- Email: [email protected]
Combined modality therapy of esthesioneuroblastoma
Otolaryngology–Head and Neck Surgery (2007) 136, 998-1002
ORIGINAL RESEARCH
Combined modality therapy of esthesioneuroblastoma J. Nicolas McLean, MD, Sunjay R. Nunley, Carmen Klass, MD, Charles Moore, MD, Susan Müller, DMD, and Peter A. S. Johnstone, MD, FACR, Atlanta, GA OBJECTIVE: Esthesioneuroblastoma (ENB) is a rare tumor of the olfactory epithelium. The objective of this study was to evaluate treatment modalities including surgery, IMRT, and chemotherapy and patient outcomes. PATIENTS AND METHODS: A retrospective analysis was performed on a total of 21 patients. Therapy included craniofacial resection (CFR), radiotherapy, chemotherapy, or a combination of these methods. RESULTS: The median follow-up period was 47 months. Surgery was performed in 90.4% of cases; radiotherapy was performed adjuvantly in 15 (72.7%) patients. Surgery, radiotherapy, and chemotherapy were administered to 7 (33.3%) patients. Eight (38.3%) patients had local recurrence. The 5-year crude overall survival was 71.4% and actuarial 5-year overall survival was 58% with confidence interval (CI, 25 and 81, respectively). The 5-year crude disease-free survival rate was 59% and the 5-year actuarial disease-free survival rate was 62% (CI, 28 and 83, respectively). CONCLUSION: Multidisciplinary therapy of ENB should be considered, especially for Kadish C and high-grade lesions. Craniofacial resection (CFR), Intensity modulated radiation therapy (IMRT), and chemotherapy should be investigated in a multiinstitution trial of ENB. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
E
sthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the anterior skull base. It accounts for approximately 6% of nasal cavity/paranasal sinus can-
From the Departments of Otolaryngology–Head and Neck Surgery (Drs McLean, Moore, and Müller), Radiation Oncology (Drs Nunley and Johnstone), and Pathology and Laboratory Medicine (Dr Müller), and the Winship Cancer Institute (Drs Klass and Johnstone), Emory University School of Medicine, Atlanta, GA. Dr Johnstone is supported in part by the Georgia Cancer Coalition. Drs Moore and Johnstone are supported in part by NCMHD grant 5P60MD000525.
cers.1,2 This tumor typically presents with advanced disease at the time of diagnosis, which is attributed to the nonspecific symptoms associated with the disease.3 The most common symptoms at presentation include nasal obstruction, epistaxis, anosmia, and headache. Because of these nonspecific symptoms, ENB is often initially mistaken for benign diseases of the nasal cavity. These tumors have a bimodal age distribution; first between age 10 and 20 years and later between age 50 and 60 years.4 There appears to be no sex predilection for the disease.5,6 No etiologic agent or exposure has been documented in human beings.7 ENBs are thought to arise from cells in the olfactory epithelium. These are mitotically active precursor cells that give rise to sustentacular and neuronal cells.8 Hyams9 described a pathologic grading system, classifying ENB in 4 grades based mainly on the level of cellular differentiation, where grade I portends a good prognosis and grade IV an ominous one. Histopathologic diagnosis, aided by immunohistochemistry, is not difficult when the tumor is well differentiated. When the tumor is undifferentiated, the differentiation from other small-cell nasal tumors by light microscopy becomes difficult and is based on a panel of immunohistochemical stains and, if necessary, electron microscopy.7 The tumor shows varied biological activity that ranges from indolent growth, with patients surviving with known tumor for more than 20 years, to a highly aggressive course, Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Toronto, September 2006. Reprint requests: Dr Charles Moore, Department of Otolaryngology– Head and Neck Surgery, Emory University School of Medicine, 1365 Clifton Rd NE, Atlanta, GA 30322. E-mail address: [email protected].
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2006.11.051
McLean et al
Combined modality therapy of . . .
capable of rapid disseminated metastasis with limited survival. Metastases have been reported to occur in 10% to 30% of cases.10 A simple staging system was introduced by Kadish et al11 in 1976, and alternative classifications have been proposed by additional investigators;12,13 however, no universally accepted staging system is available. The treatment of ENB is complicated by several factors: the rarity of the tumor, the lack of a universally accepted staging system, and a lack of consistency of treatment as a result of significant advances in this field over time. Treatment modalities include radiotherapy (RT) alone, combined RT and (CFR), and CFR alone for various stages of disease.5 The literature gives little support to single-regimen treatments. However, because the location of the primary tumor makes it difficult to obtain negative margins, postoperative radiation has been advocated to decrease the risk of local recurrence.7,10 Some recent studies have suggested a potential benefit of adding chemotherapy to the combined approach of surgery and postoperative radiotherapy.5,8,14 Locoregional recurrences and distant metastasis may occur after a prolonged period of follow-up, despite the implementation of an aggressive treatment. The purpose of this study was to evaluate treatment modalities including CFR, RT, and chemotherapy with respect to 5-year overall and disease-free survival.
