Tumori, 94: 320-326, 2008

Stage III-IV sinonasal and nasal cavity carcinoma treated with three-dimensional conformal radiotherapy
Anna Maria Gabriele1, Mario Airoldi2, Massimiliano Garzaro3, Michele Zeverino4, Simonetta Amerio4, Cecilia Condello5, and Alessandro Boidi Trotti1
1 Departments of Radiotherapy, 2Medical Oncology, and 4Medical Physics, San Giovanni Antica Sede Hospital, Turin; 31st ENT Department, and 5School of Medicine, University of Turin, Turin, Italy

ABSTRACT

Aims and background. To report the dosimetric data and clinical outcomes of patients with advanced neoplasm of the paranasal sinuses and nasal cavity, treated by three-dimensional conformal radiotherapy. Methods. Between 2000 and 2005, 31 consecutive patients were treated for locally advanced tumors of paranasal sinuses and nasal cavity. The primary tumor was located as follows: maxillary sinus 15 (48.4%); ethmoid sinus 10 (32.3%); nasal cavity 6 (19.3%). The patients were separated in two groups according to the modality of treatment: group A included 21 patients treated with postoperative three-dimensional conformal radiotherapy with or without chemotherapy; group B included 10 patients treated with radical three-dimensional conformal radiotherapy with or without chemotherapy. The median radiation dose to the planning target volume was 60 Gy (range, 56-63) for patients who underwent complete surgical resection and 68 Gy (range, 64-70) for those who did not have tumor resection or patients with residual disease. Results. The median follow-up was 42 months. Five-year local tumor control and overall survival actuarial rates were 74% and 72%, respectively, in the postoperative setting, 20% and 25%, respectively, with the primary radiotherapy. Local recurrence was the most common site of failure. No patient developed radio-induced blindness; 4 patients underwent enucleation as part of radical surgery. Dosimetric data are reported. Conclusions. The local control rate for these tumors remains low. The prognosis depends on localization, tumor stage and treatment modality. Three-dimensional conformal radiotherapy reduces the risk on optical pathways but does not modify outcome.

Introduction Sinonasal and nasal cavity cancers, although relatively rare, remain a formidable clinical challenge1,2. The nearness of a number of critical anatomical structures and the advanced stage at presentation reduce the chance of cure, leading to the frequent local recurrence and subsequent poor outcome. Five-year local control and overall survival are around 60% and 40%, respectively3-13. Treatment for sinonasal and nasal cavity cancers consists of surgery plus radiotherapy; in unresectable cancer, radiotherapy with or without chemotherapy is the treatment of choice. The literature reports many poor retrospective studies, but an optimal schedule has not been defined. Many doubts exist on the extent of surgical treatment, on the role of high-precision radiotherapy, on the benefit and timing chemotherapy with the aim to reduce the incidence of late side effects.

Key words: chemotherapy, local control, sinonasal cancer, surgery, threedimensional conformal radiotherapy. Correspondence to: Dr Massimiliano Garzaro, 1st ENT Department, San Giovanni Battista Hospital, Str. Val S. Martino sup. 18/10, 10131, Turin, Italy. Tel +39-339-5357391; fax +39-011-2052551; e-mail garz@libero.it Received May 25, 2007; accepted September 7, 2007.

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Radiotherapeutic planning is difficult due to the challenge of covering the target while sparing structures of the optical pathway. The target dose to control the tumor should be at least 66-70 Gy. The maximal tolerated dose on the optic tract is between 54 and 60 Gy3,14-18. We herein report the local control, survival, pattern of recurrence, prognostic factors and complications observed in 31 patients with locally advanced sinonasal and nasal cavity carcinomas, treated with three-dimensional conformal radiotherapy (3D-CRT).

