**Radiosurgical Treatment of Intracranial Meningiomas: Update 2011.**

M. Gerosa et al.\*

*Multidisciplinary Neuro-Oncologic Group of Verona, Department of Neurosurgery, University Hospital (AOUI) of Verona, Verona, Italy* 

## **1. Introduction**

44 Gamma Knife Radiosurgery

[42] Sperduto P, Berkey B, Gaspar L et al. (2008). "A new prognostic index and comparison

patients in the RTOG database". " Int J Radiat Oncol Biol Phys 70: 510-514". [43] Sperduto P, Kased N, Xu R et al. (2011). "Effect of Tumor Subtype on Survival and the

Metastases". Int J Radiat Oncol Biol Phys April 14, (epub ahead of print). [44] Vesagas, T. S., J. A. Aguilar, et al. (2002). "Gamma knife radiosurgery and brain

[45] Villà S, Weber DC, Moretones C, Mañes A et al. (2011). "Validation of the new Graded

[46] Weltman E, Salvajoli J, Brandt R et al. (2000). "Radiosurgery for brain metastases: a

[47] Weltman E, Salvajoli J, Brandt R et al. (2001) "Radiosurgery for brain metastases: Who

[48] Wowra, B., M. Siebels, et al. (2002). "Repeated gamma knife surgery for multiple brain

[49] Yamamoto, M., M. Ide, et al. (2002). "Gamma Knife radiosurgery for numerous brain metastases: is this a safe treatment?" Int J Radiat Oncol Biol Phys 53(5): 1279-1283. [50] Yu, C. P., J. Y. Cheung, et al. (2005). "Prolonged survival in a subgroup of patients with

may not benefit?." " Int J Radiat Oncol Biol Phys 51: 1320-1327".

metastases from renal cell carcinoma." J Neurosurg 97(4): 785-793.

507-510.

Radiat Oncol. Mar 2; 6:23.

to three other indices for patients with brain metastases: an analysis of 1960

Graded Prognostic Assessment for Patients With Breast Cancer and Brain

metastases: local control, survival, and quality of life." J Neurosurg 97(5 Suppl):

Prognostic Assessment scale for brain metastases: a multicenter prospective study."

score index for predicting prognosis." " Int J Radiat Oncol Biol Phys 46: 1155-1161".

brain metastases treated by gamma knife surgery." J Neurosurg 102 Suppl: 262-265.

Meningiomas account for 16%-25% of all intracranial tumors, and quite often they rank amongst the most frequent neuro-oncological diagnostic subgroups in European or American registries (4, 5, 8, 54) As regards their natural history, (23, 29, 46, 55, 56, 59, 61) the few reported series of conservatively managed symptomatic meningiomas–bearing adequate FU- have documented a consistent progression in approximately one-third of patients, although in a wide spectrum of variability (TABLE 1).

The average annual incidence is 5-6 new cases per 100,000 (F/M ratio roughly 3:1) and it is lower in pediatrics, even though younger patients may show quite malignant oncotypes (4, 5, 8, 24, 43, 46, 59, 61, 64, 71, 73, 81). However, younger patients may show quite aggressive oncotypes (64, 71, 73). Growing human, sanitary and social costs are more pronounced in females because of the quoted demographic data.

At uni-multivariate analysis, the main factors putatively associated with more- or-less pronounced aggressiveness seem to be represented by younger age and T2-hyperintensity, or by presence of calcifications, respectively (TABLE 1). As expected, grade 2 and 3 meningiomas entail a more severe prognosis (30, 39, 40, 48, 51, 56, 62), thereby justifying the advocated multidisciplinary treatments in such instances ( 30, 54 62, 84,85 ).

