Radiosurgery in brain tumours

Dr Debnarayan Dutta, MD

Consultant Radiation Oncologist

Apollo Speciality Hospital, Chennai

duttadeb07@gmail.com

WHO Classification. Louis D ; Acta Neuropathol 2007

CNS Tumours

Total number of tumours 132

Total number of malignant glial tumour ~ 20

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 frame required

• Single 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’

- Principles of ‘field arrangement’

- Dose distribution pattern

- Multiple isocentre

-Treatment principles

- Treatment delivery accuracy similar

- Delivered dose in single fractions

- Intra-cranial indications

CK & GK: Similarity

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

CyberknifeIndications 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 CK Comments

Immobilization device Rigid frame Orfit CK has favorable orfit

RT source Co60 6MV LA GK need to replace sources every

5/6 yrs

Planning No complex planning Inverse planning Favorable dosimetry in CK

Planning method Simple Complex Even neurosurgeons can plan in

GK

Isodose prescription Usually 50% Usually 80-95% GK: more dose heterogeniety

Fractions Single May treat multiple fraction Radiobiology favorable in CK

Tumour size Only smaller lesions can

be treated

Larger lesions also can be

treated in fractionated

schedule

Increased indications with CK

Energy source Radiation Electricity GK can work with less electricity

Verification Not possible Possible Even Intra-fraction movement can

be corrected

Indications Only brain lesions Both extra & intra cranial 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

p=0.06

p=0.03

p=0.06

Volu

me (

cc)

Jalali , Dutta et al IJROBP 2009

PTV margin in brain tumour

CTV-PTV MarginSystemic

Error ()

Random

Error ()

ICRU 62 Strooms Van Herk’s

NR only Group:

Ant-Posterior 0.1 1.36 1.05 mm 1.15 mm 1.20 mm

Med-lateral 0.28 1.04 1.01 mm 1.29 mm 1.43 mm

Sup-Inferior 0.52 1.37 1.48 mm 2.0 mm 2.26 mm

NRF Group:

Ant-Posterior 2.24 1.28 3.14 mm 5.38 mm 6.50 mm

Med-lateral 0.78 1.41 1.77 mm 2.55 mm 2.94 mm

Sup-Inferior 0.94 1.39 1.91 mm 2.85 mm 3.32 mm

PTV margin: 3 mm.

Budrukkar , Dutta et al, JCRT 2008

Prospective study

Two different head rest (NR & NRF)

220images (NR 100, NRF 120)

Error estimation with 2D EPID

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 mmGK/CK LA based SRS

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

fSRSExtended 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

Post-TreatmentPre-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

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

Outcome measures in benign/ low grade tumours

Function assessment:

Neuro-psychological assessment: IQ assessment

Neuro-cognitive assessment: LOTCA

Activities of daily living: Barthel’s , FIM FAM

Quality of life

ADL in evaluation of efficacy in benign/low grade tumour

Dutta, Jalali JNO 2008(n=38)

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

CBTRUS SEER

All cases 14.8 6.4

Benign 7.4

SEX-Male 14.5 7.6

Female 15.1 5.3

Estimated new cases 43,800 18,500

Paediatric

All 4.3

Male 4.5

Female 4.0

Lifetime Risk

Male 0.65%

Female 0.50%

Incidence*

CBTRUS

All cases 130.8

Benign 97.5

Malignant 29.5

Uncertain behaviour 3.8

Prevalence#

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

# (per 1,00,000 population)

Brain metastasis 7-10 times of primary tumour

Brain metastasis: SRSProblem with Indian Subcontinent

Median age of presentation

Developed Countries* Tata Hospital data**

Metastatic brain Tumour 61 yrs 49.4 yrs

Anaplastic astrocytoma 49 yrs 36 yrs

Glioblastoma 62 yrs 50 yrs

Oligodendroglioma 41 yrs 37 yrs

Pituitary adenoma 39 yrs 41 yrs

Meningioma 55 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) 87:111–114

Brain metastasis: WBRT alone

RPA class Features MS (mo)

1 KPS>70; Age<65; controlled primary;

no extracranial disease

7.1

2 KPS>70; Age>65; Uncontrolled primary;

extracranial metastasis

4.2

3 KPS<70 2.3

Gasper et al; 1999

Brain metastasis: SRS/SxProspective studies

MS (mo) p-value

Patchel WBRT+ Sx 9.2 0.01

WBRT only 3.4

Vecht WBRT+ Sx 10 0.04

WBRT only 6

Mintz WBRT+ Sx 5.6 0.24

WBRT only 6.3

Andrews WBRT+ Sx 6.5 0.13

WBRT only 5.7

Kondriolka WBRT+ Sx 11 0.22

WBRT only 7.5

SRS: Brain metastasis

Advantages

Surgery Radiosurgery

Lesion Larger (>4 cm), Non-eloquent

area

Small, deep lesions,

eloquent area

Effect Rapid resolution of mass effect Minimally invasive

Tumour removed Sterilized

Histopathology Confirmed Not

Anesthesia Required No

Steroid Tapped faster longer

Follow up Less intensive More

Suh J et al; NEJM 2010

SRS: Brain metastasis

Suh J et al; NEJM 2010

Well defined on imaging (MRI & CT)

Spherical or pseudospherical shape

Most <4 cm in Max diameter

Generally noninfiltrative

Located in grey-white junction

Ideal lesions for SRS

Brain metastasis: fSRSProspective studies: Larger tumours

Study Median Vol (cm3) KPS Multiple

lesions

MS (Mo)

Alexender (1995) 3 80 31% 9.4

Aucher (1996) - - 0% 13

Breneman (1997) <4 cm 90 57% 10

Shiou (1997) 1.3 90 46% 11

Shirato (1997) >2 cm:36% 60 0% 9

Pirzhall (1998) - 80 26% 5.5

Kim (2000) 2.1 90 15% 11

Nishizaki (2006) 7.2 80 45% 13

Nishizaki; Minim Invas Neurosurg 2006

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

AVMs

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

Dose response curve: obliteration rate

3Yr

obliteration

5 year

15-20 45% 85%

20-25 55% 90%

25-30 75% 75%

Obliteration after SRS depends upon marginal dose

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

Complications : AVM Radiosurgery

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

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 LA based SRS Cyberknife

Accuracy Sub-millimeter

accuracy

not Sub-millimeter

accuracy

PTV margin ~0-1 mm 1-2 mm ~0-1 mm

Isodose coverage 50% 80-90% 80-90%

Dose inhomgeniety high less less

Normal brain dose high less least

Complication probability high high Expected to be

lower

Obliteration probability same same same

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

SRS in AVMs: Indian data (n=23)

Complete obliteration rate at 2 yrs DSA evaluation 92%

Number of patient referred for SRS 87

Number of patients planned for SRS 23

Number of patients treated with SRS 21

LFU status No deficits 22

Neurological deficit persist 01

Type of Imaging done for Assessment

MRI and MRA done at 2 yrs FU 15

DSA 12

Imaging awaited on follow up 06

Last Follow up status on Imaging

MRA proven obliteration 15

Obliteration confirmed on DSA 11

No Obliteration on DSA 01

Complication after SRS

No complication 18

Temporary worsening 02

Persistent neurological deficit 01

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

Pre-SRS

Post-SRS 2 yr FU

Large AVMs

n Median

FU (mo)

Results LTNS

Chang (2008) 55 36 mo OR- 36% 15%

Pollock (2000) 10 (23) 12 mo 12 Gy Vol dose

acceptable

-

Pollock IJROBP 2010

Larger AVMs are treatable without increasing lat e neurological toxicity

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 type-

mainly occurs in children

2) papillary type- occurs exclusively in adults.

• Increasingly treated with conservative surgery + RT

• Good results with RT; 70-85% long term control

• Relatively high risk of treatment related effects

Age & Sex distribution Review of 144 published data; Adamson & Yasargil 2008

Author yr n Recurrence FU (yrs)

Carbezudo 1981 14 12 5-30

Carmel 1982 14 10 6.1

Djordjevic 1879 15 8 -

Hoff 1972 18 16 10

Hoffman 1977 15 8 2-16

Lichter 1977 9 7 1-20

McMurrary 1977 9 7 1-14

Shapiro 1979 9 7 7.8

Stahnke 1984 12 6 6.9

Sweet 1976 5 4 1-21

Thomsett 1980 11 10 8.2

131 93 (71%)

Recurrence rate 71% after only partial excision

Recurrence rate after only partial excision

Surgery alone vs Sur+ RT

Subtotal resection + RT: higher PFS

Stripp et al IJROBP 2004(n=76)

Veeravagu et al, Neurosurg Focus 2010

SRS/fSRS: Craniopharyngioma

Craniopharyngioma: SCRT- IQ assessment (n=18)

VQ: Verbal Quotient

PQ: Performance Quotient

MQ: Memory Quotient

FSIQ: Full Scale IQ

0

10

20

30

40

50

60

70

80

90

100

110

120

Pre-RT 6 month 24 month 36 month

Mea

n I

Q s

core

s

Mean IQ Scores

VQ

PQ

FSIQ

MQ

0

5

10

15

20

25

30

35

Pre-RT 6 month 24 month 36 monthM

ean

S

core

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.

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

Conti 2010

SRS/fSRS SRS+TMZ

MS (mo) 6.5 12

6-mo PFS (%) 20 60

Radionecrosis - 10%

Corticosteroid 60% 80%

Conti 2010

Recurrent GBM: Survival function

HGG: IMRT + CK boost Protocol

Eligibility Criteria:

Histopathologically confirmed high grade gliomas (AA / GBM).

Karnosky performance status >70.

Willing for IMRT and Cyberknife treatment.

(ethical committee approved)

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

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

TMH data¶ Taphoorn et al*

EORTC QLQ-C- 30*

Global score 51.7 62.8

Emotional 61.4 69.3

Cognitive 67.6 -

Social Function 69.2 67.5

Fatigue 44.4 35.3

Pain 39.4

BN-20**

Future uncertainty 23.1 40.1

Communication deficit 34.9 18.6

Seizures 38.2 NA

Drowsiness 18.5 26.4

Jalali, Buddrukar, Dutta JNO 2009

EORTC QLQ C30 & BN20 Score in HGG (n=255)

Future uncertainty & communication deficits are different in our data & western data

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