Table 1 - Patient and tumor characteristics Characteristic Group A No. (%) Group B No. (%) 10 (32.3) 60.5 45-88 7 (22.6) 3 (9.7) 37 12-57 6 (19.4) 4 (12.9) Total No. (%) 31 (100) 64 40-88 23 (74.2) 8 (25.8) 42 12-78 15 (48.4) 10 (32.3) 6 (19.3) 15 (48.5) 10 (32.2) 2 (6.5) 1 (3.2) 1 (3.2) 1 (3.2) 1 (3.2) 1 1 8 8 1 4 1 1 2 4 (3.2) (3.2) (25.8) (25.8) (3.2) (12.9) (3.2) (3.2) (6.5) (12.9)

Patients and methods Between March 2000 and October 2005, 31 consecutive patients (23 males and 8 females) were treated at the Department of Radiotherapy of the San Giovanni Antica Sede Hospital in Turin. The median age was 64 years (range, 40-88). The most frequent site was the maxillary sinus (48.4%), followed by ethmoid sinus (32.3%) and nasal cavity with maxillary sinus invasion (19.3%). The major histologic subtypes were squamous cell carcinoma (48.5%) and adenocarcinoma (32.2%) (Table 1). G3 was the most frequent histologic grade (61.3%). The extent of tumor spread was defined by physical examination, rigid and flexible endoscopy and computed tomography (CT) and/or magnetic resonance imaging (MRI). All patients were reclassified, according to the 2002 UICC-TNM staging system19. Almost all the tumors were diagnosed at an advanced stage. The 2 patients with T1 lesions had the following characteristics: one had macroscopic positive surgical margins and one had a sarcoma histologic type with neck involvement. Sites of invasion are reported in Table 1. At the time of diagnosis, all patients were M0 and only 4 patients had positive neck nodes (Table 1). Patients were separated in two groups according to the modality of treatment (Table 2). Group A included 21 patients (67.7%) treated with postoperative 3D-CRT, 2 of whom also received concomitant chemotherapy. Group B included 10 patients (32.3%) submitted to 3DCRT as radical treatment (alone with or without chemotherapy). They did not receive surgery because of unresectable tumor (n = 4), internistic contraindication to surgery (n = 3) or refusal of surgery (n = 3). Surgery Only 11 of 21 patients who underwent surgery achieved complete surgical resection. Four patients with orbital cavity invasion were submitted to orbital exenteration. In 2 patients with neck node involvement, a radical neck dissection was performed. The mean time between surgery and the start of radiotherapy was 45 days (range, 30-55).

21 (67.7) Patients Age (yr) 65 Median (yr) Range 40-77 Gender 16 (51.6) Male Female 5 (16.1) Follow-up (mo) Median 45 15-78 Range Site Maxillary sinus 9 (29.0) 6 (19.4) Ethmoid sinus Nasal cavity 6 (19.3) Histology Squamous cell 9 (29.0) carcinoma 7 (22.6) Adenocarcinoma Basospinocellular 2 (6.5) 1 (3.2) Malignant inverted pap. Sarcoma 1 (3.2) Esthesioneuroblastoma Adenoid cystic 1 (3.2) Tumor stage Nodal stage T1R1 N0 1 (3.2) T1 N2 1 (3.2) T3 N0 6 (19.4) T3R1 N0 8 (25.8) T3 N2c T4a N0 2 (6.5) T4aR1 N0 1 (3.2) T4aR2 N0 1 (3.2) T4a N1 1 (3.2) T4b N0 Clinical stage (UICC staging system) I 1 (3.2) III 13 (41.9) IVA 7 (22.6) IVB

6 (19.4) 3 (9.7)

1 (3.2)

2 (6.4) 1 (3.2) 2 (6.5)

1 (3.2) 4 (12.9)

2 (6.5) 4 (12.9) 4 (12.9)

1 15 11 4

(3.2) (48.5) (35.4) (12.9)

Chemotherapy Ten patients (32.3%) received cisplatin (100 mg/m2 days 1, 22, and 43) concomitantly with radiotherapy. Induction chemotherapy (3 cycles of cisplatin, 100 mg/m2 day 1 + fluorouracil, 1000 mg/m2/day days 1-5 q; 3 weeks) was administered in 5 patients (16.1%). Radiotherapy All patients were irradiated with a Siemens Primus Linear Accelerator (6 MV) with a multileaf collimator. For head immobilization in the supine position, a thermoplastic facial mask (MED-TEC) was used. CT scans were performed for treatment planning. The CT images were then transferred to the PLATO-Nucletron Planning System, which allowed us to obtain digitally reconstructed radiographs from the digital image set. In pa-

