Radiosurgery of Cerebral Cavernomas

Dr. Roberto Martínez Álvarez

Dpt. of Functional Neurosurgery and Radiosurgery Ruber International Hospital , Madrid, Spain

• Vessel formation: - Vasculogenesis

- Angiogenesis

• Vasculogenesis: Formation of primitive vessels in the embryo

• Angiogenesis: Set of processes for the remodeling and expansion of vessels formed in vasculogenesis. Occurs in the embryo and in the adult individual

• Vasculogenesis and angiogenesis are controlled by polypeptides called "growth factors", stimulants and inhibitors, which affect endothelial cells and other elements of the vascular wall

• Angiogenesis starts in endothelial cells and is partly controlled by blood flow conditions

CEREBROVASCULAR MALFORMATIONS:

Genesis and Biology I

CEREBROVASCULAR MALFORMATIONS:

Genesis and Biology II

• The mechanisms of abnormal vessel formation develop on three substrates: - Genetic

- Molecular- Cellular

• Genes control the formation of molecular pathways that promote:

- Vessel formation- Vascular growth- Maintenance of malformations

CEREBROVASCULAR MALFORMATIONS:

CLASSIFICATION

- Arteriovenous vascular malformationsAngiomas (AVMs)

- Cavernous vascular malformationsCavernomas (CCMs)

- Abnormalities of venous developmentVenous angiomas or

Developmental venous anomalies (DVAs)Capillary telangiectasias

ANOMALIES OF VENOUS DEVELOPMENT:VENOUS ANGIOMAS, CAPILLARY TELANGIECTASIES

- Both are variants of normal venous drainage (in telangiectasias, variants of the capillary network)

- They do not cause clinical alterations and when these occur they are due to the presence of other associated malformations (cavernomas)

- MIXED FORMS are frequent, being associated with cavernomas and occasionally arteriovenous malformations

ARTERIOVENOUS VASCULAR MALFORMATIONS:

ANGIOMAS (AVMs)

• They are formed by mature vessels forming a network and by direct arterio-venous communications called fistulas

• They have high blood flow that results in:

- Vascular recruitment

- Arterialization of venous structures

- Gliosis of peripheral nervous tissue

• Lead to severe bleeding from rupture of the vessels of the nidus, from intranidal aneurysms associated or from venous obstruction

Cavernous Malformations: cavernomas (CCMS)

- Are intracranial lesions composed of aberrantly enlarged “cavernous” endothelial channels in the course of repeated haemorrhages of the lesion

- They present a fragile vascular morphology, without mature elements of the vascular wall.

- They do not have high blood flow and they are not usually associated with severe bleeding

AVM

Cavernoma

Cavernous Malformations: cavernomas (CCMS) FEATURES

• They are formed by cavities (caverns) filled by blood and clots

• The formation of the walls of these cavities comprises a single layer of endothelial cells whose basal lamina is anomalous, they are included in a network of dysmorphic connective tissue

• These vascular walls lack "astrocytic feet" (pericytes) in their periphery, they do not have a middle or adventitial layer

• There are hemosiderin deposits at different levels

Pathobiology of Human Cerebrovascular Malformations: Basic Mechanisms

and Clinical Relevance

Judith Gault, Hemant Sarin, Nabil A. Awadallah, Robert Shenkar, Issam A. AwadNeurosurgery 55: 1-17, 2004

Immunohistochemical stains showing dissection of smooth

muscle maturation proteins in cavernomas

CAVERNOMAS (CCMs): Genetic data I

• Familial cavernomatosis is genetically heterogeneous with three described types of altered genes:

• - CCM1: It is the best known, it is located on chromosome 7 (region 7q11.2-21) and 88 mutations have been described, some of them in cases considered sporadic

• - CCM2: Located on chromosome 7 (region 7p13-15), in the process of studying with 8 described mutations.

• - CCM3: Located on chromosome 3 (region 3q25.2-27), pending study.

CAVERNOMAS (CCMs): Genetic data II

• The inheritance of the family cavernomatosis is autosomal dominant

• It is more frequent in families of Hispanic origin

• The presence of these altered genes occurs in: 40% CCM1, 20% CCM2, 40% CCM3

• The approximate penetrance of these genetic alterations is: 88% in CCM1

100% on CCM2

88% in CCM3

CAVERNOMAS (CCMs): Genetic data III

- Changes induced by these genetic alterations:

- Changes in the systems of union and division of endothelial cells by alteration of endothelial growth factors (VEGF: vascular endothelial growth factor)

- Changes in the cellular matrix, mediated by alteration of angiogenic growth factors (FGF2: fibroblast growth factor)

• Natural history has remained unclear several years in part because of difficulty of diagnosing these lesions in cranial CT and angiography.

