02_Suh SRS Hyderabad 2013 (Cancer CI 2013) John H. Suh

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Overview of Stereotactic Radiosurgery for Brain Tumors John H. Suh, M.D. Professor and Chairman, Dept. of Radiation Oncology Associate Director of the Gamma Knife Center Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center Taussig Cancer Institute

Conflict of interest:

Conflict of interest Abbott Oncology Consultant Varian Travel funds

Outline:

Outline Review the history of stereotactic radiosurgery (SRS) Discuss the role of SRS for brain metastases Review the results of SRS for benign brain tumors

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Dr. Lars Leksell

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First patient was treated with SRS in 1952

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First Gamma Knife Treatment in 1968

Therapeutic Index:

Dose (Gy) Tumor control (%) Control Complications 50 100 Therapeutic Index 0

Radiobiology of Radiosurgery:

Radiobiology of Radiosurgery Balagamwala E, Chao S, Suh J. Tech Ca Res Treat 2012

Linac Radiosurgery at CCF -- 1989-1997:

Presentation Title l l 9 Linac Radiosurgery at CCF -- 1989-1997 Adapt linear accelerator Base plate and floor stand Shotgun collimator Rotate gantry and table position to deliver 5 non-coplanar arcs First program in Ohio

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Presentation Title l l 10 Computerized plan for linac-based radiosurgery

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Presentation Title l l 11 Treatment plan

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Model B unit

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Presentation Title l l 13 Collimator helmets (4, 8, 14, 18 mm)

Model C: APS:

Model C: APS

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Perfexion

Epidemiology of Brain Metastases:

Epidemiology of Brain Metastases Wen PY, et al. In: DeVita VT Jr, et al (eds). Cancer: Principles & Practice of Oncology. 2001:2656-2670. Other known primary: 13% Annual U.S. incidence: > 170K Ratio Mets/Primary: 10:1 All Cancer Patients: 15 - 30% Autopsy incidence: 10 - 30% Mean age: 60 years Median survival: 4-6 months Lung: 48% Breast: 15% Unknown primary: 11% Melanoma: 9% Colon: 5% Primary Tumor Relative Prevalence of Brain Metastases* *Incidence increasing with better systemic Rx and improved survival

Factors Used to Assess Therapy:

Factors Used to Assess Therapy Number of metastases Size of lesion(s) Location Neurological deficits Age / KPS Primary tumor / stage Extracranial disease Patient’s input

Brain Metastases: Recursive Partitioning Analysis:

Brain Metastases: Recursive Partitioning Analysis Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37:745-51 MST 7.1 m 20% Class I Extracranial metastases: No KPS 70 Primary: Controlled Age: <65 MST 4.2 m 65% KPS < 70 Class III Class II KPS  70 KPS 70 Extracranial metastases: Yes Age: 65 and / or Primary: Uncontrolled and / or MST 2.3 m 15%

Graded Prognostic Assessment (GPA) for brain metastases:

Graded Prognostic Assessment (GPA) for brain metastases Evaluated 1960 patients from five randomized RTOG studies Develop a less subjective, more quantitative, easier to use Score Sperduto P et al Int J Radiat Oncol Biol Phys 70:510, 2008 0 0.5 1.0 Age >60 50-59 <50 KPS <70 70-80 90-100 Number of CNS metastases >3 2-3 1 Extracranial metastases Present - None 3.5-4 11.0 3 6.9 1.5-2.5 3.8 0-1 2.6 Median survival (months)

WBRT-Alternative Fractionation Regimens Lack of Progress:

WBRT-Alternative Fractionation Regimens Lack of Progress Study N Randomization (Total Dose/# Fractions) MST (months) Harwood et al. (’77) 101 30/10 vs. 10/1 4.0-4.3 Kurtz et al. (’81) 255 30/10 vs. 50/20 3.9-4.2 Borgelt et al. (’81) 138 10/1 vs. 30/10 vs. 40/20 4.2-4.8 Borgelt et al. (’81) 64 12/2 vs. 20/5 2.8-3.0 Chatani et al. (’85) 70 30/10 vs. 50/20 3.0-4.0 Haie-Meder et al. (’93) 216 18/3 vs. 36/6 vs. 43/13 4.2-5.3 Priestman et al. (’96) 30/10 vs. 12/2 2.5-2.8 Murray et al. (’97) 445 54.4/34 vs. 30/10 4.5

Side Effects of WBRT:

Side Effects of WBRT Alopecia Fatigue Skin erythema Headache Otitis media Somnolence syndrome Memory loss Radiation necrosis Leukoencephalopathy

Patients Impaired at Presentation:

Patients Impaired at Presentation Peg D Peg ND Recall Trail B Peg D Peg ND Recall Delay Trail B COWA Recog Brain met patients have high rates of baseline deficits 0 10 20 30 40 50 60 70 Delay COWA Recog Impairment = Z  1.5 Motor Function Memory Executive Function Fluency Memory N=401 Meyers CA, et al. J Clin Oncol. 2004;22:157-165. Percentage

Favorable Characteristics of Brain Metastases for SRS:

Favorable Characteristics of Brain Metastases for SRS Radiographically distinct on MRI/CT Pseudospherical shape Displaces normal brain tissue Minimal invasion of normal brain Size at presentation ≤ 3 cm

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Metastasis

Radiosurgery without WBRT:

Radiosurgery without WBRT 16.3 16.2 7.1 8.6 7.9 4.2 5.1 5.5 2.3 0 2 4 6 8 10 12 14 16 18 Class I Class II Class III RS RS/WBRT RTOG Months 272 pts RS only upfront 388 RS + WBRT (non-randomized) (10-institution retrospective study) Sneed, PK, Suh JH, et al. Int. J Radiat Oncol Biol Phys. 53:519-526, 2002. Delayed WBRT does not worsen survival

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S T R A T I F Y R A N D O M I Z E Whole brain RT to 37.5 Gy/15 fractions/2.5 Gy once daily, 5 days/ week followed by radiosurgery to all (1-3) metastases Arm 1: Arm 2: Whole brain RT to 37.5 Gy/15 fractions/2.5 Gy once daily, 5 days/ week RTOG 95-08 Number of Metastases 1. Single 2. 2-3 Extent of Extracranial disease 1. None 2. Present

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KAPLAN-MEIER SURVIVAL RTOG 9508 Andrews DW et al. Lancet 363:1665-1672, 2004 100 80 60 40 20 0 Survival Single Brain Metastasis — RT + SRS MST = 6.5 mo --- RT Alone MST = 4.9 mo p = 0.047 0 6 12 18 24 Months Percentage alive

Phase III randomized trial of SRS +/-WBRT No prior surgery, SRS, or WBRT No leukemias, lymphomas, germ-cell tumors, SCLC, leptomeningeal disease :

Phase III randomized trial of SRS +/-WBRT No prior surgery, SRS, or WBRT No leukemias, lymphomas, germ-cell tumors, SCLC, leptomeningeal disease Stratification by RPA class (I or II) number of lesions (1 or 2 vs 3) “radioresistant” histologies (melanoma or RCC vs other) ? Baseline neurocognitive function and medications (opioids, sedatives) Primary endpoint: neurocognitive function Defined as a decrease in HVLT-R total recall at 4 months by more than 5 points Trial was closed early by data monitoring committee Chang EL et al. Lancet Oncol 2009:10:1037-1044 SRS (15, 18 or 24 Gy) SRS + WBRT (30 Gy/12 fx) R A N D RPA class I /II patients with 1-3 lesions from known primary 58 pts

Neurocognitive decline:

Neurocognitive decline “A mean posterior probability of [neurocognitive] decline of 52% for the SRS plus WBRT group and 24% for the SRS only group.” (96% confidence) Chang EL et al. Lancet Oncol 2009:10:1037-1044

Phase III randomized trial of surgery or SRS +/-WBRT EORTC 22592-26001 :

Phase III randomized trial of surgery or SRS +/-WBRT EORTC 22592-26001 Primary endpoint: deterioration to WHO PS > 2 Eligibility: single < 3.5 cm; 2-3 lesions < 2.5 cm PTV = 1-2 mm margin Dose 25 Gy to center with minimum dose of 20 Gy. Observation WBRT 30 Gy/10 fx R A N D RPA class I /II patients with 1-3 brain with stable systemic dz or asymptomatic primary WHO PS 0-2 Surgery SRS 359 pts Kocher M et al. J Clin Oncol 29:134-141, 2010

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Observation WBRT p value Median time WHO PS > 2 10 m 9.5 m 0.71 Median overall survival 10.9 m 10.7 m 0.89 2-year relapse at initial site Surgery SRS 59% 31% 27% 19% 0.001 0.04 2-year relapse at new sites Surgery SRS 42% 48% 23% 33% 0.008 0.023 Kocher M et al. J Clin Oncol 29:134-141, 2010 Phase III randomized trial of surgery or SRS +/-WBRT EORTC 22592-26001

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NCCTG N0574(Intergroup) RANDOMIZE PE, QOL, & Related A S S E S S M E N T S Arm 1: RS* Arm 2: RS* + WBRT (30 Gy/12 fx) F O L L O W U P <2.0 cm 24 Gy 2 - 2.9 cm 20 Gy <2.0 cm 22 Gy 2 - 2.9 cm 18 Gy Patients with histologically confirmed extra-cerebral primary tumor and 1 to 3 brain metastases detected by MRI 152 pts

SRS of the Post-Operative Cavity:

SRS of the Post-Operative Cavity 72 patients treated at Stanford from 1998-2006 PTV = GTV in 76% 1y LC: 79% Soltys S et al. Int J Radiat Oncol Biol Phys 70, 2008 GTR vs. STR .52 Histology .49 Number of Fractions .92 Dose .92 BED .92 Conformity Index .04 Volume .29 Based on result, using 2 mm margin on GTV

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Resected Brain Met S T R A T I F Y Age <60 vs. > 60 # Brain Mets 1 vs. 2-4 Extracranial Dz Histology Lung vs. Radioresistant vs. Others Surgical Cavity < 3 vs. > 3 cm R A N D O M I Z E SRS Surgical Bed + SRS to unresected brain metastases WBRT* + SRS to unresected+ SRS to unresected metastases N107C SRS vs. WBRT Resected Brain Mets *37.5 Gy/15 fx 192 patients Determine if neurocog progression less at 6 months with SRS

Results with SRS for multiple brain metastases:

Results with SRS for multiple brain metastases Suh JH, et al. J Stereo Radiosurg SBRT 1:31-40, 2011

Challenge of radiation necrosis after SRS Diagnosis and Treatment:

Challenge of radiation necrosis after SRS Diagnosis and Treatment

Benign Brain Tumors:

Benign Brain Tumors Meningiomas Pituitary adenomas Vestibular schwannomas

Introduction: Meningiomas:

Introduction: Meningiomas Most common primary intracranial neoplasm ~30% of all intracranial neoplasms Estimated prevalence is 97.5 per 100,000 Most are identified on imaging alone F:M – 2:1 supratentorial Klaus et al. Neurosurg 57:1088, 2005 Central Brain Tumor Registry 2007

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Meningioma EPIDEMIOLOGY Most Common Brain and CNS Tumors by Age CBTRUS Statistical Report: NPCR and SEER Data 2004-2006 CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004-2006. http://www.cbtrus.org/2010-NPCR-SEER/CBTRUS-WEBREPORT-Final-3-2-10.pdf . February 2010 Age (yrs) Most Common Histology 2nd Most Common Histology 0-4 Embryonal / Medulloblastoma Pilocytic Astrocytoma 5-9 Pilocytic Astrocytoma Malignant Glioma , NOS 10-14 Pilocytic Astrocytoma Neuronal / Glial 15-19 Pituitary Pilocytic Astrocytoma 20-34 Pituitary Meningioma 35-44 Meningioma Pituitary 45-54 Meningioma Glioblastoma 55-64 Meningioma Glioblastoma 65-74 Meningioma Glioblastoma 75-84 Meningioma Glioblastoma 85+ Meningioma Neoplasm, unspecified Courtesy of L. Rogers

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Tumor Location n % Total Excision Convexity 47 96 % Orbit 5 80 % Spine 18 78 % Olfactory Groove 22 77 % Parasagittal Area/Falx 38 76 % Parasellar Region 28 57 % Posterior Fossa 31 32 % Sphenoid Ridge 36 28 % TOTAL: 225 64% Mirimanoff et al, J Neurosurg 62: 18 – 24, 1985 Meningioma Likelihood of total excision Historical MGH experience

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100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 p < 0.001 Anaplastic, n=23 ( 3.6% ) Atypical, n=156 ( 24.3% ) Benign, n=464 ( 72.1% ) Recurrence-Free Survival by Grade (643 pts) Years Percent Arie Perry et al , Am J Surg Pathol 21:1455-1465, 1997 & Cancer 85:2046-2056, 1999 Meningioma * 88% 59% 28% 5-yr RFS

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Phase II Study of IMRT for Intermediate and High Risk Meningiomas, and Observation for Low Risk Meningiomas RTOG - 0539 Schema Group 1 (Low Risk): New Grade 1, GTR or STR Group 2 (Interm Risk): Recurrent Grade 1, GTR or STR New Grade 2, GTR Group 3 (High Risk): Any Grade 3 Recurrent Grade 2 New Grade 2, STR 3D-CRT/IMRT 54 Gy / 30 fxs Strata Observation Group 1 Group 2 Group 3 IMRT 60 Gy / 30 fxs Primary endpoint: 3 yr PFS

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Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: a Phase II and observation study Current EORTC 22042-26042 Trial

University of Pittsburgh: long term results:

University of Pittsburgh: long term results Updated their 18-year experience in a cohort of 972 patients with 1045 intracranial meningiomas 70% women 645 patients had middle and posterior fossa tumors Median dose 14 Gy Kondziolka D, et al. Neurosurg 62(1):53-8, 2008

University of Pittsburgh: long term results:

University of Pittsburgh: long term results Among 75 patients with a minimum follow-up of 10 years, the local control rates for grade 1 meningiomas or lesions without histology were 91% and 95%, respectively. Local control for WHO II and III were 50% and 17%, respectively. Symptomatic peritumoral edema was 4 months at mean of 8 months. Kondziolka D, et al. Neurosurg 62(1):53-8, 2008

Treatment options for Pituitary Tumors:

Treatment options for Pituitary Tumors Observation Microsurgery Medical Radiosurgery Radiation therapy Multimodality approach Depends on symptoms, tumor size at presentation, involvement of adjacent structures, and vicinity to optic apparatus

Indications for radiation therapy and radiosurgery :

Indications for radiation therapy and radiosurgery Primary therapy Adjunctive therapy Salvage therapy

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SRS treatment plan for pituitary tumor

Pituitary adenoma 20 Gy (13 shots- 16, 8 mm with Blocking) Optic chiasm dose 7.9 Gy:

Pituitary adenoma 20 Gy (13 shots- 16, 8 mm with Blocking) Optic chiasm dose 7.9 Gy

Epidemiology of Vestibular Schwannomas:

Epidemiology of Vestibular Schwannomas 2000-3000 new cases of VS diagnosed per year in the U.S., an incidence of 1/100,000 per year 8-10% of all primary intracranial tumors 80-90% of all cerebellopontine angle tumors Commonly present between 30-50 year of age Can be associated with NF-2 Incidence of occult VS in human temporal bones: 0.57-0.87%

Presentation:

Presentation Hearing Loss (95%) Tinnitus (63%) Vestibular Nerve (61%) Trigeminal Nerve (17%) Facial Nerve (6%) Rosenberg, et al. Laryngoscope 110:497-508, 2002

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SRS treatment plan

Acoustic neuroma 13 Gy (8 shots- 4 mm with couple of blocked sectors) Cochlea dose 6.8 Gy:

Acoustic neuroma 13 Gy (8 shots- 4 mm with couple of blocked sectors) Cochlea dose 6.8 Gy

Fractionated Stereotactic Radiation Therapy:

Fractionated Stereotactic Radiation Therapy

SRS vs FSR: Jefferson Results:

SRS vs FSR: Jefferson Results Tumor Control Preserv Trigem Preserv Facial Preserv Hearing Tumor Control NF2 SRS 98% 95% 98% 33% 80% FSR 97% 93% 98% 81% 67% P value 0.6777 0.5893 0.8202 0.0228 0.6615 Andrews D, et al., Int J Radiat Oncol Biol Phys 2001; 50:1265-1278 Dosing recommendation: 46.8 Gy/26 fx Retrospective study of 125 patients with AN 69 treated with SRS (12 Gy to the 50% IDL) 56 treated with FSR (50 Gy/25 fx)

SRS vs FSR from Netherlands :

SRS vs FSR from Netherlands Local Control Preserved Hearing Preserved VII Function Preserved Vth Function FSR 94% 61% 97% 98% SRS 100% 75% 93% 92% Meijer et al. Neurosurg 2003; 56(5): 1390-1396 All treatments were linac-based from 1992 to 1999 129 patients prospectively randomized to SRS vs. FSR Dentate: FSR (20 Gy/5 fx and 25 Gy/5 fx) Edentate: SRS (10 Gy and 12.5 Gy) Mean Tumor Diameter ( FSR: 2.5 cm vs. SRS: 2.6 cm)

SRS versus FSRT for vestibular schwannomas:

SRS versus FSRT for vestibular schwannomas Combs S, et al. Int J Radiat Oncol Biol Phys 76:193-200, 2010 < 13 Gy >13 Gy 200 patients treated at Heidelberg and DFKZ Hearing preserv SRS < 13 Gy and FSRT 57.6 Gy/32 fx FSRT SRS

Conclusions:

Conclusions Stereotactic radiosurgery (SRS) is a safe and effective treatment option for a variety of brain tumors. The use of SRS for brain metastases is increasing. SRS is an effective treatment option for patients with brain metastases. SRS is an effective and safe treatment option for patients with benign brain tumors

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