Definitive Radiotherapy With or Without Chemotherapy for T3-4N0 Squamous Cell Carcinoma of the Maxillary Sinus and Nasal Cavity

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1 Jpn J Clin Oncol 2010;40(6) doi: /jjco/hyq009 Advance Access Publication 25 February 2010 Definitive Radiotherapy With or Without Chemotherapy for T3-4N0 Squamous Cell Carcinoma of the Maxillary Sinus and Nasal Cavity Na Young Jang 1,,6, Hong-Gyun Wu 1,2,3,*, Charn Il Park 1, Dae-Seog Heo 2,4, Dong-Wan Kim 2,4, Se-Hoon Lee 2,4 and Chae-Seo Rhee 5 1 Department of Radiation Oncology, Seoul National University College of Medicine, 2 Cancer Research Institute, Seoul National University College of Medicine, 3 Institute of Radiation Medicine, Medical Research Center, Seoul National University, 4 Department of Internal Medicine, Seoul National University College of Medicine and 5 Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea 6 Present address: Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea. *For reprints and all correspondence: Hong-Gyun Wu, Department of Radiation Oncology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul, Republic of Korea. wuhg@snu.ac.kr Received October 26, 2009; accepted January 12, 2009 Objective: To evaluate the efficacy and toxicity of definitive radiotherapy with or without chemotherapy for T3-4 squamous cell carcinoma of maxillary sinus and nasal cavity. Methods: Forty-two patients with T3-4N0 squamous cell carcinoma of maxillary sinus (n ¼ 30) and nasal cavity (n ¼ 12) received definitive radiotherapy. Chemotherapy was used in 34 patients and elective neck irradiation was not used. Results: The 5-year overall survival/local control rates were 34%/29% for maxillary sinus cancer and 50%/52% for nasal cavity cancer. For maxillary sinus cancers, a performance status of Eastern Cooperative Oncology Group 2 (P ¼ 0.012), biologically equivalent dose,68 Gy (P ¼ 0.011) and no use of chemotherapy (P ¼ 0.037) were significant worse predictors for overall survival on log-rank analysis. Biologically equivalent dose,68 Gy was independently associated with poor local control (hazard ratio, 3.32; 95% confidence interval, ; P ¼ 0.007) and overall survival (hazard ratio, 2.94; 95% confidence interval, ; P ¼ 0.015). Regional recurrence occurred in only 1 of 30 patients with maxillary sinus cancer and 4 of 12 patients with nasal cavity. Two radiation necrosis in brain, one osteoradionecrosis, and one retinopathy and optic neuropathy occurred. Conclusions: The treatment outcome was poor and local control was a major problem. High radiation dose, effective chemotherapy and elective neck irradiation for advanced nasal cavity cancers may improve disease control. Key words: maxillary sinus cancer nasal cavity cancer squamous cell carcinoma radiotherapy chemotherapy INTRODUCTION Squamous cell carcinoma (SCC) of the nasal cavity (NC) or paranasal sinuses (PNS) is a rare disease (1). The disease is often diagnosed in the locally advanced stage and involves multiple structures (2). Treatment results have improved 6 Present address: Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea. during the past four decades (3).Surgeryfollowedbypostoperative radiotherapy is the treatment of choice, and the reported 5-year survival rate is 40 60% for resectable locally advanced disease (4,5). Definitive radiotherapy with or without chemotherapy has been used for unresectable or medically inoperable cases. There is relatively less published data for the use of definitive radiotherapy for the PNS or NC, and most studies consist of descriptions of various histological # The Author (2010). Published by Oxford University Press. All rights reserved.

