Benign Orbital Apex Tumors Treated with Multisession Gamma Knife Radiosurgery

Alice Siew Ching Goh, MBBS, MS,1 Yoon-Duck Kim, MD, PhD,2 Kyung In Woo, MD, PhD,2 Jung-Il Lee, MD, PhD3
Objective: The orbital apex is an important anatomic landmark that hosts numerous critical neurovascular structures. Tumor resection performed at this complex region poses a therapeutic challenge to orbital surgeons and often is associated with signicant visual morbidity. This article reports the efcacy and safety of multisession gamma knife radiosurgery (GKRS) in benign, well-circumscribed tumors located at the orbital apex. Design: Retrospective interventional case series. Participants: Five patients with visual disturbances resulting from a benign, well-circumscribed orbital apex tumor (3 cases of cavernous hemangioma and 2 cases of schwannoma). Methods: Each patient treated with GKRS with a total radiation dose of 20 Gy in 4 sessions (5 Gy in each session with an isodose line of 50%) delivered to the tumor margin. Main Outcome Measures: Best-corrected visual acuity, visual eld changes, orbital imaging, tumor growth control, and side effects of radiation. Results: All patients demonstrated improvement in visual acuity, pupillary responses, color vision, and visual eld. Tumor shrinkage was observed in all patients and remained stable until the last follow-up. No adverse events were noted during or after the radiosurgery. None of the patients experienced any radiation-related ocular morbidity. Conclusions: From this experience, multisession GKRS seems to be an effective management strategy to treat solitary, benign, well-circumscribed orbital apex tumors. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:635 641 2013 by the American Academy of Ophthalmology.

The orbital apex is a complex anatomic landmark that occupies the most posterior portion of orbit and hosts numerous critical neurovascular structures. The most common benign, solitary, and well-circumscribed tumors in this region include cavernous hemangioma and schwannoma.1 Because of the close relationship of the visually critical elements in this conned area, even a small tumor growth may affect vision adversely and may warrant early intervention. Treatment options include microsurgical resection of the tumor, irradiation, or a combination of both. Surgery has been the conventional and effective method of tumor removal. The surgical approaches to the orbital apex include a transcranial, a lateral orbitotomy, a transconjunctival, and more recently, a transnasal endoscopic approach. However, attempts to resect a tumor at this critical and conned space remain a challenge and often are associated with signicant visual morbidity. Stereotactic radiosurgery has the advantage of delivering high-dose radiation to the intended target in a single session, whereas steep fall-off dose gradients minimize collateral damage. Gamma knife radiosurgery (GKRS) is a form of stereotactic radiosurgery that focuses more than 200 highenergy gamma rays to a common point directed by framebased stereotactic guidance.2 Gamma knife radiosurgery, originally developed to treat intracranial tumors, has gained wide acceptance in the treatment of many disorders, includ 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

ing orbital tumors.35 Researchers now are exploring the use of GKRS used in multiple treatment sessions, which involves the optic apparatus to reduce radiation-induced visual morbidity. Kim et al6 previously published a preliminary report on the successful use of multisession GKRS to treat various perioptic lesions. In this study, the efcacy of multisession GKRS to treat benign, well-circumscribed orbital apex tumors was investigated.

Patients and Methods

Five patients seen at the Samsung Medical Center, Seoul, Korea, with visual decits secondary to benign orbital apex tumors that underwent GKRS from 2006 through 2011 using a Leksell Gamma Knife (Elekta Instrument AB, Stockholm, Sweden) were reviewed. Compressive optic neuropathy was diagnosed clinically based on the best-corrected visual acuity with Snellen chart, afferent pupillary defect, color vision with the Ishihara chart, Humphrey visual eld (HFA Model 640; Humphrey Instruments, Inc., San Leandro, CA), and visual evoked potential examinations. All patients underwent magnetic resonance imaging (MRI) or computed tomography with contrast. The radiologic imaging in each patient revealed a tumor located at the orbital apex. Three patients were diagnosed with cavernous hemangioma and 1 patient with schwannoma based on the signal intensity in the conventional MRI scans (i.e., isointense to muscle in T1-weighted images, hyperintense in T2-weighted images) and their contrast-enhancement spread pattern in dynamic MRI scans (i.e., starting from 1 point as in cavernous hemangioma and from a wide area as in schwannoma).7 HistopathoISSN 0161-6420/13/$see front matter http://dx.doi.org/10.1016/j.ophtha.2012.08.015

