Neoadjuvant Concurrent Chemoradiation for ...

Published Ahead of Print on January 31, 2011 as 10.1200/JCO.2010.30.9278 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2010.30.9278

JOURNAL OF CLINICAL ONCOLOGY

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Neoadjuvant Concurrent Chemoradiation for Advanced Esthesioneuroblastoma: A Case Series and Review of the Literature Esthesioneuroblastoma (ENB) is a rare malignancy arising from the olfactory epithelium of the nasal vault. ENB accounts for 3% to 6% of all intranasal tumors and has the best prognosis among sinonasal malignancies with neuroendocrine differentiation.1-3 The optimal treatment continues to be controversial, but the benefit of adjuvant therapy, particularly radiotherapy, has been well described in the literature. The largest reported series evaluated neoadjuvant radiotherapy of 50 Gy, with or without neoadjuvant chemotherapy, and found improved resectability with improved patient survival.4 We present two cases of advanced ENB at our institution treated with a preoperative concurrent radiochemotherapy in a manner akin to that of small-cell carcinoma of the lung. Case Reports A review of patient charts and electronic records was conducted. Histopathologic slides were reviewed, and the diagnosis of high-grade esthesioneuroblastoma was confirmed. Complications of adjuvant therapy were scored using the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. Case 1. A 38-year-old male patient presented with anosmia and nasal fullness. A nasal endoscopy with biopsies demonstrated ENB in the right nasopharynx, Hyams grade 3.5 Figure 1 shows tumor cells positive for Synaptophysin immunohistochemical staining, at ⫻400 magnification. The staging work-up, including magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT) scan, revealed the primary tumor involving bilateral cribriform plates, bilateral ethmoid sinuses, and right maxillary

Fig 1. Journal of Clinical Oncology, Vol 28, 2011

Fig 2.

sinus, as well as bilateral neck metastases, making this Kadish stage C (Fig 2).6 After multidisciplinary discussion, treatment was to be neoadjuvant radiochemotherapy followed by a craniofacial resection and bilateral neck dissections. The preoperative regimen was to include two cycles of cisplatin (60 mg/m2 on days 1 and 23) and etoposide (120 mg/m2 on days 1 through 3 and 23 through 25) with 50 Gy of radiation in 25 fractions of 2 Gy per fraction beginning day 1. The radiotherapy target volume encompassed the primary disease and nodal drainage areas, covering the bilateral cervical chains down to the supraclavicular fossa. Treatment toxicity included neutropenic fevers after both cycles of cisplatin and etoposide, as well as grade 2 dermatitis and grade 4 mucositis requiring temporary hyperalimentation. This patient elected to discontinue radiotherapy after 46 Gy in 23 fractions were delivered. However, these complications did not delay surgery, which was performed 12 weeks after the completion of neoadjuvant therapy. A craniofacial resection, medial orbital wall excision, total ethmoidectomies, and delayed bilateral level 2 to 5 neck dissection revealed no residual malignancy. Postoperatively, he experienced right shoulder pain and weakness. However, surgical re-exploration © 2011 by American Society of Clinical Oncology

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Copyright 2011 by American Society of Clinical Oncology

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Sohrabi et al

Fig 3.