MATERIALS AND METHODS A retrospective analysis of tumor registry records of Emory University-affiliated hospitals was performed on an IRBapproved protocol for patients who presented with ENB between November 1, 1991, and June 15, 2006. Medical records, operating reports, and radiation therapy records were reviewed for patient demographics, treatment regimen, tumor recurrence, disease free survival, overall survival, and complications. All patients received their treatment at Emory University and affiliated hospitals. Available slides were reviewed and graded according to Hyams9 by a single experienced oral, head, and neck pathologist (SM) as outlined by the WHO Pathology and Genetics of Head and Neck Tumors.15 The diagnosis of ENB was based on histopathologic features and confirmed with immunohistochemical staining including chromagranin, synaptophysin, S-100 protein, glial fibrillary protein (GFAP), and cytokeratin AE1/AE3. Cases that met the clinical criteria, the characteristic morphology on hematoxylin and eosin staining, and the appropriate immunophenotype were included in the study. Available clinical and radiographic information of patients initially diagnosed with ENB at our institution were used to retrospectively stage patients with the staging system of Kadish.11 We elected to use this system to allow interseries comparison because it remains the most commonly used in the literature. The major statistical endpoints of this study were overall survival and disease-free survival at 5 years. Survival sta-
999 Table 1 Therapeutic data Modality
Number
Percentage
Surgery Craniofacial resection Endoscopic resection Surgery then RT Surgery then RT/CT
19 16 3 15 8
90.4 71.4 36.3
tistics were calculated from the end of the treatment. The recurrence time was defined as the time between the last day of treatment and the date of recurrence. Clinical, radiologic, and pathologic information was used to define evidence of recurrence of the primary tumor and local control. A 95% confidence interval (CI) was calculated with a KaplanMeier survival analysis.
RESULTS A total of 21 patients were identified and analyzed. Therapeutic data are summarized in Table 1. Median follow-up was 47 months (range, 1 to 137 months).
Surgical Treatment Surgery was performed in 90.4% (19 of 21) of the patients. Eighty-four percent (16 of 19) of surgical resections were CFR, and 14% (3 of 19) were endoscopic resections. Resection of the tumor with clear macroscopic margins was achieved in all cases, but frozen biopsy of the margins was obtained only in three cases. Frozen biopsies were not obtained in the three patients that had endoscopic surgery. Three patients were treated with surgery as the only therapy. No patient underwent elective neck dissection as part of the primary treatment.
Radiation Treatment Postoperative RT to the primary site was part of the initial treatment in 15 cases (72.7% of patients). No patient in our study received radiation alone nor was the neck treated as part of the initial course of therapy for these patients. Most RT was performed at outside facilities; records on delivered dose are incomplete. From the available data, the median dose delivered was 56.8 Gy (range, 18.9 to 61.2 Gy). The patient who received 18.9 Gy discontinued therapy to seek alternative therapies. The lowest RT dose delivered to the remaining patients was 50.4 Gy.
Chemotherapy Treatment Chemotherapy was never used as the only treatment modality; it was always combined with surgery and postoperative radiation. In the postoperative setting, chemotherapy was administered in combination with radiation
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Otolaryngology–Head and Neck Surgery, Vol 136, No 6, June 2007
in 33.3% (7 of 21) of the patients. Of these seven patients, six had stage Kadish C and one patient had stage Kadish B disease. All patients received a combination of carbo- or cisplatin plus etoposide. Of the seven patients, full chemotherapy records were only available for five patients. Carboplatin was dosed at an AUC of 6 on day 1 or cisplatin at a dose of 60 mg/m2 on day 1, etoposide at 100 to 125 mg/m2 on days 1 through 3 given every 21 days for 4 to 6 cycles. One of five patients needed dose reductions of 25% because of hematologic toxicity. Chemotherapy and radiation were stopped in one patient because of febrile neutropenia and overall toxicity. Four of five patients completed at least 4 cycles of chemotherapy; one patient received 6 cycles. It was recorded that the two patients whose chemotherapy records were not accessible completed at least 4 cycles of chemotherapy.
Survival A Kaplan-Meier curve of overall survival is included in Figure 1A. Mean overall survival was 3.4 years. The 5-year actuarial overall survival estimate was 58% with confidence intervals (CI, 25, 81). Five-year crude overall survival was 71.4% (15 patients), and the 5-year crude disease-free survival (DFS) was 59% (13 patients). The 5-year crude survival for patients with stage Kadish B was 71.4% (5 of 7) and for those with Kadish C was 75% (9 of 12). Based on the Hyams system, the 5-year crude survival for patients with grade I was 100%, for patients with grade II was 75% (2 of 8), and for patients with grade III was 57% (3 of 7).
Recurrence A Kaplan-Meier curve of disease-free survival is included in Figure 1B. The 5-year actuarial DFS was about 62% with CI (28, 83). The crude recurrence rate over the entire period was 38.3% (8 patients). All patients who developed recurrences had been initially treated with surgery and RT; four also received chemotherapy. The recurrences were distributed as follows: local in four (19%) patients, neck recur-
Figure 1
rences in three (14%) patients, and one lung metastasis in one (4.7%) patient. Local recurrence occurred at an average of 46.5 months after the initial treatment with a range of 3.9 to 102 months. Neck recurrences occurred at an average of 76 months with a range of 3.7 to 11 years. The single lung metastasis occurred 2.2 years after the diagnosis. Of the 15 patients who underwent surgery and RT, initial disease control was obtained in all, but 53.3% (8 of 15) eventually developed recurrence within the follow-up period at an average of 43 months. Of those who received additional chemotherapy, local control was obtained in 57% (4 of 7) with mean follow-up of 26.6 months (range, 6.7 to 77.7 months). No patient who underwent surgery as the only treatment developed a recurrence. Three of the recurrences were staged as Kadish B and five were Kadish C. Two of the recurrences were graded Hyams I, three recurrences were graded as Hyams II, and three were graded as Hyams III. When evaluating recurrence by different stages, patients with stage Kadish B recurred at an average of 45 months and those with stage Kadish C recurred at an average of 61.3 months. Six patients died in our study. Four of these deaths were related to the primary disease. The remaining two deaths were unrelated to the tumor.
