Radiosurgery for Benign Spinal Lesions

Radiosurgery for Benign Spinal Lesions Iris C. Gibbs, M.D. Associate Professor, Radiation Oncology Co-Director Cyberknife Radiosurgery Program Stanford University Sean Sachdev, B.S.; Robert L. Dodd, M.D., Ph.D.; Steven D. Chang, M.D.; Scott G. Soltys, M.D.; John R. Adler, M.D.; Gary Luxton, Ph.D.; Clara Y.H. Choi, M.D., Ph.D.; Laurie Tupper, N.P.

Disclosures None

Overview Primary benign spinal tumors Clinical presentation Radiosurgery techniques Indications for radiosurgery Results Lessons learned

Primary Spinal Tumors Extradural Intradural/Extramedullary Meningiomas Neurofibromas Schwannomas Intramedullary Astrocytomas Ependymomas Hemangioblastomas 52-75% of all primary spinal tumors 1, 2 1. Byrne, T. N.; Benzel, E. C.; Waxman, S. G. Diseases of the spine and spinal cord. Oxford; New York: Oxford University Press; 2000. 2. Gursinghe N.T. Spinal Cord Tumours. In Critchley, E. M. R.; Eisen, A., editors. Spinal cord disease. London; New York: Springer; 1997.

Benign Extramedullary Spinal Tumors characteristic meningioma schwannoma neurofibroma Age of presentation 5th-7th decade 5th decade 4th decade Spinal level predominance Thoracic (80%) All levels evenly Cervical (66%) Multiplicity 1-2% Rare unless NF-2 associated Common Proportion of primary spinal tumors 25% ~33% 3.5% Gender predominance Female (75-85%) None? Male Associations More commonly psammomatous or transitional histologies NF2, merlin/schwannomin gene on chromosome 22 NF1, neurofibromin gene on chromosome 17

Intradural Extramedullary Tumors Clinical Presentation: Local Pain Radicular Pain Weakness or motor deficits Sensory loss Bladder/Bowel Deficits 40 M with NF2 T10/T12 schwannoma

CHALLENGES: Relative difficult access Anterior Thoracic Meningioma

CHALLENGES: Multiple different levels of tumors Thoracic Meningiomas in NF2

CHALLENGES: Multiple Neurofibromas in NF1 Multiple lesions at multiple levels

Increasing Use of Spine Radiosurgery In recent US survey of >550 respondents Spine is 2 nd most common SBRT site 57% use 1 fraction Median dose 18 Gy Pan et al A Survey of Stereotactic Body Radiotherapy Use in the United States Cancer 2011;117:4566 72

Rationale for SRS to Treat BST Most spinal meninigiomas, schwannomas, and neurofibromas are noninfiltrative and can be completely resected by experienced surgeons. Certain patients however are less than ideal candidates for standard resection. Advanced age Medical comorbidities Recurrent tumors Multiple lesions Difficult locations requiring complex operative approaches SRS has an established role in benign intracranial pathologies.

Spinal Radiosurgery Indications surgically difficult location in the spine, recurrence after prior surgical resection, medical co-morbidities that preclude surgery Contraindications poorly defined margins, significant spinal cord compression resulting in acute neurological symptoms, ** tumors which can easily be resected with conventional surgical techniques. **

Grading Epidural Spinal Cord Compression Bilsky et al J NeurosurgSpine 13:324-28, 2010

Technical Requirements for Spinal Radiosurgery Exquisite Accuracy (submillimeter) Image-guidance Stereoscopic kv with tracking Conebeam

