Original Articles. Madhup Rastogi 1, Madanial Bhatt 1, Kundan Chufal 2, Madhu Srivastava 1, Mohan Pant 1, Kirti Srivastava 1 and Sanjay Mehrotra 3

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1 Jpn J Clin Oncol 2006;36(10) doi: /jjco/hyl086 Original Articles Esthesioneuroblastoma Treated with Non-Craniofacial Resection Surgery Followed by Combined Chemotherapy and Radiotherapy: An Alternative Approach in Limited Resources Madhup Rastogi 1, Madanial Bhatt 1, Kundan Chufal 2, Madhu Srivastava 1, Mohan Pant 1, Kirti Srivastava 1 and Sanjay Mehrotra 3 1 Department of Radiotherapy, King George s Medical University, Lucknow, Uttar Pradesh, 2 Department of Oncology, Batra Hospital and Medical Research Center, New Delhi and 3 Department of Medicine, King George s Medical University, Lucknow, Uttar Pradesh, India Received April 1, 2006; accepted June 26, 2006; published online August 22, 2006 Background: Esthesioneuroblastoma (ENB) is a rare and aggressive malignant tumor arising from olfactory epithelium. Surgical excision in the form of craniofacial surgical resection (CFR) has shown encouraging results. The purpose of the study is to analyze the outcome of this disease when managed by non-craniofacial resection (NCFR) surgery in limited resources. Methods: Between October 1998 and January 2004, eight patients with ENB were treated in the Department of Radiotherapy at KGMU, Lucknow. None of these eight patients underwent CFR surgery. All patients received six cycles of vincristine, adriamycin and cyclophosphamide (VAC) based chemotherapy followed by radiotherapy. Results: All the patients registered during this period had undergone operative procedures in the form of NCFR surgery except two. Complete response was present in five (62.5%) patients and three (37.5%) patients had partial response. Locoregional relapse-free survival at 3 years was 62.5% and median survival time was 38 months. Disease-free survival and overall survival at 3 years was 72.9 and 71.4%, respectively, and median disease-free survival time was 43 months, while mean overall survival time was 40.7 months as median overall survival time was not reached. Conclusion: Patients in developing countries often present with advanced stages and because of non-availability of technical advances and surgical expertise one tends to approach these patients with palliative intent. Most of the patients in our series were of stage C disease (75%) and still our response rate and survival were encouraging despite the fact that surgery was not optimal. This combination chemoradiotherapy schedule can be used outside the protocol setting where resources are limited. Key words: esthesioneuroblastoma craniofacial surgical resection non-craniofacial surgical resection chemotherapy radiotherapy INTRODUCTION Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare and aggressive malignant tumor of the nasal cavity and paranasal sinuses. The tumor is thought to originate from the specialized neuroepithlium of the upper nasal cavity (1,2). It accounts for 6% of nasal cavity and paranasal sinuses cancer cases (3) and 0.3% of the upper aero digestive tract For reprints and all correspondence: Madhup Rastogi, Senior Resident, Department of Radiotherapy, King George s Medical University, Chowk, Lucknow, , Uttar Pradesh, India. drmadhup1@rediffmail.com malignancies (4). This tumor has always been a matter of discussion since 1924, when Berger and Luc published its first description and till now more than 1000 cases have been reported including the recent review of 945 cases (5). The largest series, originating from single institutions, contain an average of 31 (range, 4 11) cases (6 17). These series, however, covered long periods of time during which significant changes in the management of ENB occurred. Because of the relatively small number of patients in each of the series reported, together with the heterogeneous nature of many of these series, it has been difficult to make definitive recommendations for the management of ENB at our institution. # 2006 Foundation for Promotion of Cancer Research