DISCUSSION ENB is a rare entity and most literature corresponds to reports from single institutions that evaluate their experience with a series of cases. Because of the small numbers and significant changes in the management of these tumors, no consensus has been reached for the treatment of this unusual neoplasm. We reviewed our institutional experience with ENB from 1991 to 2006. During these 15 years, a total of 21 patients were treated. In our study, the average time from the development of symptoms to the diagnosis was 18 months, longer than the 6-month interval of the UCLA experience reported by
Kaplan-Meier curves show overall survival (A) and disease-free survival (B) in ENB patients.
McLean et al
Combined modality therapy of . . .
Dulguerov.12 The most common symptoms in our patients were anosmia and nasal congestion. There were no hormone-related symptoms found in our study. Ninety-five percent of our patients were white. None of our patients had clinical or radiological evidence of neck disease at initial presentation, which is similar to what is reported in most series (5%).16 However, three (14%) patients developed neck recurrences at a mean follow-up of 76 months. All neck recurrences were treated with neck dissections. There is no standardized staging system established to evaluate patients with ENB; the most frequently used has been the Kadish staging system. This system is simple and has acceptable prognostic efficacy, despite inadequacies pointed out by some authors.12 The majority of cases of ENB when diagnosed are advanced tumors. The majority of our patients presented with Kadish C disease (13 patients), whereas only seven patients had Kadish B disease; one was not able to be classified because of incomplete staging information. This is compatible with most series. Initial symptoms are nonspecific and attributable to nasal congestion, therefore patients frequently present with advanced disease.4 Based on the Hyams grading system, four (21%) patients were classified as grade I, eight (42%) patients were classified as grade II, and seven (37%) patients were classified as grade III. Surgery followed by radiation has been widely adopted as the standard of care in Kadish stages A and B disease. For patients with Kadish C disease, the use of combined modality treatment with surgery followed by radiation and chemotherapy has been increasingly adopted over the last decade. This is supported by data that show superior disease-free survival and overall survival in patients with Kadish C treated with more aggressive approaches.17 The use of combined modality treatment with surgery, RT, and chemotherapy in various combinations has been progressively more applied over the past few years. Craniofacial resection was the procedure most commonly used in our study and accounted for 84% (16 of 19) of the cases. Six of the eight recurrences occurred in patients who had craniofacial resection. Endoscopic resection was performed in only three patients, and two of them eventually developed local recurrences within the first year of treatment. These patients received additional surgical resection. There were no elective or therapeutic neck treatments in our study, and only three patients developed recurrences in their neck after completing their treatment. One of these patients was treated with surgery only and the other two with combination of surgery, radiotherapy, and chemotherapy. All three patients had Kadish C tumors. The use of elective therapy to the ipsilateral, clinically negative neck has been recommended for all patients as reported by Resto et al.10 Macroscopic resection and gross clear margins were achieved in all cases; only three patients had margins checked by frozen section. It is unclear what exact role the adjuvant therapies may have played given the lack of confirmation of microscopically negative margins in most cases.