revealed the accessory nerve to be intact. He continues to have difficulty with grade 1 xerostomia and hypogeusia, as well as intermittent mild diplopia. With a follow-up of 30 months, including periodic imaging using MRI and PET/CT and direct visualization via nasal endoscopy, he continues to be disease free. Case 2. A 66-year-old male patient presented with recurrent epistaxis and was found to have a mass involving the bilateral nasal cavities superiorly. A biopsy revealed a Hyams grade 4 ENB, with necrotic foci seen on hematoxylin and eosin stains at ⫻125 magnification (Fig 3). The staging work-up, including MRI and PET/CT imaging, revealed intracranial extension into the bilateral frontal lobes (Fig 4). There was no evidence of regional or distant metastases outside of the locally advanced primary tumor. The planned treatment was neoadjuvant radiochemotherapy followed by a craniofacial resection. The preoperative regimen was to include two cycles of cisplatin (60 mg/m2 on days 1 and 23) and etoposide (120 mg/m2 on day 1s through 3 and 23 through 25) with 50 Gy of radiation in 25 fractions of 2 Gy per fraction beginning day 1. The radiotherapy target volume encompassed the primary disease and nodal drainage areas, covering the bilateral cervical chains down to the supraclavicular fossa. After his first cycle of chemotherapy, he was admitted with hyponatremia from syndrome of inappropriate antidiuretic hormone hypersecretion. The cisplatin was then switched to carboplatin (target area under the curve of 6.0 mg/mL/min on day 23) for the second chemotherapy cycle, without delay in administration of the dose. He also developed a soft tissue infection around his G-tube site, which required a hospitalization for less than 1 week with intravenous antibiotic treatment. He also experienced grade 1 dermatitis and grade 4 mucositis, the latter necessitating near total nutritional intake via a gastric tube. After his second round of chemotherapy, the patient had neutropenic sepsis secondary to pneumonia and required admission to the intensive care unit, with intubation and mechanical ventilation for 4 days. Respiratory cultures revealed Klebsiella species. He fully recovered and proceeded to surgery without delay, 8 weeks after completion of neoadjuvant therapy. The procedure performed included craniofacial resection, ethmoidectomy, and right medial orbital wall excision. The specimen revealed no evidence of residual malignancy. After craniofacial resection, the patient was found to have pneumocephalus and meningitis, requiring 2

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Fig 4.

endoscopic repair of the skull base defect. Follow-up scans showed resolution of pneumocephalus, and the patient’s neurocognitive function continues to improve to baseline. He continues to work full time as a financial planner. An MRI 13 months after treatment revealed osteonecrosis of the craniotomy bone flap. He began hyperbaric oxygen for this, with plans for surgical reconstruction. He also continues to have intermittent mild diplopia. With a follow-up period of 24 months, including periodic MRIs and nasal endoscopies, he continues to be disease free. Discussion A multimodal approach to the treatment of advanced ENB has been postulated to increase overall and recurrence-free survival.7-10 In the neoadjuvant setting, Polin et al4 showed significant tumor reduction (⬎ 50% in tumor volume or ⬎ 90% regression of intracranial extension) in two thirds of patients treated with preoperative radiation with or without chemotherapy (not given concurrently) and increased recurrence-free survival in those responders. Although there is no standard chemotherapy regimen used for ENB, the agents used are chiefly cisplatin and etoposide, and doxorubicin and vincristine with an alkylating agent.4,9-15 In 1990, Polonowski et al13 reported complete pathologic response to induction treatment with four cycles of cisplatin and fluorouracil. Chao et al10 reported that one of eight patients receiving neoadjuvant treatment achieved complete response. This JOURNAL OF CLINICAL ONCOLOGY

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Diagnosis in Oncology

Table 1. Preoperative Radiochemotherapy Regimens in the Literature First Author and Reference Bhattacharyya12

Resto11

Polin4

Fitzek8

Eich7

Argiris9 Chao10

Mishima14

Sohrabi (current study)

Chemotherapy Cisplatin (33 mg/m2 per day for 3 days) and etoposide (100 mg/m2 per day for 3 days), 2 cycles Cyclophosphamide, doxorubicin, and vincristine alternating with etoposide and cisplatin fluorouracil and cisplatin Cyclophosphamide (650 mg/m2) and vincristine (1.5 mg/m2; maximal dose, 2 mg) administered every 3 weeks for 6 cycles; doxorubicin used with cyclophosphamide in 2 patients; methotrexate used with vincristine in 1 patient Cisplatin and etoposide (repeated after radiotherapy in responders)

Cisplatin, cyclophosphamide, dacarbazine, etoposide, ifosfamide, teniposide, vincristine, and vindesine used in no standard regimen Cisplatin and etoposide Cyclophosphamide and vincristine (doxorubicin or dactinomycin added in 2 regimens), cisplatin and etoposide Chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide (with or without peripheral-blood stem-cell transplantation), range 2-7 cycles Cisplatin (60 mg/m2 on days 1-23) and etoposide (120 mg/m2 on days 1-3, 23-25) cisplatin changed to carboplatin (target AUC of 6.0 mg/mL/min on day 23) in patient 2

