Brain tissue injury and necrosis after Gamma Knife and Novalis

Radiosurgeryfor brain tumors, metastasis and AVM

Konstantin NikitinKonstantin NikitinDepartment of radiotherapy & Department of radiotherapy &

radiosurgery,radiosurgery,Burdenko Neurosurgical Institute, Burdenko Neurosurgical Institute,

MoscowMoscowEuropean Gamma Knife Society meeting

28 November 2009

ContentContent

► IntroductionIntroduction- incidence incidence - time of developmenttime of development- pathogenesis pathogenesis - pathologypathology- risk factors risk factors

► Results Results

► Clinical cases Clinical cases (Novalis & GK)(Novalis & GK)

► SummarySummary

IncidenceIncidence

► Severe necrosisSevere necrosis - 1 - 1,2%,2% of 760 mts or 2,4% of 377 pt of 760 mts or 2,4% of 377 pt (9 cases (9 cases after 10-MeV LINAC SRS) after 10-MeV LINAC SRS) [Valery et al, 2003][Valery et al, 2003]

► Symptomatic injurySymptomatic injury - 7% - 7% (17 of 243 pt - GK)(17 of 243 pt - GK) [Chin et al, 2001][Chin et al, 2001]

glioma glioma – – 17%, benign tumors + AVM 17%, benign tumors + AVM –– 7,5%, mts 7,5%, mts – – 5 %.5 %.

► CT/MR changesCT/MR changes (asymptomatic + symptomatic) - 28 (asymptomatic + symptomatic) - 28,8,8%%

at 2 years after LINAC SRS at 2 years after LINAC SRS [[Voges et alVoges et al, , 19961996]]

► Necrotic findingsNecrotic findings in resected tissue - 33% in resected tissue - 33% (11 of 33 pt (11 of 33 pt at 1 - 11 at 1 - 11 yyeaearrs after SRS fors after SRS for AVM)AVM) [Chang et al[Chang et al, 1997, 1997]]

► 3/4 of all complications develop 3/4 of all complications develop at firstat first 14 months 14 months

from Voges et al. Int J Radiat Oncol Biol Phys 36: 1055–1063, 1996from Voges et al. Int J Radiat Oncol Biol Phys 36: 1055–1063, 1996

Development timeDevelopment time: : median - 4 months (range edian - 4 months (range 2 – 14);;Recovery time for symptoms: 7.5 months (range 2 –

16),for imaging changes - 10.5 months (6 – 16) [Chin et al, [Chin et al,

2001]2001]

Time of development and recoveryTime of development and recovery

months after SRS 10 20 30 40

30%

20%

10%

0%

Cumulative hazard of development of CT/MR

changes after LINAC SRS

PathogenesisPathogenesis

Endothelial Endothelial damagedamage

Glial Glial damagedamage

Cytokine Cytokine releaserelease

BBB disruptionBBB disruption

Vessel Vessel obliterationobliteration

early

late

Chemotaxis of Chemotaxis of immune immune

cellscells

infarction

edema

demyelination

inflammation

PathologyPathology► Endothelial proliferation Endothelial proliferation ► Vessel wall hyalinization Vessel wall hyalinization ► Coagulation necrosis Coagulation necrosis ► DemyelinationDemyelination► CCааlcium depositslcium deposits ► Thrombosis Thrombosis ► MicrohaemorrhagesMicrohaemorrhages► LymphoidLymphoid cell infiltrationcell infiltration

Severity of changes is Severity of changes is dose-related, but theredose-related, but there is is nono

minimal dose threshold minimal dose threshold for radiation changes !for radiation changes !

Risk factorsRisk factors

► high dosehigh dose► high volumehigh volume► low selectivity low selectivity

► repeated SRS repeated SRS ► high dose inhomogeneity high dose inhomogeneity ► intraintra--parenchymal location (gliomaparenchymal location (glioma, , mts, AVM) mts, AVM)

► individual radiosensitivity ?individual radiosensitivity ?► chemotherapy ?chemotherapy ?

Significant Significant predictors:predictors:• 10-Gy vol 10-Gy vol [Chin et al, [Chin et al, 2001]2001]

• 12-Gy vol 12-Gy vol [Korytko T, [Korytko T, 2006]2006]

10-Gy total volume (total volume irradiated with more than 10 Gray dose) in 17 patients with necrosis after GK SRS and matched controls.

Median 10-Gy vol = 28,8 ccm in “necrotic” group, 7,8 ccm in control group.

from Сhin et al, J Neurosurg 2001; 94: 899–

904.

Risk factorsRisk factors

► high dosehigh dose

► high volumehigh volume

► low selectivity low selectivity

► previous SRS previous SRS ► high dose inhomogeneity high dose inhomogeneity ► intraparenchymal locationintraparenchymal location (glioma(glioma, , mts, mts,

AVM)AVM)

► individual radiosensitivity ?individual radiosensitivity ?► chemotherapy ?chemotherapy ?

Significant predictors:Significant predictors:

total total 10 - 12 Gy 10 - 12 Gy volumevolume

10 Gy volume 10 Gy volume of of brain brain

tissuetissue

[Voges et al[Voges et al, , 1996]1996]

Cumulative hazard of development of post-SRS CT/MR changes with regard of target location

Intraparenchymal(56 AVM, 6 meningioma)

Scull-base tumors

time after SRS 10 20 30 months

60%

50%

40%

30%

20%

10%

Voges et al, 1996

► high dosehigh dose

► high volumehigh volume

► low selectivity low selectivity

► repeated SRS repeated SRS

► high dose inhomogeneity high dose inhomogeneity

► intraparenchymal locationintraparenchymal location (glioma (glioma, , metastasis, metastasis, AVM)AVM)

► individual radiosensitivity ?individual radiosensitivity ?► chemotherapy ?chemotherapy ?

Significant predictors:Significant predictors:

total total 10 - 12 Gy 10 - 12 Gy volumevolume

Risk factorsRisk factors

10-Gy volume 10-Gy volume of of brain brain

tissuetissue

Results: Results: GK and Novalis SRSGK and Novalis SRS in Burdenko Neurosurgical Institutein Burdenko Neurosurgical Institute

GKGK NovalisNovalis

Patients treated since Patients treated since 20052005

12781278 622622

Patients with follow-Patients with follow-upup

716716 276276

with follow-up > 14 with follow-up > 14 monthsmonths

249249 103103

ptpt %% ptpt %%

Severe necrosisSevere necrosis (surgical removal) (surgical removal)

66 0,80,8 22 0,70,7

33 1,21,2 11 1,01,0

Symptomatic injuriesSymptomatic injuries of brain tissueof brain tissue

2020 2,82,8 1111 4,04,0

99 3,63,6 55 4,94,9

MM 11 11 yo. yo. Pilocytic astrocytomaPilocytic astrocytoma 4,5 сс4,5 ссm;m; 15,3 15,3 Gy - Gy - 8585%%..

Symptomatic injury at 5 months (facial paresis + Symptomatic injury at 5 months (facial paresis + vomiting), vomiting),

partially regressed at 10 monthspartially regressed at 10 months, , stable at 33 months.stable at 33 months.MRI at 6 monthsMRI at 6 months

Novalis SRS

Pre-operative

Post-op RT (25 х 2 Gy) Lesion

with edema

2 moths later

at 12 months

F 7 yo. F 7 yo. Pilocytic astrocytomaPilocytic astrocytoma 3,8 ccm; 16 Gy - 80% 3,8 ccm; 16 Gy - 80%

Symptomatic injury (headache + vomiting) at 6 months, Symptomatic injury (headache + vomiting) at 6 months, relieved after 4 months of steroid therapy.relieved after 4 months of steroid therapy.

at 20 months

at 6 months Novalis SRS

Ki-67 > 7 %

FF 14 yo.14 yo. Meningioma Meningioma 2,2 ccm; SRS 17,62,2 ccm; SRS 17,6 Gy - 80%.Gy - 80%.

Symptomatic injury (focal seizures) at 5 monthsSymptomatic injury (focal seizures) at 5 months,, relieved with steroids and carbamazepine.relieved with steroids and carbamazepine.

MRI at 10 months MRI atMRI at 10 months MRI at 1616 monthsmonths

Novalis SRS

F F 35 35 yo. yo. SchwannomaSchwannoma 4,4 ccm; 4,4 ccm; SRSSRS 1144,,4 4 Gy - 80%.Gy - 80%.

*Exacerbation of herpes simplex infection after 6 days *Exacerbation of herpes simplex infection after 6 days with trigeminal neuralgia following 7 months.with trigeminal neuralgia following 7 months.

MRI at 13 monthsNovalis SRS

MRI at 22 months after SRS

FF 14 yo.14 yo. Somatotropinoma Somatotropinoma 7,7 ccm;7,7 ccm;

radiotherapy (25 radiotherapy (25 хх 2 Gy) 6 years ago; SRS 21,6 2 Gy) 6 years ago; SRS 21,6 Gy - 90%. Gy - 90%. Asymptomatic injury (edema)Asymptomatic injury (edema)..

Novalis SRS

FF 35 yo. 35 yo. AVM AVM 0,5 ccm; SRS0,5 ccm; SRS 2 23,4 Gy - 90%.3,4 Gy - 90%.

Symptomatic injury (deterioration of hemiparesis) at 8 Symptomatic injury (deterioration of hemiparesis) at 8 months, months,

no improvement with medications at 24 months.no improvement with medications at 24 months.

MRI at 14 monthsMRI at 14 monthsNovalis SRS

M M 53 53 yo. yo. Pilocytic astrocytomaPilocytic astrocytoma 5 ccm, 5 ccm, 119 Gy - 9 Gy - 50%.50%.

Symptomatic injury (ataxia + nausea) at 3 months,Symptomatic injury (ataxia + nausea) at 3 months, regressed with steroids after next 7 months. regressed with steroids after next 7 months.

MRI at 3 MRI at 3 monthsmonths

Gamma-knife

M 48 yo. M 48 yo. OligodendrogliomaOligodendroglioma 18 18 ccm; 18 Gy - 50%. ccm; 18 Gy - 50%.

Symptomatic injury (epilepsy + raised ICP) at 6 month, Symptomatic injury (epilepsy + raised ICP) at 6 month, ineffective steroid therapy ineffective steroid therapy,, removal of necrosis at 13 removal of necrosis at 13

months.months.

10-Gy vol > 100 10-Gy vol > 100 ccmccm

MRI at 9 monthsMRI at 9 months

Gamma-knife

M 48 yo. M 48 yo. Lung cancer mtsLung cancer mts 6,1 ccm; 6,1 ccm; 2020 Gy - 50%. Gy - 50%. Symptomatic injury (ataxia + hemianopia) at 8 month, Symptomatic injury (ataxia + hemianopia) at 8 month, symptoms relieved after 1 month of dexamethazone.symptoms relieved after 1 month of dexamethazone.

at 5at 5 months 8 months 15 months 8 months 15 months months

Gamma-knife

M 57 yo.M 57 yo. Meningioma 8,2 ccm; Meningioma 8,2 ccm; 1212 Gy - 50%.Gy - 50%.

Symptomatic injury (hemiparesis + raised ICP) at 4 Symptomatic injury (hemiparesis + raised ICP) at 4 month,month,

relieved with dexamethazone (16mg) and mild relieved with dexamethazone (16mg) and mild dehydratation.dehydratation.MRI at 6MRI at 6 monthsmonths Perfusion CT Perfusion CT

CBVCBV

Gamma-knife

SummarySummary

► IncidenceIncidence of radiation injury of brain is a of radiation injury of brain is a function of SRS parameters (dose, volume, function of SRS parameters (dose, volume, selectivity, etc), target location and time of selectivity, etc), target location and time of follow-up.follow-up.

►Higher rateHigher rate with gliomas, high 10- or 12-Gy with gliomas, high 10- or 12-Gy volume of brain irradiated and longer follow-up.volume of brain irradiated and longer follow-up.

► Small radio-lesions in Small radio-lesions in eloquent structureseloquent structures can be symptomatic.can be symptomatic.

►Corticosteroid administration for complication prophylaxis in case of preexisting edema ?