1001 Craniofacial resection is the procedure of choice and allows en bloc resection of the tumor with better control of the margins. Other reports in the past have suggested no difference in survival between surgical excision with negative surgical margins and surgical excision with postoperative radiation therapy.13 Endoscopic resection of localized tumors followed by stereotactic radiosurgery has been described by some authors with good outcomes and fewer side effects,18,19 however, this has not been confirmed by other groups. In our study, we have only had three patients who underwent endoscopic resection; two had local recurrences. Given the small sample size, this does not allow us to draw any conclusions with respect to the value of adding endoscopic resection to standard surgical approaches. Devaiah et al20 reported a series of cases of patients with ENB surgically treated with a combined approach with endoscopic excision of the nasal and sinus component with anterior craniotomy for cribriform or anterior cranial fossa extension. They concluded that this is an effective treatment with similar results when compared with the current literature. Most authors10,13,21-23 recommend surgery followed by radiation therapy, however, some centers currently administer preoperative radiation to all stages based on the radio sensitivity of this tumor and increased chances of eye preservation.8,14 The combination of surgery and radiation seems to be superior compared with primary treatment and is associated with fewer recurrences. Several authors have found an increased local control when adding radiation to the surgical treatment.3,12,21,24 However Biller et al13 reviewed the literature and found a higher incidence of regional and distant failures after combined surgery and RT compared with surgery alone. In our study, radiation therapy when combined with surgical excision was exclusively given postoperatively. Polin et al14 found that preoperative radiation and chemotherapy can result in a reduced tumor burden, which increases the chances of macroscopic total resection and long-term disease-free progression. However, when radiotherapy is given preoperatively, determination of tumor margins and tissue planes can be complicated and result in an increased risk of incomplete resection.23,25 Although there is some agreement with respect to the use of surgical resection and radiation therapy, there is little information presented on the role of chemotherapy in the treatment of patients with advanced disease. It has been suggested that platinum-based chemotherapy is active in advanced, highgrade ENB and should be considered when treating these patients.17 In patients with Kadish stage C disease, the addition of chemotherapy resulted in significantly better event-free survival (65% vs 20%, P ⫽ 0.02).17 In our study, seven patients received adjuvant chemotherapy; 85% of these patients had advanced disease (Kadish C). Platinum-based chemotherapy in addition to etoposide was primarily used as the chemotherapy agents of choice in our study. Despite combined modality therapy and advances in surgical techniques and RT technology, frequent locoregional recurrence remains a significant problem. There were eight re-
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Otolaryngology–Head and Neck Surgery, Vol 136, No 6, June 2007
currences in our study with a rate of 38%, similar to the reported literature.4,11,12,17 One patient who underwent surgical resection only did not develop recurrence, however, combined treatment with surgery and radiation resulted in a 53% recurrence rate. Patients who were treated with the addition of chemotherapy to surgery and radiation lead to 50% of local recurrences. These findings represent a set of patients who had more advanced and aggressive disease, as manifested by their Kadish C staging. Most recurrences presented in patients with Kadish C or Hyams II-III tumors; these findings are in line with the reported literature. Most recurrences were local and the mean time after diagnosis was 46 months. Three (14%) patients developed delayed cervical metastasis at a mean latency of 76 months postdiagnosis. The literature reports a 15% to 20% recurrence rate of in the cervical lymph nodes.16 Only one (4.7%) patient presented with distant metastasis (lung) 26.4 months postdiagnosis compared with what has been observed in different series.8,16 The reported 5-year crude overall survival of 71% is comparable to other series.8,17 In our study, patients with stage Kadish B and C had similar 5-year crude survival (71.4% vs 75%), which reflects the inability of this system to predict the outcome in our study. Six patients died and all of them had Hyams II or III graded tumors. Two of these deaths were not related to the tumor. All patients with Hyams I tumors are still alive. There were no patients with Hyams IV tumors our study. Previous reports24,26 have reported a significant association of Hyams grading system with survival as is the case in our study. Despite the small number of cases, our data reveal a clear association of Hyams grade and survival; 5-year crude survival for patients with Hyams grade I tumors was 100% and decreases to 75% and 57% for patients with grade II and II tumors, respectively.
CONCLUSION ENB is a rare malignant tumor with few large studies to provide agreement in staging, treatment, and long-term follow-up. Our results indicate that histologic grading provides useful prognostic information and that patients with advanced Hyams grade tumors had a poorer response to the treatment. In addition, our data indicate that surgery and adjuvant therapy should be recommended for the treatment of esthesioneuroblastoma. Because these patients may survive for several years with or without disease, an extended follow-up period is necessary. We gratefully acknowledge the statistical support of Robert H. Riffenburgh, PhD, FASA.
REFERENCES 1. Svane-Knudsen V, Jorgensen KE, Hansen O, et al. Cancer of the nasal cavity and paranasal sinuses: a series of 115 patients. Rhinology 1998;36(1):12– 4.