2 Jpn J Clin Oncol 2010;40(6) 543 types. Treatment results of definitive radiotherapy have been generally inferior when compared with results for the use of surgery followed by postoperative radiotherapy (3,6 9). At Seoul National University Hospital, the treatment policy for SCC of the PNS or NC is surgery. Adjuvant treatments such as radiotherapy and chemotherapy may be used depending on the pathological results. Only patients with unresectable or medically inoperable tumors or patients reluctant to undergo surgery are offered definitive radiotherapy. This study describes our experience treating patients with clinical T3-4N0 SCC of the maxillary sinus (MS) and NC with definitive radiotherapy with or without chemotherapy. PATIENTS AND METHODS PATIENTS AND TUMOR CHARACTERISTICS Forty-four patients with locally advanced (T3 or T4 according to the 2002 American Joint Committee on Cancer staging system), non-metastatic (N0, M0) SCC of MS and NC were treated with definitive radiotherapy at Seoul National University Hospital from May 1990 to May Although surgical resection followed by radiotherapy with or without chemotherapy is the treatment policy, patients with unresectable or medically inoperable tumors or patients reluctant to undergo surgery were treated with definitive radiotherapy. Excluding two patients who underwent incomplete radiotherapy, we retrospectively reviewed records of 42 patients. The median follow-up time for living patients was 38 months (range: months). Clinical tumor staging was evaluated by computed tomography (CT) and/or magnetic resonance imaging (MRI). Most tumors invaded multiple adjacent structures, and the sites of tumor origin could not be clearly defined in some cases. The site of origin was assigned to the location of the epicenter of a tumor based on CT or MRI findings in these cases. Thirty patients had an MS cancer and 12 patients had an NC cancer. All tumors were histologically confirmed as SCC. Patient and tumor characteristics are listed in Table 1. TREATMENT All patients underwent definitive external beam radiotherapy. The median total radiation dose was 70 Gy (range: Gy). Because the dose per fraction, fractionation schedule and total treatment time varied, we calculated the biologically equivalent dose (BED) using the following equation: BED ¼ nd [1 þ d/(a/b)] 2 (0.693/a)(t/T pot ), where n is number of fractions, d the dose per fraction (Gy), a the linear constant equal to 0.3 Gy 21, b the quadratic constant equal to 0.03 Gy 22, t the time in days available for proliferation and T pot the potential doubling time of 5 days (10). The median BED to a tumor was 70.8 Gy, and all patients received a BED.60 Gy except for one patient. In one patient, radiotherapy was stopped after 50.4 Gy because the Table 1. Patient and tumor characteristics Characteristics Number of patients (%) Nasal cavity (n ¼ 12) Maxillary sinus (n ¼ 30) Age (years), median (range) 58 (21 74) 61 (36 81) 60 7 (58) 14 (47).60 5 (42) 16 (53) Gender Male 9 (75) 27 (90) Female 3 (25) 3 (10) Performance status ECOG 1 10 (83) 25 (83) ECOG 2 2 (17) 4 (13) ECOG 3 0 (0) 1 (3) T classification T3 2 (17) 8 (27) T4a 4 (33) 19 (63) T4b 6 (50) 3 (10) Differentiation Well differentiated 1 (8) 2 (7) Moderately differentiated 1 (8) 5 (17) Poorly differentiated 4 (33) 1 (3) Not available 6 (50) 22 (73) ECOG, Eastern Cooperative Oncology Group. patient wanted to undergo surgery. However, disease was still unresectable and radiotherapy was resumed 6 weeks later. Radiation was delivered to a primary tumor only, and elective neck irradiation (ENI) was not used. The majority of the patients received radiotherapy using a two-dimensional technique. A three-field technique was used usually. An anterior portal is combined with right and left bilateral fields. The lens was shielded at the anterior portal and the anterior border of lateral portal usually did not cross the lateral orbital canthus. After Gy, the optic nerve and chiasm