Current Spinal Radiosurgery Devices System Immobilization Image-guidance Error Analysis Cyberknife (Accuray, Inc) Head mask, cradle, vacuum bag Xsight skeletal tracking or Fiducial tracking Phantom- 0.61± 0.27mm Patient- 0.49 ± 0.22 mm Novalis (BrainLAb, Inc.) Head mask, cradle, vacuum bag Orthogonal images to set-up Optical tracking Measure iso dose 2-4% Patient- 1.36 ± 0.11 mm TomoTherapy (Tomotherapy Inc.) Head mask, vacuum bag CT Phantom- ± 0.6-1.2 mm Patient- ± 4-4.3 mm Synergy S (Elekta, Inc.) In-house systems BodyFix (Elekta) Stereotactic body frame or body cast Conebeam CT HexaPOD robotic couch CT Patient (w/o image guidance)- 5.2 ± 2.2 mm Patient (with image guidance)- 0.9-1.8 mm (translational) 0.8 1.6 o (rotational) Patient- varies from 1-3.6 mm Adapted from Sahgal et al IJROBP 71(3): 652 665, 2008 Kim et al IJROBP 73 ( 5),:1574 1579, 2009

Cyberknife Robotic Delivery System Targeting System Cyberknife Imaging X-ray sources Synchrony camera Linear accelerator Robotic Manipulator Image detectors

Volumetric Modulated Arc Therapy

Volumetric Arc Therapy

Technical Requirements for Spinal Radiosurgery Exquisite Accuracy (submillimeter) Image-guidance Stereoscopic kv with tracking Conebeam Proper immobilization evacuated cushion vacuum body fixation device Thermoplastic mask.

Spine SBRT Immobilization Devices a) evacuated cushion, b) vacuum body fixation device, c) thermoplastic S-frame mask. Li et al Impact of Immobilization on Intrafraction Motion for Spine Stereotactic Body Radiotherapy Using CBCT Int J Radiation Oncol Biol Phys, Vol. 84, No. 2, pp. 520e526, 2012

Technical Requirements for Spinal Radiosurgery Exquisite Accuracy (submillimeter) Image-guidance Stereoscopic kv with tracking Conebeam Proper immobilization evacuated cushion vacuum body fixation device Thermoplastic mask. Sophisticated treatment planning

Treatment Delivery Techniques Wowra et al Dtsch Arztebl Int 2009; 106(7): 106 12

Target Definition MRI-CT fusion Gerszten reported (93% of cases could be adequately contoured based on fusion) Challenging cases with instrumentation CT-myelogram was required Depending on the system specs GTV=PTV PTV= GTV + 2mm

Series GERSZTEN, 2008 (CK) DODD, 2006 (CK) SAGHAL 2007 (CK) Marchetti, 2013 (CK) Selch (Novalis) 2009 GERSZTEN, 2012 (Synergy) Sachdev (CK) 2011 Literature for Radiosurgery for Benign Intradural Spinal Tumors Menin g Schwann Neurofib Mea n age (yrs) Tot al #pts 13 35 25 44 73 16 30 9 46 51 2 -- 11 58 13 11 9 1 55 18 0 9 confirmed schwannoma 7 confirmed neurofibrom *Total 25 lesions 61 20 NR Indica tion 28% recurre nt/resid ual 51% recurre nt/resid ual 10/13 recurre nt/resid ual Residua l /recurre nt 10 16 14 52 45 47% residual /recurre nt 32 47 24 52 87 ~1/3rd residual / recurre nt Dose/ # Fx F/U (month s) 15-25Gy/ 1-3 8-71 16-30 Gy/ 1-5 25 10-30/ 1-5 2-37 10-13 Gy/1 18-25/4-6 43 (32-73) 12Gy/ 1 18 (12-58) 16Gy (mean max dose)/1-3 32 (3-55) 14-30 Gy/ 1-5 33 (6-87) Outcome 100% stable/decreased 3 new myelopathy 96% stable/decreased 3 repeat surgery 1 progression 1 new myelopathy 12/13 (92%) radiographically controlled 100% control no toxicity 100% control 12% improv neurol symp 1 incr pain 1 incr numbness 15/19 improved pain 100% control 1 transient dysphagia 82% symp control 99% control 7 repeat surg 1 transient myelop

Patient Characteristics 1998-2008 87 Patients with 103 Tumors PATIENTS Age (yr) Median 53 Range 12-86 Sex, no. (%) Female 44 (51) Male 43 (49) Neurofibromatosis (%) Type 1 9 (10) Type 2 14 (16) Schwannomatosis 2 (2) LESIONS Histology (%) Meningioma 32 (31) Neurofibroma 24 (23) Schwannoma 47 (46) PRESENTING SYMPTOMS Symptom Number of lesions (%) Pain 60 (58) Sensory Loss 35 (34) Weakness 30 (29) Bladder/Bowel Deficits 7 (7) Asymptomatic 26 (25) Sachdev et al Neurosurgery 69(3): 533-8, 2011