2 614 Combination chemotherapy and radiotherapy for esthesioneuroblastoma Treatment for ENB has evolved from extracranial surgical excision to multimodality treatment regimes. The most significant therapeutic advance in the treatment of this neoplasm was made several decades ago with the introduction of the craniofacial surgical resection (CFR). Disease-free survival improved from 37.5 to 82% in one study when extracranial surgical excision and craniofacial resection were compared (9). Different therapy protocols have been applied since then. These include CFR with preoperative or postoperative radiation therapy; CFR with combination radiation therapy and chemotherapy; chemotherapy with radiation therapy; and chemotherapy alone (10,13,16,18 26). It remains unclear whether combination treatment regimens improve survival over that achieved by CFR alone. Although CFR has improved survival, but it is a major surgery where skill is required in order to achieve a complete resection of the tumor. Not every center across the world is equipped with facilities to undertake such surgical procedures. Owing to lack of awareness and rarity of the tumor, patients usually present in the late and advanced stages of the disease where complete surgical excision is not achievable. Under such situations a more comprehensive management is needed comprising neoadjuvant chemotherapy followed by surgery and radiotherapy. Role of chemotherapy is uncertain, and standard chemotherapy regimens for the treatment of this malignancy have not been clearly identified. To date, chemotherapy has been reserved for recurrent and distant metastatic disease. Recently, some studies have suggested that multidisciplinary treatment strategies that combine neoadjuvant chemotherapy, surgery and radiotherapy offer potential benefits (16,18,20 22,25,26). Chemotherapy has been used in the form of cisplatin, etoposide, ifosfamide and taxanes in these studies. Patients in our country invariably come from low socioeconomic background and cannot afford costly chemotherapy that requires multiple days to administer. For our eight adolescent and adult patients with ENB, we combined chemotherapy in the form of vincristine, adriamycin and cyclophosphamide (VAC) with radiotherapy. VAC regimen is a simple and effective (11) chemotherapy regimen administered on an outpatient basis in a single day and was suitable for our patients. In this report we discuss the benefits and tolerability of this combination for the treatment of patients with advanced ENB. Because of the rarity of ENB, experience with this tumor has been limited, and no consensus has been reached in its management where facilities of CFR are not available. Our objective was to review the experience of our institution with this rare malignancy using non-craniofacial surgical resection (NCFR) method of treatment. PATIENTS AND METHODS A retrospective analysis based on medical records was performed for eight consecutive patients with biopsy proven advanced ENB following incomplete excision at the Department of Radiotherapy, King George s Medical University, Lucknow, between October 1998 and January Cases were identified by means of a computerized search, and all available medical records were reviewed. The diagnosis of ENB was based on histopathological features, including microscopic findings of uniform small round blue cells with scant cytoplasm and hyperchromatic round nuclei with inconspicuous nucleoli (Fig. 1). Other features included neurofibrils, rosettes, pseudorosettes and neurosecretary granules. For six patients, immunohistochemical analyses, including staining for chromogranin, CD56, neuron specific enolase, synaptophysin and S-100 protein (alone or in combination with each other), were performed to confirm the diagnosis of ENB. Imaging studies, including computed tomography and/or magnetic resonance imaging, were performed to evaluate the extent of primary disease and treatment response. Disease stage was classified as A, B or C according to the criteria established by Kadish et al. (6). Kadish stage A refers to disease confined to the nasal cavity; stage B refers to disease that is confined to the nasal cavity and one or more paranasal sinuses; Stage C refers to disease extending beyond the nasal cavity or paranasal sinuses and includes cases with involvement of the orbit or base of the skull as well as cases with intracranial extension; and Stage D refers to cases with tumor metastases to cervical lymph nodes or distant organs. Locoregional Relapse Free survival (LRFS) and overall survival (OS) were calculated from the time of diagnosis. Sites of recurrence and salvage