 \* R. Foroni1, M. Longhi1, A. De Simone1, F. Alessandrini2, P. Meneghelli1, B. Bonetti3, C. Ghimenton4,

T. Sava5, S. Dall'Oglio6, A. Talacchi1, C. Cavedon7, F. Sala1, R. Damante1, F. Pioli6, S. Maluta6 and

A. Nicolato1

*<sup>1</sup>Department of Neurosurgery,* 

*<sup>2</sup>Department of Neuroradiology,* 

*<sup>3</sup>Department of Neurology,* 

*<sup>4</sup>Department of Neuropathology,* 

*<sup>5</sup>Department of Medical Oncology,* 

*<sup>6</sup>Department of Radiation Oncology,* 

*<sup>7</sup>Department of Medical Physics,* 

*Multidisciplinary Neuro-Oncologic Group of Verona, University Hospital (AOUI) of Verona, Verona, Italy*

Radiosurgical Treatment of Intracranial Meningiomas: Update 2011. 47

Indeed, despite surgical advances, whenever these tumors are infiltrating the skull base, cranial nerves, or vascular structures, complete resection may not be feasible without unacceptable morbidity and sometimes mortality rates. Considering some of the largest published series, gross total removal of basal meningiomas sounds achievable in 60%- 87.5% of the patients with 30%-56% of severe complications - particularly frequent in grade 2-3 histotypes - and a median postoperative mortality rate of 3.6 % (0%-9%) (11, 12, 45, 48, 75, 76, 79, 80). The main factors conditioning the extent of removal in skull base locations have been extensively analyzed in the literature, thereby creating the "resectability grading" where the final score represents the sum of each of the most relevant limiting factors: from cranial nerve involvement to vessel encasement, from extrafossa invasion to

Table 2. Meningiomas: analysis of recurrence rate after gross total removal (GTR: TABLE 2a)

The observed wide spectrum of recurrence rates (from 0 to 17%), is seemingly linked not only to the pre-existing W.H.O.'s and Simpson's grade, but also to the duration of follow up periods, although the latter is an often disregarded/underestimated parameter in the

The non negligible problems with surgical radicality in crucial sites, may be further complicated by the presence of "aggressive" cytotypes, most often responsible for early

previous radiation treatments (45, 63, 74, 78, 82, 86).

Table 2a. (53, 10, 77)

Table 2b. (83, 53, 10, 77)

compared to subtotal removal (STR: TABLE 2b)

recurrences shortening patients' survival (TABLE 2&3).

literature (10, 53, 69, 70, 75, 76, 79).

## **2. Treatment options**

Surgery still represents the mainstay in the specific neurosurgical armamentarium. Indeed, whenever feasible, a Simpson grade 1 resection of the tumor should be considered the golden therapeutic standard, reducing immediately any mass effect, and alleviating clinical signs and symptoms (2, 10, 11, 33, 41, 45, 52- 54 , 75, 80).


Table 1. Natural history of meningiomas. Reported growth rates in conservatively treated series.

In facts, local recurrence rates at 10 year-follow up are **directly related** to Simpson's grade of radicality, with 10-33% after complete resection (Simpson 1-2), and 55-75% after partial-tominimal removal (i.e. Simpson 3-6) (33, 45, 48, 52, 53, 75, 80). This seems particularly true in the vast majority of convexity meningiomas, whereas results are less warranted in critical locations, like in skull base tumors.

Indeed, despite surgical advances, whenever these tumors are infiltrating the skull base, cranial nerves, or vascular structures, complete resection may not be feasible without unacceptable morbidity and sometimes mortality rates. Considering some of the largest published series, gross total removal of basal meningiomas sounds achievable in 60%- 87.5% of the patients with 30%-56% of severe complications - particularly frequent in grade 2-3 histotypes - and a median postoperative mortality rate of 3.6 % (0%-9%) (11, 12, 45, 48, 75, 76, 79, 80). The main factors conditioning the extent of removal in skull base locations have been extensively analyzed in the literature, thereby creating the "resectability grading" where the final score represents the sum of each of the most relevant limiting factors: from cranial nerve involvement to vessel encasement, from extrafossa invasion to previous radiation treatments (45, 63, 74, 78, 82, 86).