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Table 2 - Treatment according to disease site and T stage Group Treatment T1 A B Surgery + RT Surgery + concurrent RTCT Neoadjuvant CT + concurrent RT-CT Concurrent RT-CT RT alone 1 Maxillary sinus T3 5 1 1 T4a 2 1 1 1 T4b T3 4 2

AM GABRIELE, M AIROLDI, M GARZARO ET AL

Ethmoid sinus T4a 2 T4b

Nasal cavity T1 T3 5 1 1

Total

1 1 1 3 2 1 5

19 2 5 3 2 31

61.3 6.5 16.1 9.7 6.5 100

Total

tients who did not undergo surgery, the clinical target volume (CTV ) was determined according to the CT/MRI findings of the gross tumor volume and microscopic extension. In patients who underwent surgery, the CTV was determined according to the edges of the resection and regions with residual disease in which the tumor had invaded surrounding structures. CTV and organs at risk (OAR), especially eyes, lens, optic nerves, the chiasm, brainstem and parotid glands, were outlined on the axial images. A 5-mm expansion margin was applied to the CTV to obtain the planning target volume (PTV). The resultant PTV was, for selected patients, reduced because of dosimetric constraints for OAR. The rationale of beam arrangement adapted for treatment planning relies on the clinical choice made in order to avoid orbital structures, basically by sparing high dose delivery to contralateral eye structures and, if possible, ipsilateral structures and visual pathways, even though high-dose regions instead involve the chiasm and central nervous system. In detail we assumed the following scheme. Maximal dose limit of 30 Gy to anterior orbital contents in order to avoid acute radiation effects. Such a dose constraint was reached for each patients by designing a customized beam arrangement (i.e., asymmetrical fields, field in field technique) in relation to the tumor site. Maximal dose limit of 54 Gy to optic nerves, chiasm and brainstem. This was the most strict dose constraint, particularly for patients with a high weighted anterior field (i.e., patients with high demand of reducing lateral spread of dose distribution). An isocentric technique consisting of several (from 4 to 7) unwedged or wedged beams was applied, seldom with non-coplanar field arrangements. Usually, the irradiation technique was performed with an anterior large portal (range Gantry angle: 15) and with two large posteriorly lateral portals; a reduced anterior and/or reduced posteriorly lateral portals were often incorporated in the treatment technique (field in field). The weights of the given doses to the anterior and lateral fields were usually 2:1 or 3:1 (according to patient anatomy) in favor of the anterior field to avoid unwanted irradiation to OAR and to deliver the dose mostly to the major bulk of disease. Rotation of the collimator was

used, if necessary, to achieve a better protection of critical organs. A bolus was used in some cases with skin involvement. For all patients and treatment plans, dosevolume histograms were calculated for the PTV and OAR. Portal imaging was performed for each field during the treatment. Figure 1 shows an example of our treatment policy. The dose was prescribed at the ICRU point defined for each treatment (mean dose ranged from 87 to 95%); the dose per fraction was 1,8-2 Gy, over an average treatment time of 6-7 weeks. The median dose was 60 Gy (range, 56-63) for patients who had undergone surgical resection and 68 Gy (range, 64-70) for those who did not have tumor resection or patients with residual disease. Dose distributions within different OAR were assessed according to delivered total dose to the PTV. Four patients with lymph node involvement received 50 Gy with 6 MV X-rays to the ipsilateral or bilateral side of the neck with a single anterior field; a boost (14 Gy) was applied by direct electron beams. Response and toxicity evaluation Response to treatment was evaluated with physical examination, rigid and flexible endoscopy, CT and/or MRI scan 2 months after the end of treatment. The response and toxicity were evaluated according to WHO and RTOG-EORTC criteria, respectively. Statistical analysis All survival data were measured from the start of first treatment. The specific end points examined included local control, disease-free survival, disease-specific survival, overall survival and toxicity rates. The KaplanMeier actuarial method was used to estimate local control and survival probabilities. Univariate analysis was performed using the logrank test to identify prognostic factors for specific end points.