• 80% of cases are sporadic, without family history

• Single lesions are found in 75% of sporadic cases and between 8-9% of patients with familial history

• The presence of multiple lesions is related to familiar forms

• Patients with a history of previous cerebral irradiation have a tendency to suffer cavernomas

CAVERNOMAS (CCMs): Statistical data I

• The incidence of cavernous malformations (CMs) is estimated at 0,37to 0,5% of the general population.

• The population-based annual detection rate of CCM has beenestimated at 0.56 per 100 000 per year for adults >16 years of age.

• In 10-30% of patients CMs are associated to other vascularmalformations such as developmental venous anomalies (DVAs).

• CMs located deeply in highly eloquent areas, seem to be moreaggressive (risk of hemorrhage:3.8% per patient-year) than superficiallesions (risk of hemorrhage: 0.4% per patient-year), and the bleedingrisk seems to increase during the first months after a bleedingepisode to 34% per patient-year.

CAVERNOMAS (CCMs): Statistical data II

Annual risk of bleeding Calculation: No. of bleeds / No. of patients x average follow-up (in years)%

107 pats out of a cohort of 1311 patient-years of followup.

The prospective bleed ratein patients presentingassymptomatically with CM is 0,08% per patient year

Metaanalysis of 12 natural history studieswith 1610 pats.

Presentation modality: Seizures 30% Hemorrhage: 26%Incidental: 17%Focal déficit: 16%

Pooling 7 studies thatdid not asume CM presence since birththe anual hemorrhagerate was 2,5%

Prior hemorrhage is a significant risk factor for CM bleeding

331 pats studied with a mean follow up of 6,5 years.

Patients presentingwithout hemorrhage,Annual hem. rate 8,7%

Patients initiallypresenting with hem.Annual hem. rate 12,4%

This study verified the adverse predictors for hemorrhage and functional outcomes of thalamic CMs and demonstrated an overall annual symptomatic hemorrhage rate of 9.7% after the initial presentation.

95 cavernomas treated from 1994 to 2014.All patients had experienced at least

1 symptomatic bleeding before Rs

Median length of follow-up 78 m

Pretreatment annual hemorrhage rate was 3.06% annual hemorrhage the first 3-year latency interval: 1.4% 0.16% thereafter ( p = 0.004 )

Best dosage range for preventing bleeding was identified as between 11 and 12 Gy

No permanent neurological morbidity is reported

Results:- Age and Gender distribution-

95 CV Average age: 40 years

Men Women

Age of bleeding episode:

Age (years)

%accumulated

Results- Location -

95 CMs

64 brainstem

13 mesenc 44 pons 7 medulla

31 eloquent areas

12 thalamic 19 other

Results:- Types of Hemorrhage -

No overt bleeding 25 cases

1 overt bleeding 56 cases

Multiple overt bleeding 14 cases

Results:- Complications 7% -

Complicaciones Volume Marginal dose Maxim. dose Recovery

Headache 1346 16 32 Yes

Headache 330 12 24 Yes

Headache 164 12 20 Yes

Mass effect 3400 12 20 Yes

Hemiparesis 4900 11 18 Yes

VI CN* 750 12 20 Yes

VI CN* 2800 11 20 Yes

*VI cranial nerve

Results:- Volume, dose, rebleeding and adverse effects-

Fig 1: Patients treated with 12 Gy or higher didn´t present

rebleeding.

Fig 2: Post-treatment adverse effects appeared over 11 Gy.

Results:- Imaging follow-up-

Yes No Lost FU

39 30 26

Lesion volume regression:

Volume regression average (percentage)

Regression average time (years)

40% 4 years

Results:- 15 years follow-up -

Results:- 11 years follow-up -

Results:- 2 years follow-up -

Stereotactic radiosurgery for AVMs results in progressive luminal thrombosis in response to endothelial proliferation, creation of intraluminal myofibroblasts, and hyalinization and sclerosis of the treated blood vessel walls

Results:

• The mean number of isocenters was 2,63 (Isodose range: 50%-97%) and theaverage target volume was 1,57 cc.

• The mean lesion margin dose was 11,87 Gy (Margin dose range: 8-16 Gy) andthe mean maximum dose was 19,56 Gy (Maximum dose range: 9,5-32 Gy).

• Average patient follow-up was 78 months (Range: 24-204 m.).

• Imaging follow-up after SRS revealed a regression in targeted volume in 39 CMs,no size changes in 30 CMs and unknown imaging status in 26 CMs.

• In 94,7% of patients the post-treatment Karnofsky Functional Scale performancescores remained between 80 and 100.

• Four hemorrhages were documented within 3-year latency period (PL) afterSRS.

Results:- Decrease in Annual Hemorrhage Rate -

2,98%

1,40%

0,16%

0,00%

0,50%

1,00%

1,50%

2,00%

2,50%

3,00%

3,50%

Pre-GKRS Post-GKRS 3-years interval Post-GKRS after 3-yearsinterval

Annual Hemorrhage Rate

p: 0,00007

Results:- Predictive factors -

• Multiple Regression Model, with Akaike`s Information Criterion includingsex, showed statistically significant association between lower marginaldose and bleeding (p-value=0,03) and no association between targetvolume and bleeding (p-value=0,13).

• Volume and margin dose show a weak negative correlation with adverseradiation effects (AREs) (ρ = -0.260, p-value = 0.011).

• AREs couldn´t be related to prescribed radiation isodose, brainstemlocation nor multiple pre-treatment hemorrhages.

• Size reduction seemed to relate with patient’s age (p-value: 0,042) andmaximum dose levels (p-value: 0,028).

Optimal Margin Dose in our series:

• Ideal dose of treatment in our series to avoid bleeding and AREs

11.3 Gy

N SRS FU Marginal dose

AREs HRR(pre/post-SRS)

LP

Kondziolka(1995) 044 GKRS 43.2 16.0 Gy 26.00% 56.501.10% 2 years

A.-Hanjani(1998)

095 PBR 65.0 15.0 Gy 20.60% 17.30 4.50% 2 years

Chang (1998) 057 HI/LINAC 90.0 13.5-20 Gy 7.00% 09.40 1.60% 3 years

Karlsson (1998) 022 GKRS 78.0 18.0 Gy 27.00% NA 5.00% 4 years

Pollock (2000) 017 NA 51.0 18.0 Gy 59.00% 24.80 2.90% 2 years

Liu (2005) 125 GKRS 64.0 12.1 Gy 13.10% NA 3.30% 2 years

Liscák (2005) 107 GKRS 48.0 16.0 Gy 27.00% 02.001.60% 2 years

Lunsford (2010) 103 GKRS 67.8 16.0 Gy 11.65% 32.48 1,06% 2 years

Nagy (2010) 113 GKRS 48.0 12-15 Gy 7.30% 30.50 2.40%02.20 1.30%

2 years

Lee (2012) 49 GKRS 49.0 11.0 Gy 4.10% 31.30 3.33% 2 years

Lisçak (2013) 112 GKRS 85.0 16 Gy 15.50% 06.50 0.50% 2 years

Kim (2015) 039 GKRS 48.0* 13 Gy 10.30% 33.60% 2.04% 2 years

Azimi (2015) 100 GKRS 42.2 13 Gy 12.00% 04.10%1.90% 2 years

Sager (2015) 052 LINAC 60.0 15 Gy NA 39.00%1.21% NA

Ferdorcsák (2015) 051 GKRS NA NA NA 21,70% 0%(?) 2 years

Liu H. B. (2016) 043 GKRS 36.0 11.90 2.32% 25.00% 1.85% 2 years

Our series 095 GKRS 78 11.8 Gy 7% 2.98 0.16% 3 years

Post-treatment hemorrhage rate in literature:

Foresplot shows the post-treatment hemorrhage rate in literature and its estimated variance and respective condifence intervale. The rhombus represents global hemorrhage rate average of 0.97(p-value=0,005). REML (restricted maximum likelihood) method showed an heterogeneity index of I2=46% in results of different series.

Conclusions:

• Marginal dose was the only variable that showed predictive value forbleeding (p-value = 0.030) in our patients.

• Highly conformal GKRS with lower margin dose average (margin doseaverage: 11.3 Gy) could be related to safety of this treatment in recent series.In spite of descriptive analysis showed a trend towards relating adverseradiations effects with higher margin isodose, we didn't find statisticallysignificant association in our study.

• Incomplete knowledge of natural history of the disease makes impossible toknow which CMs may bleed repeatedly for some interval and then ceaseindependently whether treated or not.

• SRS is an alternative to observation of symptomatic CMs with high-riskbleeding rate and high-risk microsurgery resection.