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Table 1. Demographics and Clinical Characteristics of Patients
Patient no. 1 2 3 4 5 Age (yrs) 35 26 29 32 66 Duration of Symptoms (mos) 4 1 48 3 12 Best-Corrected Visual Acuity (Snellen) 20/50 20/30 Counting ngers 20/25 Counting ngers Relative Afferent Pupillary Defect

Gender Female Male Male Female Male

Eye Left Right Right Right Right

Signs and Symptoms Blurring of vision, eld defect Blurring of vision, eld defect Blurring of vision, eld defect Blurring of vision, eld defect Blurring of vision, eld defect visual visual visual visual visual

Diagnosis Schwannoma Presumed cavernous hemangioma Presumed cavernous hemangioma Presumed cavernous hemangioma Presumed schwannoma

positive.

logic examination conrmed the diagnosis of schwannoma in 1 case after partial resection. Treatment and clinical outcomes were analyzed respectively through medical records and imaging data. Treatment was performed according to a protocol approved by the authors institutional review board and informed consent was obtained from patients before treatment. The radiosurgery was performed using the Leksell Gamma Knife Model C. Before commencement of GKRS treatment, a stereotactic head frame was mounted onto the patients head under local anesthesia. T2weighted axial MRI images with a slice thickness of 2 mm followed by 3-dimensional spoiled gradient-recalled images with a slice thickness of 1 mm without slice interval after double-dose contrast enhancement then were acquired. The fat suppression technique was used to enhance the delineation of the optic nerve. The 3-dimensional treatment plan was individualized to each patient for whom the target lesion was identied and outlined using Leksell Gammaplan version 5.32 (Elekta Instruments AB, Stockholm, Sweden). All patients underwent 4 sessions of GKRS with a radiation dose of 10 Gy to the tumor and 5 Gy delivered to the tumor margin with a prescription isodose of 50%. Therefore, the cumulated dose delivered to tumor and tumor margin were 40 Gy and 20 Gy, respectively. Because GKRS was performed in 4 sessions with 12-hour intervals between sessions over a

3-day period, all patients were admitted until the completion of the irradiation treatments. Before the last session of GKRS, T2-weighted and 3-dimensional spoiled gradient-recalled images were obtained in the way similar as the initial images, except for the use of contrast enhancement. The images were used to check possible displacement of the stereotactic frame that may occur during the 3-day treatment period. Intravenous dexamethasone (5 mg per 6 hours) was administered during the course of radiosurgery treatment. The stereotactic frame was removed after completion of the treatment.

Results
The demographic and patient clinical characteristics are summarized in Table 1. Five patients, 3 men and 2 women, ranging in age from 26 to 66 years underwent GKRS treatment. All patients showed positive sign of relative afferent pupillary defect. The duration of the follow-up period ranged from 8 to 68 months.

Changes in the Lesion after Treatment

Clinical outcomes and tumor volume changes before and after radiosurgery are shown in Table 2. The tumor volume before

Table 2. Changes in the Visual Outcome and Tumor Volume before and after Gamma Knife Radiosurgery Treatment
Best-Corrected Visual Acuity (Snellen) Patient No. 1 2 3 4 5 Before 20/50 20/30 CF 20/25 CF After 20/20 20/20 20/160 20/20 20/40

Humphrey Visual Field Before Generalized defect Inferior eld defect Generalized defect Superior and inferior defect Generalized defect After Complete resolution Complete resolution Improved Complete resolution Complete resolution

Tumor Volume (mm3) Before 1700 3100 2100 220 1100 After 220 740 520 60 330 Volume Reduction (%) 87 76 75 73 70 Follow-up (mos) 68 42 30 24 8 Adverse Events None None None None None

Other Ocular Pathologic Features None None Long-standing right compressive optic neuropathy None Right epiretinal membrane

CF counting ngers.