Results Median follow-up was 42 months (range, 12-78). At 2 months after completion of radiotherapy, response was

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323

Figure 1 - 3D-CRT treatment plan for a 43-year-old man with a T4bN1Mo carcinoma of the ethmoid sinus (extended into maxillary). Prescribed dose was 70 Gy, delivered in 35 fractions, by six coplanar portals. The superior panels show central axis slice (A) and axial slice through eyes plan (B). Both slices show relative isodose distributions in which 20%, 50%, 90%, 95% and 105% are displayed. The central panels show the relative dose distributions for a sagittal plan (optic chiasm is shown in light blue, see white arrow) (C) and relative dose volume histogram for target and OAR (D). The inferior panels show two antero-posterior beams (field in field technique) (E) and an opposed couple of lateral, asymmetrical and different shaped beams overlapping on central plan (F).

as follows: 20 complete responses (2 in group B), 6 partial responses (3 in group B), 4 no change, and 1 localregional progression (all in group B). At the time of this analysis, 22 patients were alive (5 in group B), 19 without evidence of disease (3 in group B). Causes of death were local recurrence in 5 patients (3 in group B), local-regional progression in 1 (group B), distant metastases in 1 (group A), other causes in 2 (1 in group B). End treatment failures were 12: 4 local persistence (all in group B), 1 local-regional progression (group B), 7 local recurrence (3 in group B). Table 3 summarizes failure rates according to arising site, histology, modality of treatment and clinical stage. We had 4 cases of persistent disease: 1 dead due to disease at 27 months, 1 dead from other causes at 53 months, and 2 alive with stable disease. The site of recurrence was in the PTV in 5 patients and at the radiation field border in 2 patients. The median time of recurrence was 21

months from the beginning of treatment. Two patients were submitted to secondary surgery; they were alive and disease free after a median time of 37 months from surgery. The 3-year actuarial overall survival and local control rates were 85% and 63%, respectively, for all patients. In our patients who underwent surgery and postoperative radiotherapy, the local control and overall survival rates at 3 years were 83% and 94%, respectively; at 5 years they were 74% and 72%, respectively. In contrast, in patients who received radical radiotherapy with or without concomitant chemotherapy, the local control and overall survival rates at 3 years were 20% and 67%, respectively; at 5 years they were 20% and 25%, respectively, as shown in Figure 2. Treatment modality was the most powerful statistically significant prognostic factor for local control (P <0.0001), followed by T lesion (P = 0.026) and by primary

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Table 3 - Failure rates according to histology, treatment modality, primary site and clinical stage Histology Treatment modality I SCC SCC Adenoid cystic Adenocarcinoma Total SCC, squamous cell carcinoma. Surgery No surgery Surgery No surgery 1 1 III 1 1 2 Maxillary sinus IVa 2 3 5 IVb 1 1 III 1 1 Ethmoid sinus IVa 1 1 IVb 1 1 3 5 1 3 12 25.0 41.7 8.3 25.0 100 Total %

Local control
100,0 80,0 % 60,0 40,0 20,0 0,0

group A group B

Table 4 - Dose distribution in organs at risk (OAR) OAR Eye, ipsilateral Eye, contralateral Lens, ipsilateral Lens, contralateral Optic nerve, ipsilateral Optic nerve, contralateral Chiasma OAR, organs at risk. Mean dose, Gy (SD) 12.2 6.6 8.7 3.4 31.9 16.0 25.3 (4.7) (2.3) (1.3) (1.4) (12.2) (7.8) (12.7) Range 3.6-16.1 2.9-10.6 3.4-10.4 1.8-4.9 5.7-46.1 3.8-25.6 11.3-36.2

P < 0,0001

12

18

24

months

30

36

42

48

54

60

A
group A group B

Overall survival
100,0 80,0 % 60,0 40,0 20,0 0,0

P = 0,054

(tumor conformity index) = PTV volume in the 95% (90%) isodose/PTV volume; NTCI (normal tissue conformity index) = PTV volume in the 95% (90%) isodose/volume of 95% (90%) isodose. Global conformity index = [95% (90%) TCI x 95% (90%) NTCI]1/2. They are shown in Table 5 for 95% and 90% isodoses. Toxicity

