Radiosurgery in brain tumours

Dr Debnarayan Dutta, MD Consultant Radiation Oncologist Apollo Speciality Hospital, Chennai duttadeb07@gmail.com

CNS Tumours

Total number of tumours 132 Total number of malignant glial tumour ~ 20

WHO Classification. Louis D ; Acta Neuropathol 2007

Radiation therapy
Conventional RT: 1.8-2 Gy/# Majority of the tumours are treated with Conv RT Hypofractionated RT: >2 Gy/# Mainly for palliative treatment Radiosurgery: Single fraction high dose treatment Usually curative intent Fractionated Radiosurgery: Short course high dose treatment Usually curative

Radiosurgery: tools
Gamma-Knife LA based SRS Systems BrainLAB Novalis Trilogy Tomotherapy CyberKnife

Gamma knife

Gamma-knife: 201 Cobalt source

Only for intracranial lesions Rigid/ fixed Single

frame required

fraction treatment

Gamma-knife
Indications
- Small Meningiomas (<3 cm) - Small acuastic schwannoma (<3 cm) - Solitary / oligo brain metastasis with controlled primary (RPA Class I) - Small residual LGG

- AVMs (<3 cm)

- Trigeminal neuralgia (Functional disorder) More than 40 years experience / results with Gamma-Knife

CyberKnife: Unique properties

Highly precise treatment delivery
Motion management method Tumour tracking Dose painting

Excellent dose distribution

Fractionation schedule No rigid fixation

CyberKnife is an extension of Gamma-Knife

CK & GK: Similarity
- Principles of field arrangement - Dose distribution pattern - Multiple isocentre -Treatment principles - Treatment delivery accuracy similar - Delivered dose in single fractions - Intra-cranial indications

Hence, all the indications of GK are indications of CK also

Cyberknife
Indications for single fraction treatment as Gamma-Knife
- Small Meningiomas (<3 cm) - Small acuastic schwannoma (<3 cm) - Solitary / oligo brain metastasis with controlled primary - Small residual LGG

- AVMs (<3 cm)

- Trigeminal neuralgia
- Rec High grade glioma - Craniopharyngioma - Pituitary tumour

More than 40 years experience / results with Gamma-Knife

Cyberknife Vs Gamma-Knife: Dissimilarity

GK Immobilization device Rigid frame Orfit 6MV LA Inverse planning Complex Usually 80-95% May treat multiple fraction CK Comments CK has favorable orfit GK need to replace sources every 5/6 yrs Favorable dosimetry in CK Even neurosurgeons can plan in GK GK: more dose heterogeniety Radiobiology favorable in CK

RT source Co60 Planning No complex planning Planning method Simple Isodose prescription Usually 50% Fractions Single

Tumour size Only smaller lesions can be treated

Energy source Radiation Verification Not possible Indications Only brain lesions

Larger lesions also can be treated in fractionated schedule

Electricity Possible Both extra & intra cranial

Increased indications with CK

GK can work with less electricity Even Intra-fraction movement can be corrected CK more economical

Cyberknife Vs Gamma-Knife: Dissimilarity

Advantage of Inverse planning

GK planning

CK planning
Dose to mesial temporal lobe & Choclea is higher with GK Mean dose to mesial temporal lobe >6 Gy with SRS: IQ decline
Romanalli, Lancet 2009

% of patient with >10% drop in IQ

Left temporal lobe DVH

p=0.39

Volume (cc)

p=0.06

p=0.03 p=0.06

Jalali , Dutta et al IJROBP 2009

PTV margin in brain tumour

CTV-PTV Margin
Systemic Error () Random Error () ICRU 62 Strooms Van Herks

NR only Group:
Ant-Posterior Med-lateral Sup-Inferior 0.1 0.28 0.52 1.36 1.04 1.37 1.05 mm 1.01 mm 1.48 mm 1.15 mm 1.29 mm 2.0 mm 1.20 mm 1.43 mm 2.26 mm

NRF Group:
Ant-Posterior Med-lateral Sup-Inferior 2.24 0.78 0.94 1.28 1.41 1.39 3.14 mm 1.77 mm 1.91 mm 5.38 mm 2.55 mm 2.85 mm 6.50 mm 2.94 mm 3.32 mm

Prospective study
Two different head rest (NR & NRF) 220images (NR 100, NRF 120) Error estimation with 2D EPID

PTV margin: 3 mm.