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treatment ranged from 220 to 3100 mm3 and tumor volume reduction ranged from 60 to 740 mm3 after GKRS treatment. Tumor shrinkage was observed in all patients conrmed by MRI with evidence of tumor volume control up to the latest follow-up. The average tumor volume reduction was 76% (range, 70% 87%).

Discussion
The current treatment strategies for orbital apex tumors include tumor resection, irradiation therapies, or a combination of both. By enabling acute decompression of the optic nerve, microsurgical resection of tumor has been the treatment of choice for most patients. Various surgical approaches to the posterior orbit have been described and have evolved in the last few decades. The transcranial approach is invasive, involves removing a large bone ap, and often is associated with signicant morbidity. Reported complications include cerebrospinal uid leakage, intracranial injury, meningitis, postoperative ptosis, frontalis palsy, subdural hematoma, and permanent frontal lobe syndrome.8 11 The lateral orbitotomy is a common and useful approach to the orbital apex. Several modications have been made to the initial lateral orbitotomy described by Krnlein.1215 These techniques are relatively invasive and involve removal of the lateral orbital wall. The cutaneous scar and a lateral bony defect are the main disadvantages. In addition, lesions arising from the posteromedial aspect of the orbit may not be accessible with this approach. Other, less invasive surgical techniques include the transconjunctival approach (lower fornix and transcaruncular). These approaches sometimes need to be combined with other approaches to gain access to the orbital apex.12,16 In recent

Visual Outcome
All patients demonstrated improvement in visual acuity after GKRS. Three patients achieved 20/20 vision, 1 patient improved to 20/40 vision, and the other patient improved to 20/160 vision on a Snellen chart at the latest follow-up. Visual elds obtained before and after radiosurgery were monitored using the Humphrey eld analyzer. Complete resolution of the visual eld defect was seen in 4 patients and improvement was seen in 1 patient. The relative afferent pupillary defect and color vision resolved in 4 patients.

Radiation Dose and Toxicity

The prescribed marginal dose was 5 Gy in each session, and all patients underwent 4 sessions of GKRS. Therefore, the cumulative marginal dose was 20 Gy (with a 50% isodose line). Because the optic nerve was in contact with the tumor in all the patients, the cumulative maximum dose to the optic nerve was 20 Gy. The maximum dose to the retina and the lens were 3.0 and 0.7 Gy, respectively. At the last follow-up, no patient experienced any radiation-induced retinopathy or optic neuropathy after GKRS.

Figure 1. Images from a 33-year-old woman (patient 1) with histologically-conrmed schwannoma who sought treatment for deterioration of vision and generalized eld defect in the left eye. The tumor recurred 4 months after partial resection. A, T1-weighted magnetic resonance imaging scan revealing an ovoid and well-circumscribed tumor at the left orbital apex. B, T1-weighted magnetic resonance imaging scan obtained 62 months after gamma knife radiosurgery showing reduction of tumor size. Humphrey visual eld results obtained (C) before and (D) 10 months after gamma knife radiosurgery demonstrating complete resolution of visual eld defect.