12

18

24

months

30

36

42

48

54

60

Figure 2 - Actuarial local control and overall survival curves (Kaplan-Meier) in group A (21 patients) versus group B (10 patients).

site (P = 0.033). Other prognostic factors were marginally significant: treatment modality for overall survival (P = 0.054), orbital involvement for local control (P = 0.058). None of the other prognostic factors showed any impact on the outcome. Dosimetric data Dosimetric data were obtained from all 31 patients. Prescribed dose, mean and maximal doses delivered to the PTV were 64.2 Gy (range, 56-70), 60.1 Gy (range, 52.6-67.5) and 67.7 Gy (range, 56.6-77.8), respectively. Dose distribution in OAR is shown in Table 4. Quality of radiotherapy was assessed by the following indexes: TCI

Severe acute toxicity was as follows: grade III mucositis in 12 patients (38.7%) (9 with maxillary sinus disease, and 3 with nasal cavity tumor spread to the palate), grade IV mucositis in 7 patients (22.6%) (6 maxillary sinus and 1 with nasal cavity), grade III dysphagia in 3 patients (9.7%), grade III alopecia in all patients treated with chemotherapy (32.2%) and grade II alopecia in 8 patients (25.8%) in the exit area of the anterior photon beam. Acute keratoconjunctivitis was observed in 10 patients (32.2%). No severe chemotherapy-related toxicity was observed except for alopecia. Late toxicity was as follows: grade III xerostomia in 2 patients (6.5%). No patient developed radiation-induced blindness. At the time of analysis, a single eye blindness was documented in 3 cases: 2 for progressive disease, 1 for cataract.

Discussion The prognosis of locally advanced sinonasal and nasal cavity tumors remains unfavorable. Local recurrence is

USE OF 3D-CRT IN ADVANCED SINONASAL AND NASAL CAVITY TUMORS

Table 5 - Tumor conformity index (TCI), normal tissue conformity index (NTCI) and global conformity index (GCI) values for 95% and 90% isodoses TCI 95% Isodose Average (SD) Range 90% Isodose Average (SD) Range NTCI GCI

325

0.68 (0.16) 0.47-0.93 0.86 (0.12) 0.67-0.99

0.68 (0.14) 0.49-0.91 0.63 (0.14) 0.42-0.84

0.67 (0.12) 0.53-0.83 0.73 (0.12) 0.58-0.87

the major cause of failure. The low incidence and wide spectrum of histologies, along with primary sites do not permit to perform randomized clinical trials to compare different treatment approaches. Many retrospective series have reported better results with surgery followed by radiotherapy in resectable disease3,20-22. New radiotherapeutic techniques have been recently evaluated in these tumors. Roa et al.3, using 3DCRT alone, achieved a 3-year local control and overall survival rates of 32%. Padovani et al.23, in 25 patients with local advanced maxillary or ethmoid sinus carcinoma treated with 3D-CRT, reported a 2-year overall survival of 47%. Duthoy et al.11, in 39 patients treated with intensity-modulated photon radiotherapy in a postoperative setting, reported 4-year local control and survival rates of 68% and 59%, respectively. The disease and treatment characteristics reported in our study were consistent with other publications; most of the tumors were advanced at the time of presentation. The major adverse factor was advanced stage: 8/12 failures were observed in T4 lesions; 3 cases of failures had T3 lesion (2 had involvement of the pterygo-palatine fossa and 1 of the infratemporal fossa). The only T1 lesion failure was an adenoid cystic carcinoma with positive surgical margins. The worst outcome was observed in patients who did not undergo surgery or had a greater proportion of T4 tumor, G3 squamous cell carcinoma histology, and neck node involvement. Two patients also displayed initial extension to the central nervous system. The primary site affected local control: 9 of 12 failures were observed in maxillary sinus neoplasms whereas only 3 were observed in ethmoidal sinus tumors. The failures in PTV could be due to a clinical and/or surgical down-staging, with a consequent inadequate CTV pattern. In the group treated with radiation therapy alone, modalities and doses were according to the more updated literature. Dosimetric data shown in Table 5 confirm a good coverage of PTV: TCI for the 90% isodose reached a value of 0.86, which represents a reasonable index gained by the radiotherapy technique performed (3D-CRT). NTCI data were quite poor, mainly due to the advanced stage of treated tumors (T3-T4). This fact allows, in terms of dose distribution computing, dose delivery to a large volume overlapping normal