Radiotherapy

Sequence

68 Gy, composed of 70% morning photon (48 Gy) and 30% afternoon proton (20 Gy)

Chemotherapy followed by radiotherapy, followed again by chemotherapy

53.60 Gy (mean dose, without chemotherapy), postchemotherapy doses unspecified

Chemotherapy alone, or radiotherapy followed by chemotherapy; chemotherapy followed by radiotherapy Unspecified

50 Gy, fractionated

high-dose proton-photon radiotherapy to 69.2 cobalt-Gray equivalents (CGE) using 1.6-1.8 CGE per fraction twice daily in a concomitant boost schedule Target dose 50-60 Gy (range, 32-70 Gy) dose, fraction range 1.8-3 Gy, number of fractions range 16-36

Chemotherapy followed by radiotherapy (followed by chemotherapy in responders)

50-60 Gy 40-50 Gy (mean 1.8-2 Gy fraction size, median 29 fractions)

Unspecified Unspecified

40-50 Gy

Chemotherapy followed by radiotherapy

Target dose 50 Gy (25 fractions of 2 Gy starting day 1); treatment stopped after 46 Gy in patient 1

Concurrent

Chemotherapy alone preoperatively; radiotherapy alone or followed by chemotherapy without surgery

Abbreviation: AUC, area under the curve.

patient had stage B disease and received two cycles of cyclophosphamide, doxorubicin, vincristine, and dactinomycin, with 45 Gy of radiotherapy and no surgery. In the same series of eight patients, the four patients receiving cisplatin and etoposide in two or three cycles with approximately 60 Gy of radiotherapy showed less than 50% or no response. The sequence of radiotherapy and chemotherapy was not specified in the report. In 1997, Bhattacharyya et al12 reported nine successful treatments of ENB using two cycles of induction cisplatin (33 mg/m2) and etoposide (100 mg/m2), followed by 68 Gy of radiotherapy, followed by another two cycles of the same chemotherapeutic regimen. Of these nine patients, two patients underwent craniofacial resection, which revealed no tumor in the surgical specimen. The stage and grade for these tumors were not identifiable in the report. Mishima et al14 reported complete response by radiologic evaluation in eight of 12 patients treated with two cycles of combination chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide, with or without peripheral-blood stem-cell transplantation, followed by radiotherapy with 40 to 60 Gy. Ten of 12 patients had advanced disease by Kadish staging. Of note, one of these 12 patients showed complete response radiographically after the completion of chemotherapy alone.14 Kim et al16 evaluated the neoadjuvant regimen of chemotherapy alone, consisting of etoposide (75 mg/m2 on days 1 through 5) ifosfamide (1,000 mg/m2 on days 1 through 5), and cisplatin (20 mg/m2 on days 1 through 5), and they reported complete response radiographically in www.jco.org

two of 11 patients. These patients were diagnosed with Kadish stage B and C disease and received six cycles of the above regimen. Table 1 summarizes reported preoperative radiochemotherapy regimens. There is evidence supporting concurrent radiochemotherapy with platinum-based chemotherapeutic agent in treatment of head and neck squamous cell carcinoma.17-20 Concurrent radiochemotherapy with cisplatin and etoposide has also been used in treatment of smallcell lung cancer.21-23 Considering the reported successes of platinumbased agents and University of Virginia’s experience with preoperative radiotherapy of 50 Gy, we used cisplatin (60 mg/m2) with etoposide (120 mg/m2) with concomitant radiotherapy of 50 Gy for the preoperative treatment of Kadish stage C and Hyams grade 3 and 4 tumors. Both patients experienced significant complications from the preoperative treatment, requiring hospitalizations and nutritional support via gastric tubes and minor changes from the original plan. However, these hospitalizations lasted less than a week each and required only intravenous antibiotic administration. During these hospital stays, radiotherapy treatments were continued. Perhaps most importantly, these complications did not delay surgery and have been associated with minimal late sequelae after a year of follow-up. To our knowledge, this is the first report of treating high-grade, stage C ENB with neoadjuvant concurrent radiochemotherapy. Both patients enjoyed complete pathologic responses. Although the follow-up is only 30 and 24 months currently, these initial results are promising and warrant further study. © 2011 by American Society of Clinical Oncology

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In conclusion, this regimen of preoperative concurrent radiochemotherapy for locally advanced disease is promising in terms of pathologic complete response and hence deserves further study in a prospective trial.