therapies were recorded. Statistical analysis for OS and LRFS was performed using the Kaplan Meier method using SPSS statistical software (SPSS Inc., release 10.0) TREATMENT SURGERY The most optimum approach for adequate resection of these tumors is a combined anterior craniofacial resection (CFR) that involves joint skills of neurosurgeon and oncosurgeon. As these tumors originate from olfactory epithelium, they lie very close to the nasal roof. To achieve adequate surgical margins cribriform plate is resected en block with the tumor. Any surgical approach that does not include anterior cranial resection was termed as non-craniofacial resection (NCFR) surgery, which may range from biopsy to margin positive surgery. All the patients registered during this period had undergone operative procedures in the form of NCFR surgery. One patient underwent debulking surgery due to intracranial extension while other had only biopsy of the lesion as a surgical procedure. One patient underwent lateral rhinotomy, three patients had medial maxillectomy and other three had ethmoidectomy. All the patients were referred to us for further management. Post-operative CECT scan of the paranasal sinuses revealed presence of gross residual disease in four out of six patients who underwent NCFR surgery (Fig. 2). Remaining two patients were disease-free clinically and radiologically at the time of registration. All these patients were then

3 Jpn J Clin Oncol 2006;36(10) 615 Figure 1. Photomicrograph showing tumor composed of small round or oval cells which are disposed in groups. Cells enclose hyperchromatic round nuclei and small amount of light stained cytoplasm. subjected for chemotherapy and radiotherapy treatment after obtaining informed written consent. CHEMOTHERAPY All the patients received combination chemotherapy (VAC). This regime constituted chemotherapeutic agents like vincristine (1.4 mg/m 2 total dose not exceeding 2 mg, IV bolus), adriamycin (50 mg/m 2, as 30 min IV infusion) and cyclophosphamide (600 mg/m 2, IV bolus) administered on day 1. Chemotherapy was repeated in cycles of 21 days. Responses were evaluated after every other cycle, beginning with the second cycle. After chemotherapy all patients were subjected to radiotherapy treatment. A total of six cycles of VAC chemotherapy was given to all the patients before radiotherapy except in two cases. These two patients who revealed no residual disease radiologically following non-craniofacial surgery received three cycles of VAC before radiotherapy and subsequently rest of the three after radiotherapy. RADIOTHERAPY All patients underwent simulation using a Tele simulator (SAT 10, Shimadzu, Japan) with neck hyper extended. Immobilization was done with the help of orfit cast. Radiotherapy was planned with one anterior and two lateral wedge pair fields with unequal weighting and treatment was delivered via Telecobalt Unit Theratron 780C (AECL, Ottawa, Canada) with dose normalized at tumor center. Dose homogeneity requirement was % of the specified centrally absorbed dose, as mentioned in the ICRU 50 reference point. Twodimensional computer planning was done on Radplan software (TSG Corporation, India). All patients received a conventionally fractionated irradiation, i.e. 2 Gy per fraction five times in a week to a total of Gy in 4 6 weeks. STATISTICAL ANALYSIS All the statistical analysis was done in SPSS ver10.0 software. Mean and median values were calculated with descriptive analysis. Locoregional relapse-free survival, disease-free survival and overall survival from the date of commencing radiotherapy were estimated using the Kaplan Meier analysis. For overall survival all the deaths were counted as events regardless of cause. Persistent disease and locoregional relapse were counted as events in the locoregional relapse-free survival analysis with recurrence time censored at the date of first recurrence or date of last contact for the patient without disease. For disease-free survival patients expired because of disease and patients alive with disease were counted as events while patients alive without disease or expired because of other cause were censored at the date of last contact or death. RESULTS Between October 1998 and January 2004, eight patients of ENB were registered in the department of Radiation Oncology, KGMU, Lucknow, India. Mean age of these eight patients was 29.9 years ( 16.3) and mean follow-up time was 36 months