structures (with a degree depending upon the patient). We found no dose effect in the study series. Twelve patients, who had tumor recurrences, received a median dose of 58 Gy (surgery + radiotherapy) and 68 Gy (exclusively radiotherapy), which was not significantly different statistically from the whole population. In particular, tumor persistence was found among patients who underwent exclusively radiotherapy. Our results suggest that we probably should increase the already high dose delivered to the PTV. Treatment planning evaluation tools showed a sharp decrease in dose delivered to contralateral OAR compared with conventional radiotherapy, suggesting that 3D-CRT can be considered an effective treatment for this tumor. Intensity-modulated photon radiotherapy should be suitable to gain dose escalation to the PTV and can be regarded as a treatment modality which leads to a further reduction of dose delivered to OAR, whereas dose distribution in the PTV remains similar to that obtained by 3DCRT. Significant improvements in both dose reduction to OAR and dose conformation can be obtained using a proton-based delivering technique, due to physical advantages provided by such charged particles24. In attempts to improve the clinical outcome, chemotherapy has been administered in a wide variety of methods. Although very favorable results have been reported with the use of neoadiuvant13 and radio-concomitant25 settings, the definitive role of chemotherapy is still undefined. In our experience, chemotherapy was well tolerated, and in the neoadjuvant setting, 4 responses (2 partial and 2 minimal) were observed, in accord with the experience of Licitra et al.13 The concomitant chemotherapy-radiotherapy treatment was well tolerated, but its clinical impact cannot be defined. Acute radiation-related toxicity was acceptable. Dosimetric data showed a good protection for contralateral eye, and the ipsilateral eye was also partially shielded. Late toxicity to optical pathways was low; these data underline the ability of 3D-CRT in decreasing the doses delivered to OAR, even when used in advanced disease.

Conclusions Surgery with postoperative radiotherapy remains the standard treatment for resectable paranasal sinuses and nasal cavity tumors. Despite improving surgical techniques and delivering higher radiation doses with higher precision combined with chemotherapy, local control remains a major problem. 3D-CRT reduces the risk on optical pathways but does not seem to modify outcome.

References
1. Grant RN, Silverberg E: Cancer Statistics 1970. American Cancer Society, New York: 64-70, 1970.