were excluded from the field. However, in many cases, lesion abutted very closely or sometimes invaded optic apparatus. Thus, some patients received radiation.54 Gy to the optic pathway with the two-dimensional technique after discussion with the patient. Chemotherapy was recommended for all medically fit patients and was used in 34 patients. Table 2 describes the treatment details. Most of the patients underwent neoadjuvant chemotherapy with three cycles of 5-fluorouracil (1000 mg/ m 2 on days 1 5) and cisplatin (20 mg/m 2 on days 1 5 or 60 mg/m 2 on day 1). Cycles were repeated every 3 weeks. Four patients received three cycles of 5-fluorouracil (1200 mg/m 2 on days 1 3), cisplatin (40 mg/m 2 on days 2 and 3) and docetaxel (70 mg/m 2 on day 1). Three cycles of paclitaxel (175 mg/m 2 on day 1) and cisplatin (75 mg/m 2 on

3 544 Definitive radiotherapy for sinonasal cancer Table 2. Treatment characteristics Characteristics No. of patients (%) Nasal cavity (n ¼ 12) Maxillary sinus (n ¼ 30) Radiation, median (range) Total dose (Gy) 66.6 ( ) 70.1 ( ) Dose per fraction (Gy) 1.8 ( ) 1.8 ( ) Hyperfractionation No 8 (67) 21 (70) Yes 4 (33) 9 (30) Overall treatment time (days) 49 (38 67) 53 (36 103) BED (corrected for time), a Gy ( ) 70.8 ( ) Energy Cobalt-60 3 (25) 5 (17) 4 6 MV 9 (75) 25 (83) Technique Two-dimensional 8 (67) 24 (80) Three-dimensional conformal 4 (33) 5 (17) Intensity modulated 0 (0) 1 (3) Chemotherapy Received 11 (92) 23 (77) Schedule Neoadjuvant 8 (67) 19 (63) Concurrent 2 (17) 3 (10) Neoadjuvant þ concurrent 0 (0) 1 (3) Neoadjuvant þ adjuvant 1 (8) 0 (0) Regimen Fluorouracil þ cisplatin 10 (83) 17 (57) Fluorouracil þ cisplatin 0 (0) 4 (13) þ docetaxel Paclitaxel þ cisplatin 1 (8) 0 (0) Weekly cisplatin 0 (0) 3 (10) Cycle, median (range) 3 (2 6) 3 (2 5) BED, biologically equivalent dose. a This correction for time assumes potential doubling time ¼ 5 days; kick-off time ¼ 28 days; a ¼ 0.3 Gy 21 and b ¼ 0.03 Gy 22. day 1) were administered before radiotherapy in one patient with an NC cancer. Concurrent chemotherapeutic regimens were three cycles of 5-fluorouracil (1000 mg/m 2 on days 1 5) and cisplatin (100 mg/m 2 on day 1) or weekly cisplatin (30 35 mg/ m 2 on day 1). Cancer (EORTC) (11). Overall survival (OS), local control (LC), regional control (RC) and distant control (DC) rates were calculated using the Kaplan Meier method. Data for patients who were alive or dead without each type of recurrence were used as censored data in calculating LC/RC/DC rates. In calculating local recurrence-free survival (LRFS) rate, local recurrence and any type of death were defined as an event. Parameters such as age, sex, performance, T classification, BED, technique and use of chemotherapy were evaluated to identify prognostic factors using log-rank statistics and Cox s proportional hazard models. RESULTS TREATMENT OUTCOMES MAXILLARY SINUS Of the 20 patients who received neoadjuvant chemotherapy for MS cancer, 8 patients had a partial response, 7 patients had stable disease and 5 patients had progressive disease basedontherecistcriteria(12). There was no complete response after neoadjuvant chemotherapy. The 5-year OS, LC (Fig. 1), LRFS and DC rates were 34%, 29%, 22% and 78%, respectively. Regional recurrence developed in only one patient. The patterns of the first site of failure and overall failure at the time of the last follow-up in 30 patients with MS SCC are shown in Fig. 2. TOXICITY AND STATISTICAL ANALYSIS Toxicities were graded using the toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Figure 1. Kaplan Meier curves of (A) overall survival and (B) local control in patients with maxillary sinus cancer. A color version of this figure is available as supplementary data at