Budrukkar , Dutta et al, JCRT 2008

Cyberknife Vs Gamma-Knife Vs X-Knife:

CK: Accuracy similar with Gamma-Knife
Treatment delivery accuracy: GK: ~1 mm CK : ~1 mm LA based SRS: 1-2 mm (iso-centric inacurracy; LUTZ test)

PTV margin: CK: <1 mm GK: <1 mm LA based SRS: 1-2 mm

GK/CK

LA based SRS

CK has the accuracy of GK and flexibility of LA based SRS

fSRS
Extended Indications for multiple fraction treatment
- Larger meningiomas (>3 cm) - Larger acuastic schwannoma (>3 cm) - Large solitary / oligo brain metastasis with controlled primary - Larger residual LGG

- AVMs (>3 cm)

- Chordomas - Rec HCC - Craniopharyngioma - Pituitary tumour

Short term data with robotic radiosurgery

New experiences with fSRS

Pre-Treatment

Post-Treatment

- More necrosis with CK than SRT (25Gy/5# Vs 54Gy/30#) - Difficult to have radiological interpretation - Require longer duration of steroid - Associated with more oedema

Outcome measures in benign/ low grade tumours

Radiological response may not be appreciable
Lack of progression is control in low grade/benign tumours Hence, function preservation is the mainstay of assessment of Rx outcome Function assessment:
Neuro-psychological assessment: IQ assessment Neuro-cognitive assessment: LOTCA Activities of daily living: Barthels , FIM FAM Quality of life

ADL in evaluation of efficacy in benign/low grade tumour

(n=38)

Dutta, Jalali JNO 2008

Response with fSRS in benign tumour

Conventional RT lack of progression is usual. In a few patients we have observed regression or complete response

New experiences with fSRS

Radiobiology & dose equivalent may be unpredictable with high dose/Fr Conventional BED calculation may not be appropriate Need to use different methodology for calculation of dose equivalence

60Gy @ 2Gy/Fr equivalence dose

New experiences with fSRS

Low dose region is less with CK compared with LA based SRS

Balaji, Dutta, Mahadev, AROI 2010 (Abstr)

Secondary malignancies: Impact of low dose region

Low dose region is less with CK compared with LA based SRS

Dose factors & sec malignancies

Sec malignancies high with higher 1-10 Gy volume

Coudi 2010

Experiences with SRS/ fSRS

Brain metastasis Acaustic schwannoma AVMs Meningiomas Pituitary tumour Craniopharyngioma Rec HGG New indications

Demography data: Brain tumours

Incidence*
All cases Benign SEX-Male Female Estimated new cases Paediatric All Male Female Lifetime Risk Male Female CBTRUS SEER 14.8 6.4 7.4 14.5 7.6 15.1 5.3 43,800 18,500 4.3 4.5 4.0 0.65% 0.50%

Prevalence#
All cases Benign Malignant Uncertain behaviour CBTRUS 130.8 97.5 29.5 3.8

# (per 1,00,000 population)

Brain metastasis
7-10 times of primary tumour

*(per 1,00,000 person-years)

Brain metastasis: SRS

Problem with Indian Subcontinent
Median age of presentation
Developed Countries* Metastatic brain Tumour Anaplastic astrocytoma Glioblastoma Oligodendroglioma Tata Hospital data**

61 yrs 49 yrs 62 yrs 41 yrs

49.4 yrs 36 yrs 50 yrs 37 yrs

Pituitary adenoma
Meningioma

39 yrs
55 yrs

41 yrs
46.5 yrs

Malignant Tumours: presentation one decade earlier in our data

* SEER and CBTRUS. **Tata Memorial Hospital NeuroOncology registry 2006 Jalali & Datta J Neurooncol (2008) 87:111114

Brain metastasis: WBRT alone

RPA class 1 2 3 Features KPS>70; Age<65; controlled primary; no extracranial disease KPS>70; Age>65; Uncontrolled primary; extracranial metastasis KPS<70 MS (mo) 7.1 4.2 2.3

Gasper et al; 1999

Brain metastasis: SRS/Sx

Prospective studies
MS (mo) Patchel WBRT+ Sx WBRT only 9.2 3.4 p-value 0.01

Vecht
Mintz Andrews Kondriolka

WBRT+ Sx
WBRT only WBRT+ Sx WBRT only WBRT+ Sx WBRT only WBRT+ Sx WBRT only

10
6 5.6 6.3 6.5 5.7 11 7.5

0.04
0.24 0.13 0.22

SRS: Brain metastasis Advantages

Surgery Lesion Effect Histopathology Larger (>4 cm), Non-eloquent area Rapid resolution of mass effect Tumour removed Confirmed Radiosurgery Small, deep lesions, eloquent area Minimally invasive Sterilized Not