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2. Carrau RL, Myers EN: Neoplasms of the nose and paranasal sinuses. In: Bayley BJ, et al (Eds) Head & Neck Surgery Otolaryngology, Lippincott, Williams & Wilkins; 3rd edition. 2001. 3. Roa WHY, Hazuka MB, Sandler HM, Martel MK, Thornton AF, Turrisi AT, Wolf GT, Lichter AS: Results of primary and adjuvant CT-based 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses. Int J Radiat Oncol Biol Phys, 28: 857-865, 1994. 4. Stern SJ, Hanna E: Cancer of the nasal cavity and paranasal sinuses. In: Cancer of the Head and Neck, Myers EN, Suen JY (Eds), 3rd ed, pp 205-233, WB Saunders, Philadelphia, 1996. 5. Giri SPG, Reddy EK, Gemer LS, Krishnan L, Smalley SR, Evans RG: Management of advanced squamous cell carcinomas of the maxillary sinus. Cancer, 69: 657-661, 1992. 6. Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB: Malignant tumors of the nasal cavity and paranasal sinuses. Head Neck, 24: 821-829, 2002. 7. Waldron JN, OSullivan B, Warde P, Gullane P, Lui FF, Payne D, Cummings B: Ethmoid sinus cancer: Twenty-nine cases managed with primary radiation therapy. Int J Radiat Oncol Biol Phys, 41: 361-369, 1998. 8. Itami J, Uno T, Aruga M, Ode S: Squamous cell carcinoma of the maxillary sinus treated with radiation therapy and conservative surgery. Cancer, 82: 104-107, 1998. 9. Jansen EPM, Keus RB, Hilgers FJM, Haas RLM, Bing Tan I, Bartelink H: Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma? Int J Radiat Oncol Biol Phys, 48: 27-35, 2000. 10. Dulguerov P Jacobsen MS, Allal AS, Lehmann W, Calcater, ra T: Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer, 92: 3012-3029, 2001. 11. Duthoy W, Boterberg T, Claus F, Ost P, Vakaet L, Bral S, Duprez F, Van Landuyt M, Vermeersch U, De Neve W: Postoperative intensity-modulated radiotherapy in sinonasal carcinoma. Cancer, 104: 71-82, 2005. 12. Porceddu S, Martin J, Shanker G, Weih L, Russell C, Rischin D, Corry J, Peters L: Paranasal sinus tumors Peter MacCallum Cancer Institute experience. Head Neck, 26: 322330, 2004. 13. Licitra L, Locati LD, Cavina R, Garassino I, Mattavelli F, Pizzi N, Quattrone P, Valagussa P, Gianni L, Bonadonna G, Solero CL, Cantu G: Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer. Ann Oncol, 14: 367-372, 2003.

14. Jang GL, Tucker SL, Guttenberger R, Peters LJ, Morrison WH, Garden AS, Ha CS, Ang KK: Radiation-induced injury to the visual pathway. Radioter Oncol, 30: 17-25, 1994. 15. Brizel DM, Light K, Zhou S, Marks L: Conformal radiation therapy treatment planning reduces the dose to the optic structures for patients with tumors of the paranasal sinuses. Radiother Oncol, 51: 215-218, 1999. 16. Pommier P Ginestet C, Sunyach MP Zrounba P Poupart M, , , , Cruse P Ciupea C, Carrie C, Montbarbon X: Conformal ra, diotherapy for paranasal sinus and nasal cavity tumors: threedimensional treatment planning and preliminary results in 40 patients. Int J Radiat Oncol Biol Phys, 48: 485-493, 2000. 17. Lohr F, Pirzkall A, Debus J, Rhoin B, Hoss A, Schlegel W, Wannenmacher M: Conformal three-dimensional photon radiotherapy for paranasal sinus tumors. Radiother Oncol, 56: 227-231, 2000. 18. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys, 21: 109-122, 1991. 19. International Union Against Cancer (UICC). TNM classification of malignant tumours, 6th Edition. Wiley Liss, New York, 2002. 20. Jiang GL, Ang KK, Peters LJ, Wendt CD, Oswald MJ, Goepfert H: Maxillary sinus carcinomas: natural history and results of postoperative radiotherapy. Radiother Oncol, 21: 193-200, 1991. 21. Budhina M, Smid L: Carcinoma of the paranasal sinuses: Results of treatment and some prognostic factors. Strahlenther Onkol, 168: 322-327, 1992. 22. Paulino AC, Marks JE, Bricker P, Melian E, Reddy SP Emami , B: Results of treatment of patients with maxillary sinus carcinoma. Cancer, 83: 457-465, 1998. 23. Padovani L, Pommier P, Clipp S, Martel-Lafay I, Malet C, Poupart M, Zrounba P, Cruse P, Desmes S, Carrie C, Montbarbon X, Ginestet C: Three-dimensional conformal radiotherapy for paranasal sinus carcinoma: clinical results for 25 patients. Int J Radiat Oncol Biol Phys, 56: 169-176, 2003. 24. Mock U, Georg D, Bogner J, Auberger T, Potter R: Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys, 58: 147-154, 2004. 25. Harrison LB, Raben A, Fisher DG: A prospective phase II trial of concomitant CT and RT with delayed accelerated fractionation in unresectable tumor of the head and neck. Head Neck, 20: 668-673, 1998.