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 CenterRose Ella Burkhardt Brain Tumor and Neuro-oncology Center

Taussig Cancer Institute

Conflict of interest

• Abbott Oncology Consultant

• Varian Travel funds

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

Dr. Lars Leksell

First patient was treated with SRS in 1952

First Gamma Knife Treatment in 1968

Dose (Gy)

Tu

mo

r co

ntr

ol

(%)

Control

Complications

50

100

Therapeutic Index

0

Radiobiology of Radiosurgery

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

Presentation Title l l 9

Linac Radiosurgery at CCF -- 1989-Linac Radiosurgery at CCF -- 1989-19971997

• Adapt linear acceleratorAdapt linear accelerator

• Base plate and floor standBase plate and floor stand

• Shotgun collimatorShotgun collimator

• Rotate gantry and table Rotate gantry and table position to deliver 5 non-position to deliver 5 non-coplanar arcscoplanar arcs

• First program in OhioFirst program in Ohio

Presentation Title l l 10

Computerized plan for linac-based radiosurgery

Presentation Title l l 11

Treatment plan

Model B unit

Presentation Title l l 13

Collimator helmets (4, 8, 14, 18 mm)

Model C: APS

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

• 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

Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37:745-51

MST 7.1 m20%

Class I

Extracranial metastases: No

KPS 70

Primary:Controlled

Age: <65

MST 4.2 m65%

KPS <70

Class IIIClass II

KPS 70KPS 70

Extracranial metastases: Yes

Age: 65

and / or

Primary:Uncontrolled

and / or

MST 2.3 m15%

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 1.0Age >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

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

• Alopecia

• Fatigue

• Skin erythema

• Headache

• Otitis media

• Somnolence syndrome

• Memory loss

• Radiation necrosis

• Leukoencephalopathy

Patients Impaired at Presentation

Peg D

Peg N

D

Reca

ll

Tra

il 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

Dela

y

CO

WA Reco

g

Impairment = Z Impairment = Z 1.51.5

Motor Motor FunctionFunction MemoryMemory

ExecutiveExecutive FunctionFunction

FluencyFluency

MemoryMemory

N=401

Meyers CA, et al. J Clin Oncol. 2004;22:157-165.

Pe

rce

nta

ge

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

Metastasis

Radiosurgery without WBRT

16.3 16.2

7.18.6

7.9

4.25.1

5.5

2.3

0

246

81012

141618

Class I Class II Class III

RSRS/WBRTRTOG

Mo

nth

s

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

STRATIFY

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

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

Pe

rce

nta

ge

aliv

e

Phase III randomized trial of SRS +/-WBRT

No prior surgery, SRS, or WBRTNo 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)

RAND

RAND

RPA class I /II RPA class I /II patients with patients with 1-3 lesions 1-3 lesions from known from known

primaryprimary

58 pts58 pts

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 +/-WBRTEORTC 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

RAND

RAND

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

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 +/-WBRTEORTC 22592-26001

NCCTG N0574(Intergroup)

RANDOMIZE

PE,QOL,

&Related

ASSESSMENTS

Arm 1: RS*

Arm 2:RS* + WBRT (30 Gy/12 fx)

FOLLOW

UP

<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 CavitySRS 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. STRGTR vs. STR .52.52

HistologyHistology .49.49

Number of FractionsNumber of Fractions .92.92

DoseDose .92.92

BEDBED .92.92

Conformity Index .04

VolumeVolume .29.29

Based on result, using 2 mm margin on GTV

ResectedResectedBrain Brain Met Met

SSTTRRAATTIIFFYY

AgeAge <60 vs. <60 vs. >>6060

# Brain Mets# Brain Mets1 vs. 2-41 vs. 2-4

Extracranial DzExtracranial Dz

HistologyHistologyLung vs. Lung vs. Radioresistant Radioresistant vs. vs. OthersOthers

Surgical CavitySurgical Cavity<<3 vs. > 3 cm3 vs. > 3 cm

RANDOMIZE

SRS Surgical Bed + SRS to SRS Surgical Bed + SRS to unresected brain metastasesunresected brain metastases

WBRT*WBRT* + SRS to unresected+ + SRS to unresected+ SRS to unresected SRS to unresected metastasesmetastases

N107C N107C SRS vs. WBRT Resected Brain MetsSRS vs. WBRT Resected Brain Mets

*37.5 Gy/15 fx*37.5 Gy/15 fx192 patients192 patients

Determine if neurocog progression less at 6 months with SRS

Results with SRS for multiple brain metastases

Suh JH, et al. J Stereo Radiosurg SBRT 1:31-40, 2011

Challenge of radiation necrosis after SRSDiagnosis and Treatment

Benign Brain Tumors

• Meningiomas

• Pituitary adenomas

• Vestibular schwannomas

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, 2005Central Brain Tumor Registry 2007

MeningiomaEPIDEMIOLOGY

Most Common Brain and CNS Tumors by AgeCBTRUS 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

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

MeningiomaLikelihood of total excision Historical MGH experience

100

90

80

70

60

50

40

30

20

10

00 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

Per

cen

t

Arie Perry et al, Am J Surg Pathol 21:1455-1465, 1997 & Cancer 85:2046-2056, 1999

Meningioma

*

88%

59%

28%

5-yr RFS

Phase II Study of IMRT for Intermediate

and High Risk Meningiomas, and Observationfor 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

ObservationGroup 1

Group 2

Group 3IMRT 60 Gy / 30 fxs

Primary endpoint: 3 yr PFS

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

• 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

• 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

• 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

• Primary therapy

• Adjunctive therapy

• Salvage therapy

SRS treatment plan for pituitary tumor

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

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

• Hearing Loss (95%)

• Tinnitus (63%)

• Vestibular Nerve (61%)

• Trigeminal Nerve (17%)

• Facial Nerve (6%)

Rosenberg, et al. Laryngoscope 110:497-508, 2002

SRS treatment plan

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

Fractionated Stereotactic Radiation Therapy

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

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

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

• 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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