BENIGN SPINAL TUMORS mean follow up of 33 months (range: 6-104) Sachdev et al Neurosurgery 69(3): 533-8, 2011

Lesions Methods/Dosimetry 50 45 40 35 30 25 20 15 10 5 0 DOSIMETRY 17.7 19.9 21.1 mean dose (Gy) 21.0 25.1 1 2 3 4 5 Fractions >50% Average tumor volume, TV (cm 3 ) 5.14 (0.05-54.52) Average prescribed dose, TD (cgy) 1940 (1400-3000) Average maximum dose, Dmax (cgy) 2490 (1867-3750) Median Number of Fractions 2 (1-5) Sachdev et al Neurosurgery 69(3): 533-8, 2011

Dose Fractionation Details Sachdev et al Neurosurgery 69(3): 533-8, 2011

Clinical Results: Meningioma RADIOSURGERY EFFECT ON MENINGIOMA SYMPTOMS Presenting (%) Pain Weakness/Motor Deficits Sensory Loss Bladder/Bowl Deficits Asymptomatic Overall Symptomatic Response (%) Improved Stable Worsened Pain Response (%) Improved Stable Worsened 47 28 38 9 25 46 45 9 57 43 -- Overall 91% stable or improved with treatment Sachdev et al Neurosurgery 69(3): 533-8, 2011

Clinical Results: Schwannoma RADIOSURGERY EFFECT ON SCHWANNOMA SYMPTOMS Presenting (%) Pain Weakness/Motor Deficits Sensory Loss Bladder/Bowl Deficits Asymptomatic Overall Symptomatic Response (%) Improved Stable Worsened Pain Response (%) Improved Stable Worsened 57 21 28 4 32 50 36 14 53 29 18 Overall 86% stable or improved with treatment Sachdev et al Neurosurgery 69(3): 533-8, 2011

Clinical Results: Neurofibroma RADIOSURGERY EFFECT ON NEUROFIBROMA SYMPTOMS Presenting (%) Pain Weakness/Motor Deficits Sensory Loss Bladder/Bowl Deficits Asymptomatic Overall Symptomatic Response (%) Improved Stable Worsened Pain Response (%) Improved Stable Worsened 75 46 42 8 13 17 50 33 11 56 33 Overall poorer symptomatic response to treatment; 67% Sachdev et al Neurosurgery 69(3): 533-8, 2011

Radiographic Results EFFECT OF CYBERKNIFE ON TUMOR SIZE Histology Meningiomas Stable Decrease Increase 47% 53% -- Schwannomas 51% 47% 2%* Neurofibromas 82% 18% -- **Usual marked by <10% transient increase in size at 6 months followed by reduction Sachdev et al Neurosurgery 69(3): 533-8, 2011

Recurrent Spinal Schwannoma at T-7 Before Treatment 6 months 24 months 74 months

L4 radiation-induced meningioma A Pre-treatment B Treatment plan C 2 years post treatment

38 yr old with NF1 A B C Figure 3: 38 year old man with neurofibromatosis type 1 and multiple innumerable spinal and peripheral neurofibromas presenting with progressive weakness. (A) the left C2 neurofibroma indicated by the yellow arrow was targeted for radiosurgery, (B) the radiosurgery plan of 18 Gy in 2 fractions shows the tumor outlined in red with yellow dots, the thin spinal cord outlined in green, the prescription isodose curve in light green and the 50 % isodose curve in purple. (C) at 1-year follow-up the tumor was radiographically stable, although not symptomatically improved

L3-4 Recurrent Schwannoma A Pre-treatment B 21 Gy in 3 fractions C 2 years post treatment 72 year old woman with recurrent L3-4 schwannoma, 3 years after resection