4 616 Combination chemotherapy and radiotherapy for esthesioneuroblastoma Figure 2. Preoperative, post-operative and post-chemo-radiotherapy Contrast Enhanced Computed Tomography (CECT) of paranasal sinuses (PNS) of one patient. (a) Preoperative CECT of PNS showing soft tissue growth invading nasopharynx with extension into nasal cavity and bilateral maxillary sinuses. (b) Post-operative CECT of PNS showing gross residual disease in the maxilla on either side and in the nasal cavity. (c) Post-chemo-radiotherapy CECT PNS showing complete regression of disease. ( 3.6). Details of patients characteristics are shown in Table1. Six (75%) patients were of stage C disease. Nasal obstruction was the presenting complaint in seven out of eight patients. None of the eight patients underwent craniofacial resection. In one patient with stage C disease, only debulking surgery was done, while one patient did not undergo any form of surgery because of advanced disease and poor performance status. All the patients underwent six cycles of chemotherapy with VAC regimen. Six patients received radiation therapy after completing six cycles of chemotherapy while in two patients it was delivered after three cycles of chemotherapy followed by rest of the three cycles. All toxicities were noted as per NCI-CTC criteria version 2.0. None of the patients had grade III neutropenia and only two patients had grade II neutropenia. Thrombocytopenia with grade I was present in three patients while the rest did not experience any thrombocytopenia. Three patients had grade II anemia and were managed with blood transfusions. Nausea and vomiting was present in mild form in all the patients and was adequately managed with oral antiemitics. Late toxicity was mainly present in the form of peripheral neuropathy, which was grade II in five patients at 4 months after receiving chemotherapy. Overall toxicities were mild and were manageable with Table 1. Demographic and initial sign or symptoms in eight patients with esthesioneuroblastoma Patient No. Age (years) Gender Kadish stage Signs and symptoms 1 22 Female C Anosmia, nasal obstruction 2 15 Male B Nasal obstruction 3 45 Female C Epistaxis, nasal obstruction 4 18 Male B Nasal obstruction, facial pain 5 23 Male C Nasal obstruction, diplopia 6 60 Male C Cranial nerve III paralysis 7 17 Female C Facial pain, nasal obstruction 8 39 Male C Nasal obstruction, proptosis Summary Mean age Male = 5 B = 2 Most common presentation was nasal obstruction (Mean and Female = 3 C = 6 frequency distribution) symptomatic care. After completion of treatment objective response was present in 100% of the patients, which was evaluated clinically and radiologically. Complete response

5 Jpn J Clin Oncol 2006;36(10) 617 Table 2. Treatment and outcome of eight patients with esthesioneuroblastoma No. Surgery Chemotherapy RT Response Recurrence Treatment at relapse Follow up time (months) Status at last follow up 1 NCFR VAC 6 cycles 60 Gy CR Local recurrence CT 49 Alive with ENB 2 NCFR VAC 6 cycles 56 Gy CR No recurrence No treatment 51 Alive without ENB 3 NCFR VAC 6 cycles 60 Gy PR Residual CT 22 Death with ENB 4 NCFR VAC 6 cycles 60 Gy CR No recurrence No treatment 46 Alive without ENB 5 NCFR VAC 6 cycles 60 Gy CR Distant metastases CT 43 Alive with ENB 6 Debulking VAC 6 cycles 40 Gy PR Residual CT 18 Alive with ENB surgery 7 Biopsy VAC 6 cycles 60 Gy PR Residual Surgery 21 Death without ENB 8 NCFR VAC 6 cycles 60 Gy CR Distant metastases CT 38 Death with ENB NCFR, non-craniofacial resection; VAC, chemotherapy with vincristine, adriamycin and cyclophosphamide; RT, radiotherapy dose; CR, complete response; PR, partial response; CT, chemotherapy; ENB, esthesioneuroblastoma. Figure 3. Kaplan Meier survival curve showing locoregional relapse-free survival. was present in five (62.5%) patients (Fig. 2) and three (37.5%) patients had partial response (Table 2). Two patients both with stage B disease, who had complete response to the treatment, are still alive without disease at the end of 46 and 51 months. Four patients had locoregional relapse and two had distant metastases. Overall six patients relapsed. One patient underwent surgery with medial maxillectomy while other four received chemotherapy in the form of cisplatin and etoposide. A patient who underwent