2. Skarsgard DP, Groome PA, Mackillop WJ, et al. Cancers of the upper aerodigestive tract in Ontario, Canada, and the United States. Cancer 2000;88(7):1728 –38. 3. Cummings Otolarynsology Head and Neck Surgery, 4th Edition, Vol. 4. Head and Neck Cancer 2005:3749 –52. 4. Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res 1997;17(4A):2683–706. 5. Simon JH, Zhen W, McCulloch TM, et al. Esthesioneuroblastoma: the University of Iowa experience 1978-1998. Laryngoscope 2001;111(3): 488 –93. 6. Irish J, Dasgupta R, Freeman J, et al. Outcome and analysis of the surgical management of esthesioneuroblastoma. J Otolaryngol 1997; 26(1):1–7. 7. http://www.emedicine.com/med/topic748.htm. 8. Oskouian RJ Jr, Jane JA Sr, Dumont AS, et al. Esthesioneuroblastoma: clinical presentation, radiological, and pathological features, treatment, review of the literature, and the University of Virginia experience. Neurosurg Focus 2002;12(5):e4. 9. Hyams VJ, Olfactory neuroblastoma. In: Hyams VJ, Batsakis JG, Michaels L, editors. Tumors of the upper respiratory tract and ear. Washington DC: Armed Forces Institute of Pathology; 1988: p. 240 – 8. 10. Resto VA, Eisele DW, Forastiere A, et al. Esthesioneuroblastoma: the Johns Hopkins experience. Head Neck 2000;22(6):550 – 8. 11. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma: a clinical analysis of 17 cases. Cancer 1976;37(3):1571– 6. 12. Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970-1990. Laryngoscope 1992;102(8):843–9. 13. Biller HF, Lawson W, Sachdev VP, et al. Esthesioneuroblastoma: surgical treatment without radiation. Laryngoscope 1990;100(11): 1199 –201. 14. Polin RS, Sheehan JP, Chenelle AG, et al. The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience. Neurosurgery 1998;42(5):1029 –37. 15. Bradley PJ, Jones NS, Robertson I. Diagnosis and management of esthesioneuroblastoma. Curr Opin Otolaryngol Head Neck Surg 2003; 11:112– 8. 16. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. L Barnes, JW Eveson, P Reichart, D Sidransky (Eds) (2005) IARC Press, Lyon. pp 66 –70. 17. Eich HT, Muller RP, Micke O, et al. Esthesioneuroblastoma in childhood and adolescence: better prognosis with multimodal treatment? Strahlenther Onkol 2005;181(6):378 – 84. 18. Walch C, Stammberger H, Anderhuber W, et al. The minimally invasive approach to olfactory neuroblastoma: combined endoscopic and stereotactic treatment. Laryngoscope 2000;110(4):635– 40. 19. Unger F, Walch C, Stammberger H, et al. Olfactory neuroblastoma (esthesioneuroblastoma): report of six cases treated by a novel combination of endoscopic surgery and radiosurgery. Minim Invasive Neurosurg 2001;44(2):79 – 84. 20. Devaiah AK, Larsen C, Tawfik O, et al. Esthesioneuroblastoma: endoscopic nasal and anterior craniotomy resection. Laryngoscope 2003; 113(12):2086 –90. 21. Morita A, Ebersold MJ, Olsen KD, et al. Esthesioneuroblastoma: prognosis and management. Neurosurgery 1993;32(5):706 –14; discussion 714 –5. 22. Chao KS, Kaplan C, Simpson JR, et al. Esthesioneuroblastoma: the impact of treatment modality. Head Neck Sep 2001;23(9):749 –57. 23. Eriksen JG, Bastholt L, Krogdahl AS, et al. Esthesioneuroblastoma: what is the optimal treatment? Acta Oncol 2000;39(2):231–5. 24. Foote RL, Morita A, Ebersold MJ, et al. Esthesioneuroblastoma: the role of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 1993;27(4):835– 42. 25. Constantinidis J, Steinhart H, Koch M, et al. Olfactory neuroblastoma: the University of Erlangen-Nuremberg experience 1975-2000. Otolaryngol Head Neck Surg 2004;130(5):567–74. 26. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol 2001;2(11):683–90.
ORIGINAL RESEARCH
Combined modality therapy of esthesioneuroblastoma J. Nicolas McLean, MD, Sunjay R. Nunley, Carmen Klass, MD, Charles Moore, MD, Susan Müller, DMD, and Peter A. S. Johnstone, MD, FACR, Atlanta, GA OBJECTIVE: Esthesioneuroblastoma (ENB) is a rare tumor of the olfactory epithelium. The objective of this study was to evaluate treatment modalities including surgery, IMRT, and chemotherapy and patient outcomes. PATIENTS AND METHODS: A retrospective analysis was performed on a total of 21 patients. Therapy included craniofacial resection (CFR), radiotherapy, chemotherapy, or a combination of these methods. RESULTS: The median follow-up period was 47 months. Surgery was performed in 90.4% of cases; radiotherapy was performed adjuvantly in 15 (72.7%) patients. Surgery, radiotherapy, and chemotherapy were administered to 7 (33.3%) patients. Eight (38.3%) patients had local recurrence. The 5-year crude overall survival was 71.4% and actuarial 5-year overall survival was 58% with confidence interval (CI, 25 and 81, respectively). The 5-year crude disease-free survival rate was 59% and the 5-year actuarial disease-free survival rate was 62% (CI, 28 and 83, respectively). CONCLUSION: Multidisciplinary therapy of ENB should be considered, especially for Kadish C and high-grade lesions. Craniofacial resection (CFR), Intensity modulated radiation therapy (IMRT), and chemotherapy should be investigated in a multiinstitution trial of ENB. © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
E
sthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the anterior skull base. It accounts for approximately 6% of nasal cavity/paranasal sinus can-
From the Departments of Otolaryngology–Head and Neck Surgery (Drs McLean, Moore, and Müller), Radiation Oncology (Drs Nunley and Johnstone), and Pathology and Laboratory Medicine (Dr Müller), and the Winship Cancer Institute (Drs Klass and Johnstone), Emory University School of Medicine, Atlanta, GA. Dr Johnstone is supported in part by the Georgia Cancer Coalition. Drs Moore and Johnstone are supported in part by NCMHD grant 5P60MD000525.
cers.1,2 This tumor typically presents with advanced disease at the time of diagnosis, which is attributed to the nonspecific symptoms associated with the disease.3 The most common symptoms at presentation include nasal obstruction, epistaxis, anosmia, and headache. Because of these nonspecific symptoms, ENB is often initially mistaken for benign diseases of the nasal cavity. These tumors have a bimodal age distribution; first between age 10 and 20 years and later between age 50 and 60 years.4 There appears to be no sex predilection for the disease.5,6 No etiologic agent or exposure has been documented in human beings.7 ENBs are thought to arise from cells in the olfactory epithelium. These are mitotically active precursor cells that give rise to sustentacular and neuronal cells.8 Hyams9 described a pathologic grading system, classifying ENB in 4 grades based mainly on the level of cellular differentiation, where grade I portends a good prognosis and grade IV an ominous one. Histopathologic diagnosis, aided by immunohistochemistry, is not difficult when the tumor is well differentiated. When the tumor is undifferentiated, the differentiation from other small-cell nasal tumors by light microscopy becomes difficult and is based on a panel of immunohistochemical stains and, if necessary, electron microscopy.7 The tumor shows varied biological activity that ranges from indolent growth, with patients surviving with known tumor for more than 20 years, to a highly aggressive course, Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Toronto, September 2006. Reprint requests: Dr Charles Moore, Department of Otolaryngology– Head and Neck Surgery, Emory University School of Medicine, 1365 Clifton Rd NE, Atlanta, GA 30322. E-mail address: [email protected].