Anesthesia
Steroid Follow up

Required
Tapped faster Less intensive

No
longer More

Suh J et al; NEJM 2010

SRS: Brain metastasis

Ideal lesions for SRS
Well defined on imaging (MRI & CT) Spherical or pseudospherical shape Most <4 cm in Max diameter Generally noninfiltrative

Located in grey-white junction

Suh J et al; NEJM 2010

Brain metastasis: fSRS

Prospective studies: Larger tumours
Study Alexender (1995) Median Vol (cm3) 3 KPS 80 Multiple lesions 31% MS (Mo) 9.4

Aucher (1996)
Breneman (1997) Shiou (1997) Shirato (1997) Pirzhall (1998) Kim (2000) Nishizaki (2006)

<4 cm 1.3 >2 cm:36% 2.1 7.2

90 90 60 80 90 80

0%
57% 46% 0% 26% 15% 45%

13
10 11 9 5.5 11 13

Nishizaki; Minim Invas Neurosurg 2006

AVMs
Epidemiology - Account for 10% SAH and 1% of strokes - Autopsy studies show 4-5% incidence in general population - Males: Female 2:1 Presentation - Hemorrhage (50%) usually during 2nd-4th decades - 10-20% risk of death if bleeds - 10-20% risk of long-term disability - Increased risk of re-bleed of 6% during first year after initial bleed - Seizures (25%) - HA (15%) migraine-type - Pulsatile tinnitus

Dose response curve: obliteration rate

3Yr obliteration 15-20 20-25 25-30 45% 55% 75%

5 year 85% 90% 75%

Obliteration after SRS depends upon marginal dose

Flickinger et al.. Rad Onc 2002; 63:347-354.

Complications : AVM Radiosurgery

Persistent neurological toxicity depends upon 12 Gy normal brain volume & location

Flickenger et al. IJROBP, 38(3):485-490,1997.

AVMs: SRS dosimetry

Dose prescription (Isocentre)

Marginal dose ( Gy)

12 Gy normal brain volume (cc)

Obliteration depends upon: marginal dose Complication depends upon: 12 Gy normal brain volume

Radiosurgery in AVMs
Gamma Knife
Accuracy PTV margin Isodose coverage Dose inhomgeniety Normal brain dose Complication probability Obliteration probability Sub-millimeter accuracy ~0-1 mm 50% high high high same

LA based SRS
not 1-2 mm 80-90% less less high same

Cyberknife
Sub-millimeter accuracy ~0-1 mm 80-90% less least Expected to be lower same

Cyberknife: sub-millimeter accuracy of gamma knife & higher dose homogeniety of LA based SRS

SRS in AVMs: Indian data (n=23)

Number of patient referred for SRS Number of patients planned for SRS Number of patients treated with SRS LFU status No deficits Neurological deficit persist Type of Imaging done for Assessment MRI and MRA done at 2 yrs FU DSA Imaging awaited on follow up Last Follow up status on Imaging MRA proven obliteration Obliteration confirmed on DSA No Obliteration on DSA Complication after SRS No complication Temporary worsening Persistent neurological deficit 87 23 21 22 01 15 12 06 15 11 01 18 02 01

Pre-SRS

Post-SRS 2 yr FU

Complete obliteration rate at 2 yrs DSA evaluation 92%

Jalali, Dutta et al. J Cancer Res Ther, 2009

Large AVMs

n Chang (2008) Pollock (2000) 55 10 (23)

Median FU (mo) 36 mo 12 mo

Results OR- 36% 12 Gy Vol dose acceptable

LTNS 15% -

Larger AVMs are treatable without increasing lat e neurological toxicity

Pollock IJROBP 2010

Meningiomas: SRS
- SRS is an option for small meningiomas (Incidental findings or symptomatic ) - Dose: 10-15 Gy; single Fr - Local control rate: 80-90% at 10 yrs - However, now emerging data, larger lesions (para-sagital) / Recurrent meningiomas may be treated with fractionated approach

CK Society website 2010

Atypical/ anaplastic meningiomas: SRS

Craniopharyngioma
Epithelial tumou rising from rathkes pouch remnants 2-5% of all primary intracranial tumours Common age of presentation <20 yrs 5-15% of primary tumour in children Two histopathological types: 1) Aadamantinomatous typemainly occurs in children 2) papillary type- occurs exclusively in adults.