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years, an endoscopic approach to the orbital apex has gained much popularity.1720 The endoscopic approach is less invasive, provides good illumination, and yields excellent cosmetic results. The lack of binocular vision that is critical when attempting tumor resection at the orbital apex is the main drawback.21 More recently, reports on decompression of the apex as an alternative approach to manage apical apex tumors also have been published.22,23 However, a surgical decompression procedure is associated with complications such as postoperative ptosis, diplopia, and enophthalmos. In addition, decompression may provide only temporary relief of compressive optic neuropathy in the event of tumor regrowth. The authors also hypothesize that in the conned apical area, the brous annulus of Zinn may prevent the orbital apex from achieving adequate decompression. Despite new advances in surgical approaches and microsurgical techniques, surgical resection of tumors at the orbital apex has remained a challenge to orbital surgeons. Careful dissection within the posterior segment of the orbit requires both patience and technical prociency. Occasionally, tumor resection cannot be accomplished without damage to the intricately involved vessels and nerves. Fractionated radiotherapy is an alternative approach to treat inaccessible and nonresectable tumors. There has been very little experience with radiotherapy with regard to treating benign, well-circumscribed tumors in the orbital apex. Extensive clinical experience has established dose and fractionation regimens for radiotherapy for pituitary and cranial base tumors, and these result in a relatively low risk of optic neuropathy.24 28 However, in the treatment of orbital apex tumors, the traditional fractionated radiotherapy imposes substantial radiation risk to the optic nerve because it usually is exposed to almost equal dose of radiation as the target lesion.29,30 In contrast to the spatially less accurate radiotherapy, radiosurgery has the capacity to minimize irradiation of nearby structures, thus minimizing collateral damage. In addition, the biological equivalent dose of high single-dose radiosurgery permissibly may exceed that of the total dose delivered by conventional radiotherapy, thus yielding better tumor shrinkage. However, the dose gradient that can be achieved with all forms of single-session radiosurgery typically is inadequate for the safe treatment of a lesion close to the anterior visual pathway. Studies have demonstrated a risk of visual injury when irradiation with more than 8 to 10 Gy in a single session is applied to lesions close to the optic apparatus.29,3134 In this regard, multisession radiosurgery exploits the advantages of conventional fractionated radiotherapy (i.e., an increased therapeutic index resulting from the different responses to fractionated irradiation between normal tissue and tumor).6 Published reports on multisession stereotactic radiosurgery in the treatment of perioptic tumors are scarce. Adler et al35 described the use of CyberKnife (Accuray,

Figure 2. Images from a 26-year-old man (patient 2) who sought treatment for blurring of vision and inferior arcuate defect of 1 months duration in the right eye. A, Pretreatment T1-weighted fat-suppressed contrast-enhanced magnetic resonance imaging scan showing a well-enhanced large benign intraconal tumor extending into the right orbital apex. B, Magnetic resonance imaging scan of a similar section obtained 16 months after gamma knife radiosurgery demonstrating reduction in tumor size. Humphrey visual eld results showing (C) a distinctive right inferior arcuate defect that (D) resolved completely 7 months after gamma knife radiosurgery.

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Figure 3. Images from a 32-year-old woman (patient 4) who sought treatment for blurring of vision and a visual eld defect in the right eye. Axial and sagittal views of magnetic resonance imaging scans obtained (A) before and (B) 19 months after gamma knife radiosurgery. C, Humphrey visual eld results showing a superior and inferior arcuate defect that resolved completely 6 months after gamma knife radiosurgery.

Inc., Sunnyvale, CA) radiosurgery in 49 patients with perioptic lesions of various pathologic origins: meningioma (n 27), pituitary adenoma (n 19), craniopharyngioma (n 2), and mixed germ cell tumor (n 1). Of the 27 meningiomas, 2 were located at the orbital apex. Forty-six (94%) of 49 patients demonstrated either improved or stable visual elds after a mean follow-up of 49 months. Hirschbein et al36 reported 16 cases of orbital tumors treated with Accuray CyberKnife radiosurgery. Two of the cases were benign tumors located close to the optic nerve (1 case of optic nerve sheath meningioma and 1 case of medial orbit meningioma). The total treatment dose was 18 and 24 Gy, and radiosurgery was performed in 2 and 3 sessions, respectively. After the mean follow-up of 6 months, there was no deterioration of visual acuity in these 2 patients. Visual eld improved in 1 patient and was preserved in the other. The current case series comprised 5 patients with benign, well-circumscribed tumors located at the orbital apex. Three patients with presumed cavernous hemangioma and 1 pa-