Clinical Results: Post SRS Surgery Histology Location Age Time after SRS Tumor Control Symptoms Effect of Surgery Meningioma T9-10 68 10 months Stable Unchanged No improvement Neurofibroma C6 32 13 months Stable Unchanged Better Neurofibroma C6-7 52 18 months Stable Unchanged No improvement Schwannoma C3-4 37 12 months Stable Unchanged Better Schwannoma C2 25 30 months Stable Unchanged Better Schwannoma C2-3 71 30 months Stable Worse Better Schwannoma C5-6 62 73 months Decreased Worse No improvement

Clinical Results: Extended Follow-up 21 lesions had follow up > 48 months. 1 tumor increased in size 3 patients underwent surgical resection for persistent Sx. 2 patients in this group died, one of natural causes and one after a fall from a ladder.

Stanford series: Complications No treatment related mortality One case of radiation-induced myelopathy One spinal lamina fracture during fiducial placement

Other complications reported Transient dysphagia Dermatitis Worsening baseline symptoms Numbness Pain motor Myelopathy

Radiation-Induced Myelopathy C7-T2 Meningioma after 24 Gy in 3Fx Pre Post

Radiosurgery Complication One patient suffered from transient radiation induced myelitis 9 months post treatment >27Gy C7-T2 meningioma 7.57cm 3 treated to 24Gy in 3frx SC: 4.7cm 3 >8Gy, 0.1cm 3 SC Dmax = 29.9 Gy No previous radiation Neurologically stable after intervention (corticosteroids and physical therapy) Pre-treatment Post-treatment

Results Summary Mean follow-up 33 months Majority of schwannomas and meningiomas stable to improved symptoms (67 100%) Only ~50% of neurofibromas improved symptoms 98% tumor control (95% 4-yr actuarial control rate) One late failure observed at 6 years No treatment related mortality One transient radiation-induced myelopathy 7 patients had repeat surgery- 6 for worsening symptoms; 1-progression

Series GERSZTEN, 2008 (CK) DODD, 2006 (CK) SAGHAL 2007 (CK) Marchetti, 2013 (CK) Selch (Novalis) 2009 GERSZTEN, 2012 (Synergy) Sachdev (CK) 2011 Literature for Radiosurgery for Benign Intradural Spinal Tumors Menin g Schwann Neurofib Mea n age (yrs) Tot al #pts 13 35 25 44 73 16 30 9 46 51 2 -- 11 58 13 11 9 1 55 18 0 9 confirmed schwannoma 7 confirmed neurofibrom *Total 25 lesions 61 20 NR Indica tion 28% recurre nt/resid ual 51% recurre nt/resid ual 10/13 recurre nt/resid ual Residua l /recurre nt 10 16 14 52 45 47% residual /recurre nt 32 47 24 52 87 ~1/3rd residual / recurre nt Dose/ # Fx F/U (month s) 15-25Gy/ 1-3 8-71 16-30 Gy/ 1-5 25 10-30/ 1-5 2-37 10-13 Gy/1 18-25/4-6 43 (32-73) 12Gy/ 1 18 (12-58) 16Gy (mean max dose)/1-3 32 (3-55) 14-30 Gy/ 1-5 33 (6-87) Outcome 100% stable/decreased 3 new myelopathy 96% stable/decreased 3 repeat surgery 1 progression 1 new myelopathy 12/13 (92%) radiographically controlled 100% control no toxicity 100% control 12% improv neurol symp 1 incr pain 1 incr numbness 15/19 improved pain 100% control 1 transient dysphagia 82% symp control 99% control 7 repeat surg 1 transient myelop

Lessons learned from these studies Multiple studies Good follow-up >3 years Different platforms Dose 12-16 Gy in 1 fraction 18-30 Gy in 2-4 fractions (especially for Grade 3 ESCC) Tumor control 92-100% Symptom control >80% for most tumors; more challenging for neurofibroma UCLA study showed only 12% improved symptoms (?lower dose of 12 Gy)

Conclusions Image-guided radiosurgery for benign intradural tumors is feasible and safe. The most effective dosing schemes are still being determined. Longer term follow up data is needed to determine efficacy for such slow growing lesions, however the presented results suggest tumor growth control during the study period.