Sohrab Sohrabi, Joseph J. Drabick, Henry Crist, David Goldenberg, Jonas M. Sheehan, and Heath B. Mackley Penn State Hershey Cancer Institute, Hershey, PA

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. 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 36:12-14, 1998 2. McCormack LJ, Harris HE: Neurogenic tumors of the nasal fossa. JAMA 157:318-321, 1955 3. Rosenthal DI, Barker JL Jr, El-Naggar AK, et al: Sinonasal malignancies with neuroendocrine differentiation: Patters of failure according to histologic phenotype. Cancer 101:2567-2573, 2004 4. 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 42:1029-1037, 1998 5. Hyams VJ, Batsakis JG, Michaels L: Olfactory neuroblastoma, in Tumors of the Upper Respiratory Tract and Ear. Washington, DC, Armed Forces Institute of Pathology, 1988, pp 240-248 6. Kadish S, Goodman M, Wang CC: Olfactory neuroblastoma: A clinical analysis of 17 cases. Cancer 37:1571-1576, 1976 7. Eich HT, Hero B, Staar S, et al: Multimodality therapy including radiotherapy and chemotherapy improves event-free survival in stage C esthesioneuroblastoma. Strahlenther Onkol 179:233-240, 2003 8. Fitzek MM, Thornton AF, Varvares M, et al: Neuroendocrine tumors of the sinonasal tract: Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer 94:2623-2634, 2002 9. Argiris A, Dutra J, Tseke P, et al: Esthesioneuroblastoma: The Northwestern University Experience. Laryngoscope 113:155-160, 2003 10. Chao KS, Kaplan C, Simpson JR, et al: Esthesioneuroblastoma: The impact of treatment multimodality. Head Neck 23:749-757, 2001

11. Resto VA, Eisele DW, Forastiere A, et al: Esthesioneuroblastoma: The Johns Hopkins experience. Head Neck 22:550-558, 2000 12. Bhattacharyya N, Thornton AF, Joseph MP, et al: Successful treatment of esthesioneuroblastoma and neuroendocrine carcinoma with combined chemotherapy and proton radiation. Arch Otolaryngol Head Neck Surg 123: 34-40, 1997 13. Polonowski JM, Brasnu D, Roux FX, et al: Esthesioneuroblastoma: Complete tumor response after induction chemotherapy. Ear Nose Throat J 69:743746, 1990 14. Mishima Y, Nagasaki E, Terui Y, 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 adults with esthesioneuroblastoma. Cancer 101:1437-1444, 2004 15. Porter AB, Bernold DM, Giannini C, et al: Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol 90:201-204, 2008 16. Kim DW, Jo YH, Kim JH, et al: Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer 101:2257-2260, 2004 17. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 18. Dimery IW, Hong WK: Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst 85:95-111, 1993 19. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16:1318-1324, 1998 20. Krstevska V, Stojkovski I, Lukarski D: Concurrent radiochemotherapy in advanced hypopharyngeal cancer. Radiat Oncol 5:39, 2010 21. Kawase A, Nagai K: Treatment strategy for neuroendocrine carcinoma of the lung. Gan To Kagaku Ryoho 36:1619-1622, 2009 22. Hann CL, Rudin CM: Management of small-cell lung cancer: Incremental changes but hope for the future. Oncology (Williston Park) 22:1486-1492, 2008 23. Le QT, Moon J, Redman M, et al: Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol 27:3014-3019, 2009

DOI: 10.1200/JCO.2010.30.9278; published online ahead of print at www.jco.org on January 31, 2011

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© 2011 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at PENN STATE UNIVERSITY HARRELL LIBRARY H127 Copyright © 2011on American February Society 4, 2011 of from Clinical 64.74.144.100 Oncology. All rights reserved.