surgery was disease free but expired at 21 months because of cardiac cause. Mean time to recurrence was 25.4 months ( 20.1). Locoregional relapse-free survival at 3 year was 62.5% and median survival time was 38 months (Fig. 3). Disease-free survival and overall survival at 3 years was 72.9 (Fig. 4) and 71.4% and median disease-free survival time was 43 months, while mean overall survival time was 40.7 months as median overall survival time was not reached. Treatment details and outcome are summarized in Table 2. Figure 4. Kaplan Meier survival curve showing disease-free survival. DISCUSSION ENB is a rare malignancy of the neuroepithelium. Fewer than 1000 cases have been reported in the literature and most reports were in small series similar to the present study. Because of the rarity of this tumor, prospective studies are extremely difficult to conduct. Pathological classification is challenging because these tumors must be differentiated from other small blue cell neoplasm of the nasal cavity such as lymphoma, sarcoma and melanoma. Differentiating ENB from neuroendocrine carcinoma is also difficult and some think the entities are a continuous spectrum with varying biological aggressiveness. A newer technique like immunohistochemistry has added more specificity and sensitivity with improved accuracy in the diagnosis. We reviewed our institutional experience with ENB from October 1998 to January In 1979 Elkon reviewed the existing literature (27) and reported a bimodal age distribution with an early peak from 11 to 20 and a later peak between 51

6 618 Combination chemotherapy and radiotherapy for esthesioneuroblastoma and 60 years of age. The current study reports a mean age at diagnosis of 22 years, which is consistent with the earlier peak. ENB is mostly seen in advanced stages. In our series 75% of the patients were of Kadish stage C disease (Table 1). The reasons for the late diagnosis are unspecified symptoms such as nasal obstruction, anosmia and recurrent epistaxis (24). The most common symptom in our patients was nasal obstruction, which has also been reported by other investigators (8,14), whereas one patient presented with isolated third cranial nerve paralysis. Headaches, anosmia, epistaxis and visual disturbances were common presenting symptoms in our series (Table 1). The Kadish staging system for ENB has been widely used in the literature. The inadequacies of this system, however, have been pointed out by Dulguerov et al. (12) First, the incidence of Stage A disease is very low because with new developments in imaging technique such as contrast enhanced computed tomography, more and more patients are diagnosed with involvement of ethmoid sinuses, thus upstaging the disease. There was not a single patient in our study who presented with Stage A disease. Similar observations have been reported in other series and the overall incidence of Kadish Stage A disease is estimated to be 5%. (7,13,16) Modern imaging makes a diagnosis of Kadish Stage A disease less likely. A second flaw is the lack of a clear prognostic significance of stage A and Stage B disease. This may be because sinus involvement does not adversely impact surgical respectability and, hence, should not represent an adverse prognostic factor. A third shortcoming is that, most tumors are stage C disease, which includes tumors with spectrum of spread patterns and biological behaviors that should have prognostic significance. Finally, the regional disease was not included in the staging system because of its rarity. Some have suggested this should be classified as Kadish D disease (13). Despite the inadequacies and attempts to use a TNM classification (10,12) Kadish system is still the most commonly used and, hence, was applied to our patients. Optimum management for ENB remains to be defined. An improved local control after CFR in comparison with extracranial approaches has been suggested (9,10). Therefore, CFR coordinated with neurosurgery, otolaryngology and ophthalmology has become the most commonly used surgical procedure for ENB. Extensive surgical resection in the form of CFR demands advanced surgical set up and expertise, which is not always available especially in centers in developing countries like ours. If we manage these patients with NCFR, the resection usually remains incomplete. Despite aggressive CFR, local recurrence after