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2006.11.051
McLean et al
Combined modality therapy of . . .
capable of rapid disseminated metastasis with limited survival. Metastases have been reported to occur in 10% to 30% of cases.10 A simple staging system was introduced by Kadish et al11 in 1976, and alternative classifications have been proposed by additional investigators;12,13 however, no universally accepted staging system is available. The treatment of ENB is complicated by several factors: the rarity of the tumor, the lack of a universally accepted staging system, and a lack of consistency of treatment as a result of significant advances in this field over time. Treatment modalities include radiotherapy (RT) alone, combined RT and (CFR), and CFR alone for various stages of disease.5 The literature gives little support to single-regimen treatments. However, because the location of the primary tumor makes it difficult to obtain negative margins, postoperative radiation has been advocated to decrease the risk of local recurrence.7,10 Some recent studies have suggested a potential benefit of adding chemotherapy to the combined approach of surgery and postoperative radiotherapy.5,8,14 Locoregional recurrences and distant metastasis may occur after a prolonged period of follow-up, despite the implementation of an aggressive treatment. The purpose of this study was to evaluate treatment modalities including CFR, RT, and chemotherapy with respect to 5-year overall and disease-free survival.
MATERIALS AND METHODS A retrospective analysis of tumor registry records of Emory University-affiliated hospitals was performed on an IRBapproved protocol for patients who presented with ENB between November 1, 1991, and June 15, 2006. Medical records, operating reports, and radiation therapy records were reviewed for patient demographics, treatment regimen, tumor recurrence, disease free survival, overall survival, and complications. All patients received their treatment at Emory University and affiliated hospitals. Available slides were reviewed and graded according to Hyams9 by a single experienced oral, head, and neck pathologist (SM) as outlined by the WHO Pathology and Genetics of Head and Neck Tumors.15 The diagnosis of ENB was based on histopathologic features and confirmed with immunohistochemical staining including chromagranin, synaptophysin, S-100 protein, glial fibrillary protein (GFAP), and cytokeratin AE1/AE3. Cases that met the clinical criteria, the characteristic morphology on hematoxylin and eosin staining, and the appropriate immunophenotype were included in the study. Available clinical and radiographic information of patients initially diagnosed with ENB at our institution were used to retrospectively stage patients with the staging system of Kadish.11 We elected to use this system to allow interseries comparison because it remains the most commonly used in the literature. The major statistical endpoints of this study were overall survival and disease-free survival at 5 years. Survival sta-
999 Table 1 Therapeutic data Modality
Number
Percentage
Surgery Craniofacial resection Endoscopic resection Surgery then RT Surgery then RT/CT
19 16 3 15 8
90.4 71.4 36.3
tistics were calculated from the end of the treatment. The recurrence time was defined as the time between the last day of treatment and the date of recurrence. Clinical, radiologic, and pathologic information was used to define evidence of recurrence of the primary tumor and local control. A 95% confidence interval (CI) was calculated with a KaplanMeier survival analysis.
RESULTS A total of 21 patients were identified and analyzed. Therapeutic data are summarized in Table 1. Median follow-up was 47 months (range, 1 to 137 months).
Surgical Treatment Surgery was performed in 90.4% (19 of 21) of the patients. Eighty-four percent (16 of 19) of surgical resections were CFR, and 14% (3 of 19) were endoscopic resections. Resection of the tumor with clear macroscopic margins was achieved in all cases, but frozen biopsy of the margins was obtained only in three cases. Frozen biopsies were not obtained in the three patients that had endoscopic surgery. Three patients were treated with surgery as the only therapy. No patient underwent elective neck dissection as part of the primary treatment.
Radiation Treatment Postoperative RT to the primary site was part of the initial treatment in 15 cases (72.7% of patients). No patient in our study received radiation alone nor was the neck treated as part of the initial course of therapy for these patients. Most RT was performed at outside facilities; records on delivered dose are incomplete. From the available data, the median dose delivered was 56.8 Gy (range, 18.9 to 61.2 Gy). The patient who received 18.9 Gy discontinued therapy to seek alternative therapies. The lowest RT dose delivered to the remaining patients was 50.4 Gy.