tient with schwannoma underwent GKRS treatment as a primary treatment method. One patient with schwannoma had undergone a previous partial resection where the tumor recurred after 4 months. The diagnoses of cavernous hemangioma and schwannoma were made based on the typical radiologic ndings in the conventional and dynamic MRI scans. In the event of uncertainty in the diagnosis, a tissue biopsy is recommended before commencement of GKRS treatment. All 5 patients demonstrated improvement in visual acuity, with 3 patients achieving 20/20 vision on a Snellen chart. Two patients did not achieve maximal visual function: 1 patient had long-standing compressive optic neuropathy and the other had pre-existing epiretinal membrane. Complete resolution of the visual eld defect was seen in 4 patients (Figs 1, 2, and 3). The average tumor volume reduction was 76% (range, 70% 87%). Although the maximum tolerable dose to the ocular structures has not been dened clearly, the dose range in our series (i.e., lens,

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0.1 0.7 Gy; retina, 0.4 3 Gy) was not associated with any adverse effects. In this case series, the benecial effects of multisession GKRS in the treatment of benign orbital apex tumor were evident: shrinkage of tumor size, improvement of visual acuity, and resolution of visual eld defect without recurrence of tumor at the latest follow-up. Furthermore, none of the patients demonstrated any radiation-related visual morbidity. In addition to relative safety and intermediate-term efcacy, multisession GKRS allowed a shortened treatment period and resultant cost-effectiveness. However, there are other systems that enable frameless stereotactic radiosurgery; the discomfort with stereotactic head frame xation over a 3-day period may be a disadvantage of GKRS treatment. Conversely, the advantages of GKRS include minimal interfractional displacement error and high cumulative energy delivered to the target with the same marginal dose. This is because of the usual dose prescription at 50% isodose, instead of the 80% commonly used in radiosurgery with a linear accelerator.6 The cost and availability of the technique differ in each country. Although the cost of GKRS may be more expensive than that of conventional fractional radiotherapy such as 3D conformal therapy, the major advantage of GKRS is not only in the fewer treatment sessions, but also in the high accuracy permitting high-dose irradiation with a lower possibility of complications. This study demonstrated that multisession GKRS with a marginal dose of 5 Gy and 50% isodose in 4 sessions seems to be an effective management strategy to treat well-circumscribed benign orbital apex tumors. This treatment strategy avoids the complications associated with surgical resection and conventional radiotherapy. However, a long-term follow-up with a larger case series is warranted to validate the procedure completely.
7. Tanaka A, Mihara F, Yoshiura T, et al. Differentiation of cavernous hemangioma from schwannoma of the orbit: a dynamic MRI study. AJR Am J Roentgenol 2004;183:1799 804. 8. Hassler W, Eggert HR. Extradural and intradural microsurgical approaches to lesions of the optic canal and the superior orbital ssure. Acta Neurochir (Wein) 1985;74:8793. 9. McDermott MW, Durity FA, Rootman J, Woodhurst WB. Combined frontotemporal-orbitozygomatic approach for tumors of the sphenoid wing and orbit. Neurosurgery 1990;26: 10716. 10. Maroon JC, Kennerdell JS. Surgical approaches to the orbit: indications and techniques. J Neurosurg 1984;6:1226 35. 11. Scheuerle AF, Steiner HH, Kolling G, et al. Treatment and long-term outcome of patients with orbital cavernomas. Am J Ophthalmol 2004;138:237 44. 12. McCord CD Jr. A combined lateral and medial orbitotomy for exposure of the optic nerve and orbital apex. Ophthalmic Surg 1978;9:58 66. 13. Viale GL, Pau A. A plea for postero-lateral orbitotomy for microsurgical removal of tumours of the orbital apex. Acta Neurochir (Wein) 1988;90:124 6. 14. Kennerdell JS, Maroon JC, Celin SE. The posterior inferior orbitotomy. Ophthal Plast Reconstr Surg 1998;14:277 80. 15. Goldberg RA, Shorr N, Arnold AC, Garcia GH. Deep transorbital approach to the apex and cavernous sinus. Ophthal Plast Reconstr Surg 1998;14:336 41. 16. Harris GJ. Cavernous hemangioma of the orbital apex: pathogenetic considerations in surgical management. Am J Ophthalmol 2010;150:764 73. 17. Karaki M, Kobayashi R, Mori N. Removal of an orbital apex hemangioma using an endoscopic transethmoidal approach: technical note. Neurosurgery 2006;59(suppl):ONSE159 60. 18. Tsirbas A, Kazim M, Close L. Endoscopic approach to orbital apex lesions. Ophthal Plast Reconstr Surg 2005;21:2715. 19. Sethi DS, Lau DP. Endoscopic management of orbital apex lesions. Am J Rhinol 1997;11:449 55. 20. Yoshimura K, Kubo S, Yoneda H, et al. Removal of a cavernous hemangioma in the orbital apex via the endoscopic transnasal approach: a case report. Minim Invasive Neurosurg 2010;53:779. 21. Sethi DS, Pillay PK. Endoscopic management of lesions of the sella turcica. J Laryngol Otol 1995;109:956 62. 22. Almond MC, Cheng AG, Schiedler V, et al. Decompression of the orbital apex: an alternate approach to surgical excision for radiographically benign orbital apex tumors. Arch Otolaryngol Head Neck Surg 2009;135:1015 8. 23. Kloek CE, Bilyk JR, Pribitkin EA, Rubin PA. Orbital decompression as an alternative management strategy for patients with benign tumors located at the orbital apex. Ophthalmology 2006;113:1214 9. 24. Fisher BJ, Gaspar LE, Noone B. Radiation therapy of pituitary adenoma: delayed sequelae. Radiology 1993;187:843 6. 25. Hughes MN, Llamas KJ, Yelland ME, Tripcony LB. Pituitary adenomas: long-term results for radiotherapy alone and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 1993;27: 1035 43. 26. Maire JP, Caudry M, Guerin J, et al. Fractionated radiation therapy in the treatment of intracranial meningiomas: local control, functional efcacy, and tolerance in 91 patients. Int J Radiat Oncol Biol Phys 1995;33:31521. 27. McCord MW, Buatti JM, Fennell EM, et al. Radiotherapy for pituitary adenoma: long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 1997;39:437 44. 28. Pourel N, Auque J, Bracard S, et al. Efcacy of external fractionated radiation therapy in the treatment of meningiomas: a 20-year experience. Radiother Oncol 2001;61:6570.

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29. Leber KA, Bergloff J, Pendl G. Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 1998;88:4350. 30. Leber KA, Bergloff J, Langmann G, et al. Radiation sensitivity of visual and oculomotor pathways. Stereotact Funct Neurosurg 1995;64(suppl):233 8. 31. Tishler RB, Loefer JS, Lunsford LD, et al. Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 1993;27:21521. 32. Hoshi M, Hayashi T, Kagami H, et al. Late bilateral temporal lobe necrosis after conventional radiotherapy. Neurol Med Chir (Tokyo) 2003;43:213 6. 33. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2003;55:117781. 34. Girkin CA, Comey CH, Lunsford LD, et al. Radiation optic neuropathy after stereotactic radiosurgery. Ophthalmology 1997;104:1634 43. 35. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD. Visual eld preservation after multisession CyberKnife radiosurgery for perioptic lesions. Neurosurgery 2006;59:244 54. 36. Hirschbein MJ, Collins S, Jean WC, et al. Treatment of intraorbital lesions using the Accuray CyberKnife system. Orbit 2008;27:97105.

Footnotes and Financial Disclosures

Originally received: November 8, 2011. Final revision: August 8, 2012. Accepted: August 8, 2012. Available online: November 11, 2012.
1

Manuscript no. 2011-1616.

Department of Ophthalmology, Hospital Serdang, Kuala Lumpur, Malaysia. Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Presented at: Asia Pacic Academy of Ophthalmology Annual Meeting, March 2011, Sydney, Australia; and the European Society of Ophthalmic Plastic and Reconstructive Surgery Annual Meeting, September 2011, Lake Como, Cerbionno, Italy. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Yoon-Duck Kim, MD, PhD, Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwondong, Gangnam-gu, Seoul, 135-710 Korea. E-mail: ydkimoph@skku.edu.

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