surgery alone occurs in 20 60% of cases depending on the length of follow-up. Therefore adjuvant radiation therapy in advanced (stages B or C) disease even after a complete resection has been advocated to improve local control (12 14). However the role of radiation therapy in the management of ENB is still controversial. Biller et al. (10) reviewed the literature and found a higher incidence of regional and distant failures after combined surgery and radiation therapy compared with surgery alone. This finding was probably the result of the treatment selection bias in which advanced disease, with a known higher risk of regional metastases, was often treated with radiation. Foote et al. (13) reported improved local control (87% versus 41%) after post-operative radiation compared with surgery alone despite a selection bias against combined modality therapy. Patients treated with surgery and radiation therapy had a higher proportion of advanced disease (81% versus 41% stage C) and high-grade tumors (38% versus 14%) in comparison with the surgery alone group. Now combined modality treatment including surgery and radiation therapy has become an integral part of management protocol (13,16,24,28). The experience with chemotherapy for ENB is lacking and seems under-reported. Traditionally, chemotherapy has been reserved for unresectable, recurrent or metastatic disease. The role of chemotherapy as part of combined modality in the standard treatment of ENB is thus still investigational, but some of the latest series have shown promising results (16,18,20 22,25,26). Recently a non-surgical approach has also been tried with some success where two cycles of neoadjuvant chemotherapy with cisplatin and etoposide was followed by proton beam radiotherapy (18). Eight of the nine patients do not require surgery but the follow-up was too short to allow any definitive comments on this approach. Dong-Wan Kim et al. (29) have reported the use of neoadjuvant etoposide, ifosfamide and cisplatin for the treatment of olfactory neuroblastoma. Median duration of survival was 18 months and 3 year survival rate was 40% (estimated from survival curve). Only 2 patients out of 11 achieved CR, while after subsequent treatment with radiotherapy four more (36%) patients achieved CR (only 54% of the patients in this series received radiotherapy). Another study by Mishima et al. (30) using cyclophosphamide, doxorubicin and vincristine based chemotherapy with continuous infusion cisplatin and etoposide with peripheral blood stem cell transplantation showed a good complete response rate of 66.7%. Radiotherapy (60 Gy) was an integral part of their protocol. In this study one cannot comment on long-term results as four patients had follow-up of less than 6 months, while there were only two patients who had followup of more than 30 months. Here it is important to emphasize on the complexity of chemotherapy protocol used by the author. In our series of eight patients, we have shown that incorporating chemotherapy with moderate doses of radiation had substantial effect on outcome. None of the eight patients underwent CFR and still we managed to achieve 58% OS rate at 3 years and LRFS rate of 41.7%. Median LRFS time was 38 months and overall survival time was 43 months. We have used radiotherapy with chemotherapy as an integral part of the treatment protocol, and 100% of our patients received radiation either before chemotherapy or after chemotherapy. In our series, chemotherapy was in moderate doses and the protocol was very simple to follow and administer, thus, requiring low resources. Chemotherapy alone is not sufficient to have long-term improvement in survival nor any surgery less than

7 Jpn J Clin Oncol 2006;36(10) 619 CFR. To have better outcome it seems logical to combine radiation with chemotherapy. In our series despite having NCFR, outcome in terms of survival was satisfactory and probably this was possible because radiation and chemotherapy were combined with limited surgery in all the patients. CONCLUSION Results of this study are important for the oncology centers in developing countries where one can employ this protocol with NCFR. Usually patients in developing countries present with advanced stages, and one tends to approach these patients with palliative intent because of non-availability of technical advances and surgical expertise. Most of the patients in our series were of stage C disease (75%); however, our response rate and survival were encouraging despite the fact that surgery was not optimal. References 1. McCormack LJ, Harris HE. Neurogenic tumors of the nasal fossa. JAMA 1955;157: Spiro JD, Soo KC, Spiro RH. Nonsquamous cell malignant neoplasms of the nasal cavities and paranasal sinuses. Head Neck 1995;17: Svane-Knudsen V, Jorgensen KE, Hansen O, Lindgren A, Marker P. Cancer of the nasal cavity and paranasal sinuses: a series of 115 patients. Rhinology 1998;36: Skarsgard DP, Groome PA, Mackillop WJ, Zhou S, Rothwell D, Dixon PF, et al. Cancers of the upper aerodigestive tract in Ontario, Canada, and the United States. Cancer 2000;88: Broich G, Pagliari A, Ottavkiani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of tumor in Anticancer Res 1997;17: Kadish S, Goodman M. Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer 1976;37: Jekunen AP, Kairemo KJ, Lehtonen HP, Kajanti MJ. Treatment of olfactory neuroblastoma. A report of 11 cases. Am J Clin Oncol 1996;19: Koka VN, Julieron M, Bourhis J, Janot F, Le Ridant AM, Marandas P, et al. Aesthesioneuroblastoma. J Laryngol Otol 1998;112: Levine PA, McLean WC, Cantrell RW. Aesthesioneuroblastoma: the University of Virginia experience Laryngoscope 1986;96: Biller HF, Lawson W, Sachdev VP, Som P. Esthesioneuroblasoma: surgical treatment without radiation. Laryngoscope 1990;100: Eden BV, Debo RF, Larner JM, Kelly MD, Levine PA, Stewart FM, et al. Esthesioneuroblastoma. Long-term outcome and patterns of failure the University of Virginia experience. Cancer 1994;73: Dulguerov P, Calcaterra T. Esthesioneuroblastoma. The UCLA experience Laryngoscope 1992;102: Foote RL, Morite A, Ebersold MJ, Olsen KD, Lewis JE, Quast LM, et al. Esthesioneuroblastoma: the role of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 1993;27: IrishJ, DasguptaR, FreemanJ, GullaneP, GentiliF, BrownD, etal. Outcome and analysis of the surgical management of esthesioneuroblasoma. J Otolaryngol 1997;26: Morita A, Ebersold MJ, Olsen KD, Foote RL, Lewis JE, Quast LM. Esthesioneuroblastoma: prognosis and management. Neurosurgery 1993;32: discussion Polin RS, Sheehan JP, Chenelle AG, Munoz E, Larner J, Phillips CD, et al. The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience. Neurosurgery 1998;42: Shah JP, Feghali J. Esthesioneuroblastoma. CA Cancer J Clin 1998;33: Bhattacharyya N, Thornton AF, Joseph MP, Goodman ML, Amrein PC. Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Results in 9 cases. Arch Otolaryngol Head Neck Surg 1997;123: Chapman P, Carter RL, Clifford P. The diagnosis and surgical management of olfactory neuroblastoma: the role of craniofacial resection. J Laryngol Otol 1981;95: Heros DO, Hoch berg FH. Treatment of esthesioneuroblastoma with chemotherapy: a report of two cases. J Neurooncol 1988;6: McElroy EA Jr, Buckner JC, Lewis JE. Chemotherapy for advance esthesioneuroblastoma: the Mayo Clinci experience. Neurosurgery 1998;42: O Conor GT Jr, Drake CR, Johns ME, Cail WS, Winn HR, Niskanen E. Treatment of advanced esthesioneuroblastoma with high-dose chemotherapy and autologous bone marrow transplantation. A case report. Cancer 1985;55: Shah JP, Galicich JH. Esthesioneuroblastoma. Treatment by combined craniofacial resection. NY State J Med 1979;79: Spaulding CA, Kranyak MS, Constable WC, Stewart FM. Esthesioneuroblastoma: a comparison of two treatment eras. Int J RAdiat Oncol Biol Phys 1988;15: Walters TR, Pushparaj N, Ghander AZ. Olfactory neuroblastoma. Response to combination chemotherapy. Arch Otolaryngol 1980; 106: Weiden PL, Yarington CT Jr. Richardson RG. Olfactory neuroblastoma. Chemotherapy and radiotherapy for extensive disease. Arch Otolaryngol 1984;110: Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC. Esthesioneuroblastoma. Cancer 1979;44: Resto VA, Eisele DW, Forastiere A, Zahurak M, Lee DJ, Westra WH. Esthesioneuroblastoma: the John Hopkins experience. Head Neck 2000;22: Kim DW, Jo YH, Kim JH, Wu HG, Rhee CS, Lee CH, et al. Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer 2004;101: Mishima Y, Nagasaki E, Terui Y, Irie T, Takahashi S, Ito Yoshinori, et al. Combination chemotherapy (cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide) and radiotherapy with stem cell support can be beneficial for adolescents and adult with esthesioneuroblastoma. Cancer 2004;101: