 cycles of chemo. Median F/U 3.7 years
*** Outcome: 5-year OS 74%; 5-year LC 88%
*** Toxicity: 1 patient unilateral vision loss after induction chemo. 4 patients frontal/temporal lobe damage by MRI. 2 patients soft tissue/bone necrosis. No radiation-induced visual loss
*** Conclusion: This approach is successful, with radical surgery reserved for nonresponders
* Chiba; 2007 (1999-2005) PMID 17398027 -- "Proton-beam therapy for olfactory neuroblastoma." (Nishimura H, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):758-62. Epub 2007 Mar 29.)
** Retrospective. 14 patients (Kadish A 2/14, Kadish B 5/14, Kadish C 7/14). Dose 65 GyE in 2.5 Gy/fx. Median F/U 3.3 years
** Outcome: 5-year LC 84%, 5-year RFS 71%, 5-year OS 93%
** Toxicity: Liquorrhea 1 patient, no other Grade 3+
** Conclusion: Excellent local control and survival outcome, without serious side effects

### Treatment Planning

* PSI
** Paranasal; 2003 PMID 12559516 -- "Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus." (Lomax AJ, Radiother Oncol. 2003 Jan;66(1):11-8.)
*** Treatment planning. Paranasal case, three dose levels 76 Gy, 66 Gy, and 54 Gy. IMRT vs IMPT comparison
*** Outcome: Comparable target conformality and sparing of critical structures; low dose regions or target homogeneity trade-off in IMRT plan
*** Conclusion: Comparable target conformality and sparing of critical structures, low dose regions better with IMPT
** Paraorbital; 2000 PMID 10863085 -- "Optimizing radiotherapy of orbital and paraorbital tumors: intensity-modulated X-ray beams vs. intensity-modulated proton beams." (Miralbell R, Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):1111-9.)
*** Treatment planning. 4 orbital/paraorbital tumors. IMRT vs IMPT.
*** Outcome: PTV coverage comparable. DVHs for OAR better with IMPT, though predicted severe NTCP equally low
*** Conclusion: Both IMRT and IMPT optimally treated PTV and reduced severe late toxicity; IMPT better at low/mid dose regions