Chemotherapy Treatment Chemotherapy was never used as the only treatment modality; it was always combined with surgery and postoperative radiation. In the postoperative setting, chemotherapy was administered in combination with radiation
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in 33.3% (7 of 21) of the patients. Of these seven patients, six had stage Kadish C and one patient had stage Kadish B disease. All patients received a combination of carbo- or cisplatin plus etoposide. Of the seven patients, full chemotherapy records were only available for five patients. Carboplatin was dosed at an AUC of 6 on day 1 or cisplatin at a dose of 60 mg/m2 on day 1, etoposide at 100 to 125 mg/m2 on days 1 through 3 given every 21 days for 4 to 6 cycles. One of five patients needed dose reductions of 25% because of hematologic toxicity. Chemotherapy and radiation were stopped in one patient because of febrile neutropenia and overall toxicity. Four of five patients completed at least 4 cycles of chemotherapy; one patient received 6 cycles. It was recorded that the two patients whose chemotherapy records were not accessible completed at least 4 cycles of chemotherapy.
Survival A Kaplan-Meier curve of overall survival is included in Figure 1A. Mean overall survival was 3.4 years. The 5-year actuarial overall survival estimate was 58% with confidence intervals (CI, 25, 81). Five-year crude overall survival was 71.4% (15 patients), and the 5-year crude disease-free survival (DFS) was 59% (13 patients). The 5-year crude survival for patients with stage Kadish B was 71.4% (5 of 7) and for those with Kadish C was 75% (9 of 12). Based on the Hyams system, the 5-year crude survival for patients with grade I was 100%, for patients with grade II was 75% (2 of 8), and for patients with grade III was 57% (3 of 7).
Recurrence A Kaplan-Meier curve of disease-free survival is included in Figure 1B. The 5-year actuarial DFS was about 62% with CI (28, 83). The crude recurrence rate over the entire period was 38.3% (8 patients). All patients who developed recurrences had been initially treated with surgery and RT; four also received chemotherapy. The recurrences were distributed as follows: local in four (19%) patients, neck recur-
Figure 1
rences in three (14%) patients, and one lung metastasis in one (4.7%) patient. Local recurrence occurred at an average of 46.5 months after the initial treatment with a range of 3.9 to 102 months. Neck recurrences occurred at an average of 76 months with a range of 3.7 to 11 years. The single lung metastasis occurred 2.2 years after the diagnosis. Of the 15 patients who underwent surgery and RT, initial disease control was obtained in all, but 53.3% (8 of 15) eventually developed recurrence within the follow-up period at an average of 43 months. Of those who received additional chemotherapy, local control was obtained in 57% (4 of 7) with mean follow-up of 26.6 months (range, 6.7 to 77.7 months). No patient who underwent surgery as the only treatment developed a recurrence. Three of the recurrences were staged as Kadish B and five were Kadish C. Two of the recurrences were graded Hyams I, three recurrences were graded as Hyams II, and three were graded as Hyams III. When evaluating recurrence by different stages, patients with stage Kadish B recurred at an average of 45 months and those with stage Kadish C recurred at an average of 61.3 months. Six patients died in our study. Four of these deaths were related to the primary disease. The remaining two deaths were unrelated to the tumor.
DISCUSSION ENB is a rare entity and most literature corresponds to reports from single institutions that evaluate their experience with a series of cases. Because of the small numbers and significant changes in the management of these tumors, no consensus has been reached for the treatment of this unusual neoplasm. We reviewed our institutional experience with ENB from 1991 to 2006. During these 15 years, a total of 21 patients were treated. In our study, the average time from the development of symptoms to the diagnosis was 18 months, longer than the 6-month interval of the UCLA experience reported by
Kaplan-Meier curves show overall survival (A) and disease-free survival (B) in ENB patients.
McLean et al
Combined modality therapy of . . .
Dulguerov.12 The most common symptoms in our patients were anosmia and nasal congestion. There were no hormone-related symptoms found in our study. Ninety-five percent of our patients were white. None of our patients had clinical or radiological evidence of neck disease at initial presentation, which is similar to what is reported in most series (5%).16 However, three (14%) patients developed neck recurrences at a mean follow-up of 76 months. All neck recurrences were treated with neck dissections. There is no standardized staging system established to evaluate patients with ENB; the most frequently used has been the Kadish staging system. This system is simple and has acceptable prognostic efficacy, despite inadequacies pointed out by some authors.12 The majority of cases of ENB when diagnosed are advanced tumors. The majority of our patients presented with Kadish C disease (13 patients), whereas only seven patients had Kadish B disease; one was not able to be classified because of incomplete staging information. This is compatible with most series. Initial symptoms are nonspecific and attributable to nasal congestion, therefore patients frequently present with advanced disease.4 Based on the Hyams grading system, four (21%) patients were classified as grade I, eight (42%) patients were classified as grade II, and seven (37%) patients were classified as grade III. Surgery followed by radiation has been widely adopted as the standard of care in Kadish stages A and B disease. For patients with Kadish C disease, the use of combined modality treatment with surgery followed by radiation and chemotherapy has been increasingly adopted over the last decade. This is supported by data that show superior disease-free survival and overall survival in patients with Kadish C treated with more aggressive approaches.17 The use of combined modality treatment with surgery, RT, and chemotherapy in various combinations has been progressively more applied over the past few years. Craniofacial resection was the procedure most commonly used in our study and accounted for 84% (16 of 19) of the cases. Six of the eight recurrences occurred in patients who had craniofacial resection. Endoscopic resection was performed in only three patients, and two of them eventually developed local recurrences within the first year of treatment. These patients received additional surgical resection. There were no elective or therapeutic neck treatments in our study, and only three patients developed recurrences in their neck after completing their treatment. One of these patients was treated with surgery only and the other two with combination of surgery, radiotherapy, and chemotherapy. All three patients had Kadish C tumors. The use of elective therapy to the ipsilateral, clinically negative neck has been recommended for all patients as reported by Resto et al.10 Macroscopic resection and gross clear margins were achieved in all cases; only three patients had margins checked by frozen section. It is unclear what exact role the adjuvant therapies may have played given the lack of confirmation of microscopically negative margins in most cases.
1001 Craniofacial resection is the procedure of choice and allows en bloc resection of the tumor with better control of the margins. Other reports in the past have suggested no difference in survival between surgical excision with negative surgical margins and surgical excision with postoperative radiation therapy.13 Endoscopic resection of localized tumors followed by stereotactic radiosurgery has been described by some authors with good outcomes and fewer side effects,18,19 however, this has not been confirmed by other groups. In our study, we have only had three patients who underwent endoscopic resection; two had local recurrences. Given the small sample size, this does not allow us to draw any conclusions with respect to the value of adding endoscopic resection to standard surgical approaches. Devaiah et al20 reported a series of cases of patients with ENB surgically treated with a combined approach with endoscopic excision of the nasal and sinus component with anterior craniotomy for cribriform or anterior cranial fossa extension. They concluded that this is an effective treatment with similar results when compared with the current literature. Most authors10,13,21-23 recommend surgery followed by radiation therapy, however, some centers currently administer preoperative radiation to all stages based on the radio sensitivity of this tumor and increased chances of eye preservation.8,14 The combination of surgery and radiation seems to be superior compared with primary treatment and is associated with fewer recurrences. Several authors have found an increased local control when adding radiation to the surgical treatment.3,12,21,24 However Biller et al13 reviewed the literature and found a higher incidence of regional and distant failures after combined surgery and RT compared with surgery alone. In our study, radiation therapy when combined with surgical excision was exclusively given postoperatively. Polin et al14 found that preoperative radiation and chemotherapy can result in a reduced tumor burden, which increases the chances of macroscopic total resection and long-term disease-free progression. However, when radiotherapy is given preoperatively, determination of tumor margins and tissue planes can be complicated and result in an increased risk of incomplete resection.23,25 Although there is some agreement with respect to the use of surgical resection and radiation therapy, there is little information presented on the role of chemotherapy in the treatment of patients with advanced disease. It has been suggested that platinum-based chemotherapy is active in advanced, highgrade ENB and should be considered when treating these patients.17 In patients with Kadish stage C disease, the addition of chemotherapy resulted in significantly better event-free survival (65% vs 20%, P ⫽ 0.02).17 In our study, seven patients received adjuvant chemotherapy; 85% of these patients had advanced disease (Kadish C). Platinum-based chemotherapy in addition to etoposide was primarily used as the chemotherapy agents of choice in our study. Despite combined modality therapy and advances in surgical techniques and RT technology, frequent locoregional recurrence remains a significant problem. There were eight re-
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currences in our study with a rate of 38%, similar to the reported literature.4,11,12,17 One patient who underwent surgical resection only did not develop recurrence, however, combined treatment with surgery and radiation resulted in a 53% recurrence rate. Patients who were treated with the addition of chemotherapy to surgery and radiation lead to 50% of local recurrences. These findings represent a set of patients who had more advanced and aggressive disease, as manifested by their Kadish C staging. Most recurrences presented in patients with Kadish C or Hyams II-III tumors; these findings are in line with the reported literature. Most recurrences were local and the mean time after diagnosis was 46 months. Three (14%) patients developed delayed cervical metastasis at a mean latency of 76 months postdiagnosis. The literature reports a 15% to 20% recurrence rate of in the cervical lymph nodes.16 Only one (4.7%) patient presented with distant metastasis (lung) 26.4 months postdiagnosis compared with what has been observed in different series.8,16 The reported 5-year crude overall survival of 71% is comparable to other series.8,17 In our study, patients with stage Kadish B and C had similar 5-year crude survival (71.4% vs 75%), which reflects the inability of this system to predict the outcome in our study. Six patients died and all of them had Hyams II or III graded tumors. Two of these deaths were not related to the tumor. All patients with Hyams I tumors are still alive. There were no patients with Hyams IV tumors our study. Previous reports24,26 have reported a significant association of Hyams grading system with survival as is the case in our study. Despite the small number of cases, our data reveal a clear association of Hyams grade and survival; 5-year crude survival for patients with Hyams grade I tumors was 100% and decreases to 75% and 57% for patients with grade II and II tumors, respectively.
CONCLUSION ENB is a rare malignant tumor with few large studies to provide agreement in staging, treatment, and long-term follow-up. Our results indicate that histologic grading provides useful prognostic information and that patients with advanced Hyams grade tumors had a poorer response to the treatment. In addition, our data indicate that surgery and adjuvant therapy should be recommended for the treatment of esthesioneuroblastoma. Because these patients may survive for several years with or without disease, an extended follow-up period is necessary. We gratefully acknowledge the statistical support of Robert H. Riffenburgh, PhD, FASA.
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