4 Jpn J Clin Oncol 2010;40(6) 545 Figure 2. Patterns of failure in patients with maxillary sinus cancer. (A) Site of first failure. (B) Site of overall failure at last follow-up. The most common site of failure was at the primary site. Of the 22 patients with isolated local recurrence, 10 patients received salvage treatments. Three patients underwent salvage surgery with or without chemotherapy. Of these patients, two patients had progressive disease and one patient developed a biopsy proven radiation-induced malignant fibrous histiocytoma with residual SCC. Two patients received salvage re-irradiation. One patient who received a dose of 54 Gy had an initial partial response followed by progressive disease, and the other patient who received a dose of 32 Gy had progressive disease. Five patients received only palliative chemotherapy. One patient had a neck relapse in the ipsilateral level I at 18 months after radiotherapy, and the patient underwent ipsilateral neck dissection. However, local recurrence was developed at 15 months after neck dissection. The patient underwent second radiotherapy with a dose of 50 Gy using a fractionated stereotactic radiotherapy technique with chemotherapy. At 16 months after the second radiotherapy, the patient underwent a contralateral neck dissection for multiple metastatic lymph nodes. The patient refused further salvage treatment and died from the disease after 8 months. Sites of distant metastases included the lung (n ¼ 1), liver (n ¼ 1), brain (n ¼ 1), and bone and brain (n ¼ 1). NASAL CAVITY For NC cancers, nine patients received neoadjuvant chemotherapy. Of these patients, six patients had a partial response, two patients had stable disease and one patient had progressive disease. The 5-year OS, LC, RC and DC rates were 50%, 52%, 60% and 47%, respectively (Fig. 3). The patterns of first failure and overall failure at the time of the last follow-up are shown in Fig. 4. Of the two patients with isolated local recurrence, one patient underwent salvage surgery. However, the patient experienced local progression with an ipsilateral level II recurrence and lung metastasis. Despite chemotherapy, the disease had progressed and the patient decided to receive hospice care only. One patient with local and ipsilateral level II recurrences underwent salvage surgery including ipsilateral neck dissection followed by chemotherapy. Four months after salvage treatment, the patient developed local progression and received a second salvage operation with chemotherapy. However, the disease was progressed and no further salvage treatment was recommended. Overall, 4 of 12 patients with NC SCC experienced regional recurrence. One patient had simultaneous local and regional recurrence, and one patient had local failure followed by regional and distant failure, as described previously. One patient had simultaneous regional and distant Figure 3. Kaplan Meier curves of (A) overall survival and (B) local control in patients with nasal cavity cancer. A color version of this figure is available as supplementary data at

5 546 Definitive radiotherapy for sinonasal cancer Figure 4. Patterns of failure in patients with nasal cavity cancer. (A) Site of first failure. (B) Site of overall failure at last follow-up. failure. The patient received palliative radiotherapy to the bone alone and died from the disease. One patient had simultaneous local, regional and distant failure. The patient planned to receive palliative radiotherapy to the neck and bone, but did not complete radiotherapy because of a poor general condition and the patient died 3 months later. The sites of neck recurrence were as follows: ipsilateral level II, two patients; ipsilateral level I and contralateral levels II IV, one patient; and contralateral level I, one patient. Sites of distant metastases were the lung (n ¼ 2) and bone (n ¼ 4). PROGNOSTIC FACTORS For MS cancers, a performance status of Eastern Cooperative Oncology Group (ECOG) 2 (P ¼ 0.012), BED,68 Gy (P ¼ 0.011) and no use of chemotherapy (P ¼ 0.037) were significant worse predictors for OS on univariate log-rank analysis. Regarding response to neoadjuvant chemotherapy, a good responder had a good prognosis. Four of the 8 patients with partial response, 6 of the 7 patients with stable disease, 5 of the 5 patients with progressive disease and 8 of the 10 patients with no chemotherapy had died at the time of analysis. A statistically significant multivariate predictor was a BED,68 Gy (hazard ratio, 2.94; 95% confidence interval, ; P ¼ 0.015) on Cox s proportional hazard models. A performance status of ECOG 2 (P ¼ 0.051) and BED,68 Gy (P ¼ 0.004) were associated with a poor LC rate by log-rank test and a BED,68 Gy (hazard ratio, 3.32; 95% confidence interval, ; P ¼ 0.007) remained as an independent predictor for LC. Statistically significant prognostic factors of LRFS were the same as LC with a performance status of ECOG 2 (P ¼ 0.051) and BED,68 Gy (P ¼ 0.008) in univariate analysis and BED,68 Gy (hazard ratio, 2.96; 95% confidence interval, ; P ¼ 0.012) in multivariate analysis. For NC cancers, the sample size was insufficient (n ¼ 12) to show a statistical difference. Only a BED,68 Gy was associated with a worse OS (P ¼ 0.045) on univariate analysis. We evaluated possible prognostic parameters including the primary site (MS or NC) for all 42 patients. A performance status of ECOG 2 (P ¼ 0.041) and a BED,68 Gy (P ¼ 0.005) were significant worse prognostic factors for OS and no use of chemotherapy appeared as marginally significant (P ¼ 0.085). On multivariate analysis, a BED,68 Gy (hazard ratio, 2.70; 95% confidence interval, ; P ¼ 0.008) remained as an independent prognostic factor for OS. A BED,68 Gy (P ¼ 0.048) was the only significant predictor for local recurrence on log-rank test. A primary site in the NC was a significant predictor for regional recurrence on both univariate (P ¼ 0.009, Fig. 5) and multivariate analyses (hazard ratio, 10.49; 95% confidence interval, ; P ¼ 0.036). For a distant metastasis, a T4b tumor (hazard ratio, 7.18; 95% confidence interval, ; P ¼ 0.004) and a BED,68 Gy (hazard ratio, 4.41; 95% confidence interval, ; P ¼ 0.042) were significant predictors on both univariate and multivariate analyses. TOXICITY Treatment-related toxicities Grade 2 are listed in Table 3. In one patient with tumor necrosis with infection, mass was very extensive at diagnosis. Fungating mass with ulceration in the hard palate and erythematous swelling of the cheek were seen. Neoadjuvant chemotherapy consisting of Figure 5. Kaplan Meier curves of regional control in patients with maxillary sinus (MS) and nasal cavity (NC) cancer. A color version of this figure is available as supplementary data at

6 Jpn J Clin Oncol 2010;40(6) 547 Table 3. Treatment-related toxicities (Grade 2 according to RTOG/ EORTC toxicity criteria) Toxicity No. of cases Acute Patchy moist desquamation 1 Confluent moist desquamation 1 Phlebitis, progressed to septicemia 1 Patchy mucositis 15 Mucosal ulceration 2 Otitis media requiring medication 4 Dry mouth, sticky saliva 4 Tumor necrosis/infection, progressed to brain abscess 1 Chronic Otitis media requiring surgery 1 Dry mouth, carry water at all times 1 Cataract, retinopathy and optic neuropathy 1 Osteoradionecrosis 1 Brain necrosis 2 Secondary malignant fibrous histiocytoma 1 RTOG, Radiation Therapy Oncology Group; EORTC, European Organization for Research and Treatment of Cancer. 5-fluorouracil and cisplatin followed by hyperfractionated radiotherapy with a BED of 70.9 Gy were delivered. Tumor necrosis combined with infection occurred after treatment, and an abscess had progressed to the brain. During the time to resolve the brain abscess, phlebitis had developed and had progressed to septicemia. The patient was admitted to the intensive care unit, but the patient expired after 10 days. In one patient, a radiation-induced cataract and retinopathy were reported 15 months after radiotherapy, and optic neuropathy was detected 6 years after radiotherapy. This patient had a T4b tumor and the eyeball and optic nerve received a considerable radiation dose. This patient developed a 1 cm-sized enhancing nodule at the left anterior frontal base (within the radiation field) 19 months after radiotherapy, and the patient underwent radiosurgery with a gamma knife. However, the mass increased in size, and the patient underwent a craniotomy and mass removal. The mass was diagnosed as radiation necrosis and the patient was still alive without disease recurrence at the time of the last follow-up (10 years after radiotherapy). One patient developed a single metastatic nodule at the temporal lobe 2 years after radiotherapy. The BED of the previous radiotherapy was 78 Gy, which is the highest dose used in this study. The patient received involved field radiotherapy only to avoid an overlap with the previous radiation field. Five years later, the temporal lesion disappeared, but a large cystic mass in the left frontal base (within the first radiation field) was detected. The patient underwent brain surgery for a suspicious recurrent metastatic nodule and the pathological diagnosis was radiation necrosis. At approximately the same time, the patient underwent dental extraction and an oroantral fistula occurred. The patient underwent repair surgery and the patient was alive without disease at the time of the last follow-up (15 years after initial definitive radiotherapy). DISCUSSION Because of the rarity and surgical treatment policy, there have been relatively few reported results of definitive radiotherapy for cancers of the PNS or NC. Similar to our results, treatment results of definitive radiotherapy have been generally poor (3,6 9,13). Most previous studies have described various histological types such as SCC, poorly differentiated carcinoma, adenocarcinoma, adenoid cystic carcinoma and neuroendocrine carcinoma. However, Dulguerov et al. (3) reported different actuarial locoregional control and carcinoma-specific actuarial survival for different types of histology. The incidence of nodal spread varies with the histologic type, i.e. 17% with SCC and poorly differentiated carcinomas versus 4% with adenocarcinoma, adenoid cystic carcinoma and mucoepidermoid carcinoma (14). Thus, we included only SCC in this study. In this study, various radiation schedules were used. We calculated the BED and used the BED as a parameter for prognostic factor analysis. A BED,68 Gy was a significant worse prognostic factor for OS and LC. There have been small studies that have supported the benefit of the use of a higher dose of radiotherapy. Giri et al. (15) reported treatment results of 41 cases of advanced SCC of the MS. Nineteen patients received radiotherapy alone. A dose.65 Gy correlated with better LC in patients treated with radiation therapy alone (75% versus 45%). Le et al. (13) also reported similar results. The 5-year LC rate was 12% for a radiation dose,65 Gy and 29% for a radiation dose 65 Gy (P ¼ 0.04). The radiation dose (favoring a higher dose, P ¼ 0.007) and the overall time (favoring a shorter time, P ¼ 0.04) were independent prognostic indicators for LC. Recently, Hoppe et al. (9) reported long-term results of unresectable stage IVB PNS carcinoma treated with definitive radiotherapy. A BED 65 Gy was a prognostic factor to predict improvement for both local progression-free survival (P ¼ 0.055) and OS (P ¼ 0.05) on log-rank test. Although 65 or 68 Gy is not an absolute threshold dose, these findings suggest that a higher dose given to a tumor may lead to better LC and improved survival. There are limitations in the radiation dose that can be safely delivered without causing injuries to adjacent critical structures, such as the optic pathway. In this study, radiation was delivered using a two-dimensional technique in 76% of cases and all reported severe late toxicities occurred in cases with the use of the two-dimensional technique. Techniques that are more precise such as intensity-modulated radiotherapy or proton therapy may provide low rates of radiation-induced toxicity with high LC and survival.

7 548 Definitive radiotherapy for sinonasal cancer The role of elective neck treatment has been debated. Most of the published retrospective studies have consisted of descriptions of various types of primary sites, stages, histology and treatments. Few studies have directly evaluated the role of ENI. Some institutions recommend ENI for locally advanced SCC and undifferentiated carcinoma of the PNS (9,14,16 18), whereas other institutions do not recommend the use of ENI (19). In this study, local failure was a major problem. Regional recurrence occurred in only 1 of 30 patients with an MS cancer, whereas 4 of 12 patients with an NC cancer had a neck recurrence. In the analysis of predictors for regional recurrence, an NC primary tumor was significantly associated with regional recurrence. Thus, ENI could be considered for an advanced stage SCC of the NC. The use of chemotherapy was associated with improved survival on univariate analysis but not on multivariate analysis. This finding may be reasonably explained as only patients with good performance may have received chemotherapy. However, the number of patients was insufficient to determine the real effect of chemotherapy on outcome. Also, good responders had a better prognosis than non-responders or patients who did not receive chemotherapy. Thus, the use of a more effective chemotherapy regimen and predictive factors for chemotherapy response should be investigated. Definitive radiotherapy was administered mainly for unresectable tumors, and the outcomes of patients with unresectable tumors treated with definitive radiotherapy have been dismal. Radiotherapy techniques have evolved and treatment results have improved during the past four decades. More precise radiotherapy techniques with more effective chemotherapy may provide low rates of radiation-induced toxicity, with high LC and survival in patients with T3-4N0 SCCoftheMSandNC.ForanNCprimarytumor,ENIto ipsilateral levels I II could be considered. Funding This work was supported by grant no from the SNUH Research Fund. Conflict of interest statement None declared. References 1. Roush GC. Epidemiology of cancer of the nose and paranasal sinuses: current concepts. Head Neck Surg 1979;2: Muir CS, Nectoux J. Descriptive epidemiology of malignant neoplasms of nose, nasal cavities, middle ear and accessory sinuses. Clin Otolaryngol Allied Sci 1980;5: 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: Dirix P, Nuyts S, Geussens Y, Jorissen M, Vander Poorten V, Fossion E, et al. Malignancies of the nasal cavity and paranasal sinuses: long-term outcome with conventional or three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2007;69: DuthoyW,BoterbergT,ClausF,OstP,VakaetL,BralS,etal. Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients. Cancer 2005;104: Amendola BE, Eisert D, Hazra TA, King ER. Carcinoma of the maxillary antrum: surgery of radiation therapy? Int J Radiat Oncol Biol Phys 1981;7: Blanco AI, Chao KS, Ozyigit G, Adli M, Thorstad WL, Simpson JR, et al. Carcinoma of paranasal sinuses: long-term outcomes with radiotherapy. Int J Radiat Oncol Biol Phys 2004;59: Chen AM, Daly ME, Bucci MK, Xia P, Akazawa C, Quivey JM, et al. Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement? Int J Radiat Oncol Biol Phys 2007;69: Hoppe BS, Nelson CJ, Gomez DR, Stegman LD, Wu AJ, Wolden SL, et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2008;72: Hall E, Giaccia A. Radiobiology for the Radiologist. 6th edn. Philadelphia: Lippincott Williams & Wilkins Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). IntJRadiatOncolBiolPhys 1995;31: Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92: Le QT, Fu KK, Kaplan M, Terris DJ, Fee WE, Goffinet DR. Treatment of maxillary sinus carcinoma: a comparison of the 1997 and 1977 American Joint Committee on cancer staging systems. Cancer 1999;86: Jiang GL, Ang KK, Peters LJ, Wendt CD, Oswald MJ, Goepfert H. Maxillary sinus carcinomas: natural history and results of postoperative radiotherapy. Radiother Oncol 1991;21: Giri SP, Reddy EK, Gemer LS, Krishnan L, Smalley SR, Evans RG. Management of advanced squamous cell carcinomas of the maxillary sinus. Cancer 1992;69: Hoppe BS, Stegman LD, Zelefsky MJ, Rosenzweig KE, Wolden SL, Patel SG, et al. Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting the MSKCC experience. Int J Radiat Oncol Biol Phys 2007;67: Le QT, Fu KK, Kaplan MJ, Terris DJ, Fee WE, Goffinet DR. Lymph node metastasis in maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2000;46: Paulino AC, Fisher SG, Marks JE. Is prophylactic neck irradiation indicated in patients with squamous cell carcinoma of the maxillary sinus? Int J Radiat Oncol Biol Phys 1997;39: Kim GE, Chung EJ, Lim JJ, Keum KC, Lee SW, Cho JH, et al. Clinical significance of neck node metastasis in squamous cell carcinoma of the maxillary antrum. Am J Otolaryngol 1999;20: