1. 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

2. Conflict of interest
• Abbott Oncology Consultant
• Varian Travel funds

3. 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

4. Dr. Lars Leksell

5. First patient was treated with SRS in 1952

6. First Gamma Knife Treatment in 1968

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

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

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
Presentation Title l l 9

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

11. Treatment plan
Presentation Title l l 11

12. Model B unit

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

14. Model C: APS

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

17. 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

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

19. 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 Median survival (months)
0 0.5 1.0 3.5-4 11.0
Age >60 50-59 <50 3 6.9
KPS <70 70-80 90-100 1.5-2.5 3.8
Number of CNS >3 2-3 1 0-1 2.6
metastases
Extracranial Present - None
metastases
Sperduto P et al Int J Radiat Oncol Biol Phys 70:510, 2008

20. WBRT-Alternative Fractionation Regimens
Lack of Progress
Randomization MST
Study N (Total Dose/# Fractions) (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. 4.2-4.8
40/20
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. 216 18/3 vs. 36/6 vs. 43/13 4.2-5.3
(’93)
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

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

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

23. 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

24. Metastasis

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

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

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

28. Phase III randomized trial of SRS +/-WBRT
No prior surgery, SRS, or WBRT
No leukemias, lymphomas, germ-cell tumors, SCLC, leptomeningeal disease
RPA class I /II
patients with R
R SRS (15, 18 or 24 Gy)
1-3 lesions A
A
from known
primary N
N
D SRS + WBRT (30 Gy/12 fx)
58 pts D
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

29. 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

30. Phase III randomized trial of surgery or SRS +/-WBRT
EORTC 22592-26001
RPA class
I /II patients R
with 1-3 brain R Observation
Surgery A
with stable A
systemic dz or SRS N
N WBRT 30 Gy/10 fx
asymptomatic 359 pts
D
D
primary
WHO PS 0-2
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.
Kocher M et al. J Clin Oncol 29:134-141, 2010

31. Phase III randomized trial of surgery or SRS +/-WBRT
EORTC 22592-26001
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 59% 27% 0.001
SRS 31% 19% 0.04
2-year relapse at new sites
Surgery 42% 23% 0.008
SRS 48% 33% 0.023
Kocher M et al. J Clin Oncol 29:134-141, 2010

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

33. SRS of the Post-Operative Cavity
• 72 patients treated at Stanford from 1998-2006
• PTV = GTV in 76%
• 1y LC: 79%
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
Soltys S et al. Int J Radiat Oncol Biol Phys 70, 2008

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

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

36. Challenge of radiation necrosis after SRS
Diagnosis and Treatment

37. Benign Brain Tumors
• Meningiomas
• Pituitary adenomas
• Vestibular schwannomas

38. 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

39. Meningioma
EPIDEMIOLOGY
Most Common Brain and CNS Tumors by Age
CBTRUS Statistical Report: NPCR and SEER Data 2004-2006
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
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
Courtesy of L. Rogers

40. Meningioma
Likelihood of total excision
Historical MGH experience
Tumor Location n % Total Excision
96 %
Convexity 47
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

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

42. RTOG - 0539 Schema
Phase II Study of IMRT for Intermediate
and High Risk Meningiomas, and Observation
for Low Risk Meningiomas
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
Primary endpoint: 3 yr PFS
Group 1
Observation
Group 2
Strata 3D-CRT/IMRT 54 Gy / 30
fxs
Group 3
IMRT 60 Gy / 30 fxs

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

45. 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

46. 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

47. 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

48. Indications for radiation therapy and radiosurgery
• Primary therapy
• Adjunctive therapy
• Salvage therapy

49. SRS treatment plan for pituitary tumor

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

51. 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%

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

53. SRS treatment plan

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

55. Fractionated Stereotactic Radiation Therapy

56. SRS vs FSR: Jefferson Results
•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)
Tumor Preserv Preserv Preserv Tumor Control
Control Trigem Facial Hearing 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
Dosing recommendation: 46.8 Gy/26 fx
Andrews D, et al., Int J Radiat Oncol Biol Phys 2001; 50:1265-1278

57. SRS vs FSR from Netherlands
•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)
Local Control Preserved Preserved VII Preserved Vth
Hearing Function Function
FSR 94% 61% 97% 98%
SRS 100% 75% 93% 92%
Meijer et al. Neurosurg 2003; 56(5): 1390-1396

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

59. 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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