Age & Sex distribution

Increasingly treated with conservative surgery + RT Good results with RT; 70-85% long term control Relatively high risk of treatment related effects
Review of 144 published data; Adamson & Yasargil 2008

Recurrence rate after only partial excision

Author Carbezudo Carmel Djordjevic Hoff Hoffman Lichter McMurrary Shapiro Stahnke Sweet Thomsett yr 1981 1982 1879 1972 1977 1977 1977 1979 1984 1976 1980 n 14 14 15 18 15 9 9 9 12 5 11 131 Recurrence 12 10 8 16 8 7 7 7 6 4 10 93 (71%) FU (yrs) 5-30 6.1 10 2-16 1-20 1-14 7.8 6.9 1-21 8.2

Recurrence rate 71% after only partial excision

Surgery alone vs Sur+ RT

Subtotal resection + RT: higher PFS (n=76)

Stripp et al IJROBP 2004

SRS/fSRS: Craniopharyngioma

Veeravagu et al, Neurosurg Focus 2010

Craniopharyngioma: SCRT- IQ assessment (n=18)

120 110 100 90 80 Mean IQ scores 70 60 50 40 30 20 10 0 Pre-RT 6 month 24 month 36 month VQ PQ FSIQ MQ 5 0 Pre-RT 6 month 24 month 36 month Mean Score

Mean IQ Scores
35 30 25 20 15 10

Mean Anxiety Score

Anxiety Trait (C1) Anxiety State (C2)

Mean IQ Scores are maintained at post-RT follow up. State anxiety had reduced after RT.

VQ: Verbal Quotient PQ: Performance Quotient MQ: Memory Quotient FSIQ: Full Scale IQ Dutta, Jalali et al WFNO 2009

Pituitary tumour: SRS

Problems with SRS: Pituitary tumour close to Optic pathway/ chiasm. Tumor close to chiasm may not be treated with surgery Also not possible to treat with single fraction SRS Constraint to chiasm: 10 Gy SRS dose required: 12 Gy fSRS is possible Higher dose can be delivered without increasing chiasm injury SRS/ fSRS increases early hormonal control without increasing toxicity (12 vs 40 mo)
Plowman Clinical Endocrinology 1999

Recurrent HGG: SRS studies

Romanelli, Neurosurg focus 2009

Recurrent GBM: SRS

SRS/fSRS MS (mo) 6-mo PFS (%) Radionecrosis Corticosteroid 6.5 20 60% SRS+TMZ 12 60 10% 80%

Conti 2010

Recurrent GBM: Survival function

Conti 2010

HGG: IMRT + CK boost Protocol

Eligibility Criteria: Histopathologically confirmed high grade gliomas (AA / GBM). Karnosky performance status >70. Willing for IMRT and Cyberknife treatment.

Methodology:
Conformal RT (50 Gy/25#/5 wks) CK 20Gy/5#

Conc TMZ (75mg/m2) x 6 wks Adj TMZ (200 mg/m2) x 6 cy

End point:
Survival function, Activities of daily livings QOL (ethical committee approved)

New Indications: SRS

-Temporal lobe epilepsy - Resistant seizure disorder - Behavioral disorders - Mood disorder - Obesity - Child hood attention deficit disorder / absence seizure - Skull base tumour

Quality of life is paramount important

EORTC QLQ C30 & BN20 Score in HGG (n=255)
TMH data EORTC QLQ-C- 30* Global score Emotional Cognitive Social Function Fatigue Pain BN-20** Future uncertainty Communication deficit Seizures Drowsiness 51.7 61.4 67.6 69.2 44.4 39.4 23.1 34.9 38.2 18.5 Taphoorn et al* 62.8 69.3 67.5 35.3 40.1 18.6 NA 26.4

Future uncertainty & communication deficits are different in our data & western data
Jalali, Buddrukar, Dutta JNO 2009

SRS in brain tumours Conclusions

- SRS is one of the standard of care is many small & benign brain tumours. - It seems, clinical outcome of robotic radiosurgery is similar to GK in these subset of pts - fSRS is an attractive option in larger benign/low grade and malignant tumours