Table 2a. (53, 10, 77)

46 Gamma Knife Radiosurgery

Surgery still represents the mainstay in the specific neurosurgical armamentarium. Indeed, whenever feasible, a Simpson grade 1 resection of the tumor should be considered the golden therapeutic standard, reducing immediately any mass effect, and alleviating clinical

> Average growth rate

(1998) (23)] 35 74 4 (11.4) 3.2 mm/year Calcification

37 50.4 9 (24.3) 1.36 cm3/year Younger age,

41 43 14 (34) 0.796 cm3/year Younger age, T2

43 67 16 (37) 4 mm/year Younger age,

Table 1. Natural history of meningiomas. Reported growth rates in conservatively treated

In facts, local recurrence rates at 10 year-follow up are **directly related** to Simpson's grade of radicality, with 10-33% after complete resection (Simpson 1-2), and 55-75% after partial-tominimal removal (i.e. Simpson 3-6) (33, 45, 48, 52, 53, 75, 80). This seems particularly true in the vast majority of convexity meningiomas, whereas results are less warranted in critical

67 >60 25 (37.3) 1.9 mm/year T2

Factors commonly associated with an aggressive cell kinetic

Factors commonly observed in resting tumors

hyperintensity Calcification

hyperintensity Calcification

hyperintensity Calcification

Calcification

Calcification, smaller tumors

Larger size, T2 hyperintensity, male sex

larger tumors

sphenoid ridge

**2. Treatment options** 

No. of patients

(2000) (59) 40 41.8 14 (35)

locations, like in skull base tumors.

Author (year) (Reference)

Olivero et al. (1995) (61)

Go et al.

Kuratsu et al. (2000) (43)

Niiro et al.

Yoneoka et al. (2000) (81)

Nakamura et al. (2003) (55)

Herscovici et al. (2004) (29)

Yano and Karatsu (2006) (80)

series.

signs and symptoms (2, 10, 11, 33, 41, 45, 52- 54 , 75, 80).

Mean follow-up (mo)

No. (%) showing growth

45 32 10 (22.2) 2.4 mm/year

63 27.8 20 (31.7) T2


Table 2b. (83, 53, 10, 77)

Table 2. Meningiomas: analysis of recurrence rate after gross total removal (GTR: TABLE 2a) compared to subtotal removal (STR: TABLE 2b)

The observed wide spectrum of recurrence rates (from 0 to 17%), is seemingly linked not only to the pre-existing W.H.O.'s and Simpson's grade, but also to the duration of follow up periods, although the latter is an often disregarded/underestimated parameter in the literature (10, 53, 69, 70, 75, 76, 79).

The non negligible problems with surgical radicality in crucial sites, may be further complicated by the presence of "aggressive" cytotypes, most often responsible for early recurrences shortening patients' survival (TABLE 2&3).

Radiosurgical Treatment of Intracranial Meningiomas: Update 2011. 49

on the hyperostotic bone might have the same meaning of Simpson's grade 1 in surgical

3. a deeper radiobiological experience. Radiosurgery, like most radiation treatments, hitting the biological target, results in the formation of free radicals as electrons are freed from their atoms. Their main in vivo effect is closely related to a variety of local conditions: first of all the particular oncotype and its cellular peculiarities ("alphabeta ratio" (35), superoxide-enzyme characterization, sister–chromatide exchange potential etc.) defining the radio-sensitivity; then the quality and quantity of radiation dosimetry, the targeted volume etc., up to the microscopic model of energy deposition. On the basis of these features, meningiomas mostly belong to relatively radiosensitive, "late responding tissues" (LRT) frequently exploiting local hypoxic

As a consequence effective dosages are in the lower range, not far from normal cell radiosensitivity thresholds, whilst the time-interval for the effect is close to maximum in


It is generally accepted that the putative mechanism of action of SRS is intimately dependent not only upon the mentioned technical variables (dose-volume integral, timing, target cytology), but as well as upon the goal we are pursuing ("tumor growth control", necrotic evolution, "ephaptic block" etc.) (38, 39, 40). As regards meningiomas, routine protocols are focused on "Tumor Growth Control" (TGC) probably obtained through a combined mechanism: 1. Direct cytotoxicity, presumably promoting apoptosis; 2. Damage to the neoplastic vascular supply, mediated by inhibited growth factors (VEGF, EGF, Factor 8th etc.) 3. Inactivation/destruction of hormonal receptors (e.g. Octreotide- r) (57, 58). **Moreover, it should be stressed that meningiomas located in highly vascularized-oxygenated regions of the brain (cavernous sinus, sagittal sinus etc), due to still poorly known mechanisms (e.g. mutilation of the the superoxide dismutase chain etc.)** usually exibit a more pronounced radiosensitivity, with sometimes spectacular

If we examine clinical and radiological results in the largest published series of intracranial meningiomas treated during the last decade with different radiosurgical techniques (TABLE 4), some qualifying tenets of these therapeutic approaches appear certainly significant and

A. The overall neuro-radiological results are rewarding and stable. Unfortunately, the available literature is of poor statistical quality, also because of the difficulties in performing prospective randomized, adequately stratified clinical trials. Therefore most comparative analyses are based on EBM Class III Data, with only a few studies presenting Class II informations. However, given the definition of "Local Tumor Control" as a post-treatment computerized target volume equal-to or smaller than the original, the 5yr actuarial Tumor Control Rates after GKRS range from 86.2% to

meningiomas actually representing approximately one third of these patients.

shields (3, 13, 30, 49), particularly in the elderly (59).

vivo doubling time (3, 7, 16, 31, 68, 69, 70, 71, 72).

approaches (67).

results (Fig. 1).

97.9%.

reliable.


Table 3. Recently published series of malignant meningiomas: 5- 10 yr survival.

Finally, also the tackling issues of meningiomatosis, contribute to explain the special momentum of combined, multidisciplinary approaches including Gamma Knife Radio Surgery (GKR).

## **3. Gamma knife radiosurgery**

The fundamental reasons for the growing role of this technique, particularly in highly critical intracranial meningiomas, may be briefly summarized as follows:


The "ideal" – i.e. the most biologically justified – targeting dose- volume in these peculiar lesions, is still a matter of debate, with a spectrum of options: from including "only" the gross, T1 contrast enhancing tumor, plus a supposedly infiltrated margin of a few mm (39,40,50), up to the controversial inclusion either of the "dural tail", or of the hyperostotic bone. However, the former - according to extremely refined studies – has been shown to be essentially composed by hypervascular dura with surprisingly none of the expected tumor colonies (34). The latter - according to Pieper- should be almost constantly (25/26 cases) infiltrated, even in presence of negative imaging (67). In these cases, ablative radiosurgery

0% 10 yr

35% 10 yr

15% 10 yr

Author (ref) Period N.Pts Mal. Definition Survival Harris (27) 1987-2001 12 WHO 2000 59% 5yr

Perry (64-65) 1970-1997 27 Frank anaplasia 32% 5yr Hug (30) 1973-1995 16 WHO 1993 51% 5yr Palma (62) 1951-1986 29 WHO 1993 64% 5yr

Ware (84) 1988-2002 17 WHO 1993 59% 5 yr

Ojemann (60) 1991-1999 22 WHO 1993 40% 5 yr Goldsmith (24) 1967-1990 23 Unique grading scheme 58% 5 yr.

Finally, also the tackling issues of meningiomatosis, contribute to explain the special momentum of combined, multidisciplinary approaches including Gamma Knife Radio

The fundamental reasons for the growing role of this technique, particularly in highly

1. fine tuning of the dosimetry planning. With the advent of hardware and software stereotactic sophistication, the process of 3D recognition of the tumor – as well as to spare the adjacent critical structures has gradually become more and more refined. A major role to this regard has been played by image co-registration, morpho-functional integration (functional MRI / spectroscopy, specific metabolic PET scan mapping etc.) on one side, and by the use of "hybrid shots" with the new "Perfexion" whenever

2. the introduction of dedicated algorhitms accurately "driving" the dose planning system, with probabilistic models including stockastic monitoring, quadrature-sum analysis (20) and linear-quadratic formalisms (32). These techniques, and the concomitant diffusion of phantom studies, have repeatedly confirmed the reliability of such referrals, consistently improving the main conformity indexes. To date, the recommended "surface- or "peripheral "doses" for meningiomas range from 11 - to - 15

The "ideal" – i.e. the most biologically justified – targeting dose- volume in these peculiar lesions, is still a matter of debate, with a spectrum of options: from including "only" the gross, T1 contrast enhancing tumor, plus a supposedly infiltrated margin of a few mm (39,40,50), up to the controversial inclusion either of the "dural tail", or of the hyperostotic bone. However, the former - according to extremely refined studies – has been shown to be essentially composed by hypervascular dura with surprisingly none of the expected tumor colonies (34). The latter - according to Pieper- should be almost constantly (25/26 cases) infiltrated, even in presence of negative imaging (67). In these cases, ablative radiosurgery

Table 3. Recently published series of malignant meningiomas: 5- 10 yr survival.

critical intracranial meningiomas, may be briefly summarized as follows:

dealing with crucial targeting (7, 36, 50, 57, 58, 66).

Surgery (GKR).

**3. Gamma knife radiosurgery** 

Gy (16, 36, 37, 41, 47, 49, 54, 72).

on the hyperostotic bone might have the same meaning of Simpson's grade 1 in surgical approaches (67).

3. a deeper radiobiological experience. Radiosurgery, like most radiation treatments, hitting the biological target, results in the formation of free radicals as electrons are freed from their atoms. Their main in vivo effect is closely related to a variety of local conditions: first of all the particular oncotype and its cellular peculiarities ("alphabeta ratio" (35), superoxide-enzyme characterization, sister–chromatide exchange potential etc.) defining the radio-sensitivity; then the quality and quantity of radiation dosimetry, the targeted volume etc., up to the microscopic model of energy deposition. On the basis of these features, meningiomas mostly belong to relatively radiosensitive, "late responding tissues" (LRT) frequently exploiting local hypoxic shields (3, 13, 30, 49), particularly in the elderly (59).

As a consequence effective dosages are in the lower range, not far from normal cell radiosensitivity thresholds, whilst the time-interval for the effect is close to maximum in vivo doubling time (3, 7, 16, 31, 68, 69, 70, 71, 72).


It is generally accepted that the putative mechanism of action of SRS is intimately dependent not only upon the mentioned technical variables (dose-volume integral, timing, target cytology), but as well as upon the goal we are pursuing ("tumor growth control", necrotic evolution, "ephaptic block" etc.) (38, 39, 40). As regards meningiomas, routine protocols are focused on "Tumor Growth Control" (TGC) probably obtained through a combined mechanism: 1. Direct cytotoxicity, presumably promoting apoptosis; 2. Damage to the neoplastic vascular supply, mediated by inhibited growth factors (VEGF, EGF, Factor 8th etc.) 3. Inactivation/destruction of hormonal receptors (e.g. Octreotide- r) (57, 58). **Moreover, it should be stressed that meningiomas located in highly vascularized-oxygenated regions of the brain (cavernous sinus, sagittal sinus etc), due to still poorly known mechanisms (e.g. mutilation of the the superoxide dismutase chain etc.)** usually exibit a more pronounced radiosensitivity, with sometimes spectacular results (Fig. 1).

If we examine clinical and radiological results in the largest published series of intracranial meningiomas treated during the last decade with different radiosurgical techniques (TABLE 4), some qualifying tenets of these therapeutic approaches appear certainly significant and reliable.

A. The overall neuro-radiological results are rewarding and stable. Unfortunately, the available literature is of poor statistical quality, also because of the difficulties in performing prospective randomized, adequately stratified clinical trials. Therefore most comparative analyses are based on EBM Class III Data, with only a few studies presenting Class II informations. However, given the definition of "Local Tumor Control" as a post-treatment computerized target volume equal-to or smaller than the original, the 5yr actuarial Tumor Control Rates after GKRS range from 86.2% to 97.9%.

Radiosurgical Treatment of Intracranial Meningiomas: Update 2011. 51

2001 Pendl et al 63 Graz (Austria) 197 (198 tumors) GK 98 (for 164

2002 Nicolato et al 58 Verona (Italy) 122 GK 96.5 at 5yr 2003 Chang et al1 6 Seoul (Korea) 179 (194 tumors) GK 97.1

2004 DiBiase et al 13 Camden (USA) 137 GK 86.2 at 5 yr

2005 Kreil et al41 Graz (Austria) 200 GK 98.5 at 5yr

2008 Iwai et al31 Osaka (Japan) 108 GK 93 at 5 yr

2009 Colombo et al19 Vicenza (Italy) 199 CyberKnife 93.6 at 5yr

Table 4. GKR-, PROTON BEAMLINAC- and Cyberknife-based stereotactic radiosurgery in meningiomas. Synopsis of the largest published series of the last two decades comparing

140 (117 benign, 23 malignant)

which 106 benign)

**technique**

Proton Beam

190 (206 tumors) GK 93 for the benign,

330 (356 tumors) GK 94

277 (309 tumors) GK 87 (typ), 49 (atyp),

211 (243 tumors) GK 86.3 at 4yr

368 (400 tumors) GK 98 at 5 yr

972 (1,045 tumors) GK 97 (ben) at 5yr

115 GK 87 at 5 yr

101 GK 95.5% in cav.sin.

210 LINAC 96 for benign,

Graz (Austria) 121 GK 98.3

**LTC % (5 yr)** 

89 (ben), 48 (mal)

tumors

patients)

at 5 years

68 for the atypical and 0 for the malignant tumors

77 for atypical and 19 for malignant tumors at 5 yr

0 (mal) at 5 yr

98.4% in post.fossa

LINAC 89.3 for the benign

 **Authors Group No. Pts. SRS** 

San Francisco (USA)

1998 Hakim et al (26) Boston (USA) 127 (155 tumors, of

(USA)

(USA)

Gainesville (USA)

(United Kingdom)

(Germany)

Komaki, (Japan)

Republic)

Pittsburgh (USA)

Sapporo (Japan)

Stafford et al 77 Rochester

**Pubblication Year** 

2001

1994 Goldsmith et al (24)

2002 Eustacchio et al18

2005 Friedman et al.21

2007 Hasegawa et al128

2008 Kondziolka et al139-40

2009 Takanashi et al178

local tumor control rates.

2003 Pollock et al 69-70 Rochester

2005 Malik et al49 Sheffield

2007 Feigl et al19 Hannover

2007 Kollová et al37 Prague (Czech

Fig. 1. Left cavernous sinus meningioma before (top) and two years after GKRS. Note the drastic shrinkage of the tumor, not unusual in these locations.

Furthermore, in GKR treated patients, primary or "imaging diagnosed" meningiomas share a significantly higher 5yr-PFS (87%-95%) than recurrences (34%-97%).

B. Clinical outcome usually matches these observations, also in our experience (122). Adopting the concept of clinical improvement as the resolution of neurological symptoms, and/or increased pre-operative performances, the vast majority of cases shows stable or improved KPS and neurological gradings at 5-7 years or longer FU. A recent review published by the Pittsburgh Gamma Knife Center (39, 40) confirms in a cohort of 972 patients, with a long term follow up (for some of them up to 20 years) an overall tumor control rate up to 97% a definitively low overall morbidity rate (7.7%) slightly higher for crucial locations such as the cavernous sinus and petroclival region.

As a rule, the cytological grading is the main determinant of the radiosurgical effectiveness. Malignant meningiomas maybe extremely aggressive (Fig. 2) – as mentioned above, with marked endovascular infiltration and neoangiogenesis, requiring multimodality management that include resection, fractionated radiation therapy, brachytherapy, and proton-photon therapy (84, 85, 86).

Similarly, patients with benign histotypes (gr. 1) are usually characterized by 5yr actuarial tumor control rates (87%-96%) much higher than those with atypic (49%-77%) or anaplastic (0%-19%) lesions (21, 24, 37, 49, 63, 73, 77). As shown in (TABLE 4), the still limited number of reports with a mean follow up period of 7-10 years have consistently confirmed these differential LTC levels (3, 15, 41, 63, 70)


Fig. 1. Left cavernous sinus meningioma before (top) and two years after GKRS. Note the

share a significantly higher 5yr-PFS (87%-95%) than recurrences (34%-97%).

Furthermore, in GKR treated patients, primary or "imaging diagnosed" meningiomas

B. Clinical outcome usually matches these observations, also in our experience (122). Adopting the concept of clinical improvement as the resolution of neurological symptoms, and/or increased pre-operative performances, the vast majority of cases shows stable or improved KPS and neurological gradings at 5-7 years or longer FU. A recent review published by the Pittsburgh Gamma Knife Center (39, 40) confirms in a cohort of 972 patients, with a long term follow up (for some of them up to 20 years) an overall tumor control rate up to 97% a definitively low overall morbidity rate (7.7%) slightly higher for crucial locations such as the cavernous sinus and petroclival region. As a rule, the cytological grading is the main determinant of the radiosurgical effectiveness. Malignant meningiomas maybe extremely aggressive (Fig. 2) – as mentioned above, with marked endovascular infiltration and neoangiogenesis, requiring multimodality management that include resection, fractionated radiation therapy, brachytherapy, and

Similarly, patients with benign histotypes (gr. 1) are usually characterized by 5yr actuarial tumor control rates (87%-96%) much higher than those with atypic (49%-77%) or anaplastic (0%-19%) lesions (21, 24, 37, 49, 63, 73, 77). As shown in (TABLE 4), the still limited number of reports with a mean follow up period of 7-10 years have consistently confirmed these

drastic shrinkage of the tumor, not unusual in these locations.

proton-photon therapy (84, 85, 86).

differential LTC levels (3, 15, 41, 63, 70)


Table 4. GKR-, PROTON BEAMLINAC- and Cyberknife-based stereotactic radiosurgery in meningiomas. Synopsis of the largest published series of the last two decades comparing local tumor control rates.

Radiosurgical Treatment of Intracranial Meningiomas: Update 2011. 53

D. A comparative analysis of Cyberknife-based (9,44) radiosurgical experiences in meningiomas versus GKR experiences clearly shows that follow up period is longer for GKR – several reports reaching 8-10 years mean FU vs. 5-6 years for Linac series. Targeted tumor volumes are extremely variable with both approaches, whereas the relative marginal dosages (12-15 Gy) as well as the tumor control rates (usually over 90%) are quite similar. The incidence of sequelae with both techniques is quantitatively (3-13%) and qualitatively reasonable, severe neurological worsening is extremely rare,

E. **Oncogenicity**. The relative risk of carcinogenesis after radiosurgery in the central nervous system has been calculated by means of probabilistic methods, and varies from 1.57 to 8.75 for a dose of 1 Gy, increasing in time up to 18.4 between 20 and 25 years (7, 55). The long-term (30 year) risk of newer radiation induced tumors in meningioma patients has been estimated in 1 per 1,000 treated patients (4, 5, 24, 42, 55). The natural incidence of new gliomas in the population (1/10,000 every year), and the number of meningiomas treated over 3 decades with SRS worldwide (75,000) must be the basic reference for any reliable statistical evaluation. As a consequence, the so far extremely rare (4 cases) reported instances of malignant brain tumors diagnosed in SRS - treated meningioma patients are probably an underestimation of the real incidence, that,

however, does not seem to defray further development of this technique.

[1] Abeloos L, Levivier M, Devriendt D, et al: Internal carotid occlusion following gamma

[2] Bambakidis NC, Kakarla UK, Kim LJ, et al: Evolution of surgical approaches in the

[3] Bledsoe JM, Link MJ, Stafford SL, et al: Radiosurgery for large-volume (> 10 cm3) benign

[4] Central Brain Tumor Registry in the United States: Statistical report: primary brain

[5] Central Brain Tumor Registry of the United States: Statistical report: primary brain

[6] Chang JH, Chang JW, Choi JY, et al: Complications after gamma knife radiosurgery for benign meningiomas. J Neurol Neurosurg Psychiatry 74:226-230, 2003. [7] Clark BG, Candish C, Vollans E, et al: Optimization of stereotactic radiotherapy

[8] Claus EB, Bondy ML, Schildkraut JM, et al: Epidemiology of intracranial meningioma.

[9] Colombo F, Casentini L, Cavedon C, et al: Cyberknife radiosurgery for benign meningiomas: short-term results in 199 patients. Neurosurgery 64:A7-13, 2009.

treatment delivery technique for base-of-skull meningiomas. Med Dosim 33:239-

tumors in the Unites States, 1992-1997. Hinsdale, Il: CBTRUS, 2001.

tumors in the United States, 1998-2002. Hinsdale, Il: CBTRUS, 2005.

knife radiosurgery for cavernous sinus meningioma. Stereotact Funct Neurosurg

treatment of petroclival meningiomas: a retrospective review. Neurosurgery

dosimetry area (1, 15).

with no reported mortality.

**4. References** 

85:303-306, 2007.

247, 2008

62(Suppl 3):1182-1191, 2008

meningiomas. J Neurosurg Sept 18, 2009

Neurosurgery 57:1088-1095, 2005.

d. finally, potential problems with undue hotspots on strategic vessels within the

Fig. 2. Anaplastic (gr.3) meningioma. Note the pronounced endo-perivascular tumor cell coating.

Furthermore, it is worth stressing that – even treating larger volumes – either with reduced dosages or with fractionated schedules, the literature shows no evidence of significantly increased "Adverse Radiation Effects" ("ARE"). Probably because the risk of "ARE" gradually subsides with lower prescription doses (3, 18, 19, 22, 31, 38, 47, 49, 64, 65, 70).

	- a. The satellite edema, particularly pronounced in the convexity regions or in parasagittal locations and rarely documented in skull base tumors, probably represent the dominant figure in the early stages of the "Peritumoral Imaging Changes". The main conditioning factors that may heavily influence the severity of these processes, are essentially related to the specific radiosurgical parameters: e.g. dose volume integral, conformity index etc. (6, 20, 22, 56, 72, 83, 86) However, recent reports have emphasized the extremely high chances to maintain adequate LTC rates – without increasing side effects- by treating larger meningiomas with either fractionated schedules or reduced dosages (3, 13, 18, 19, 22, 24, 31, 32).
	- b. the controversial or disappointing results obtained in atypic and anaplastic lesions (17, 25, 27, 30, 51, 73), sometimes characterized by intra- or extraneuraxis metastatization (17) or by enhanced growth after radiosurgery (6, 14, 42);
	- c. the still pronounced morbidity rate of this technique on sensory nerves (6, 14, 77).

## **4. References**

52 Gamma Knife Radiosurgery

Fig. 2. Anaplastic (gr.3) meningioma. Note the pronounced endo-perivascular tumor cell

Furthermore, it is worth stressing that – even treating larger volumes – either with reduced dosages or with fractionated schedules, the literature shows no evidence of significantly increased "Adverse Radiation Effects" ("ARE"). Probably because the risk of "ARE" gradually subsides with lower prescription doses (3, 18, 19, 22, 31, 38, 47, 49, 64, 65, 70).

C. Nonetheless, also in meningioma radiosurgical treatments, several limits, pitfalls and

metastatization (17) or by enhanced growth after radiosurgery (6, 14, 42); c. the still pronounced morbidity rate of this technique on sensory nerves (6, 14, 77).

a. The satellite edema, particularly pronounced in the convexity regions or in parasagittal locations and rarely documented in skull base tumors, probably represent the dominant figure in the early stages of the "Peritumoral Imaging Changes". The main conditioning factors that may heavily influence the severity of these processes, are essentially related to the specific radiosurgical parameters: e.g. dose volume integral, conformity index etc. (6, 20, 22, 56, 72, 83, 86) However, recent reports have emphasized the extremely high chances to maintain adequate LTC rates – without increasing side effects- by treating larger meningiomas with either fractionated schedules or reduced dosages (3, 13, 18, 19, 22, 24, 31, 32). b. the controversial or disappointing results obtained in atypic and anaplastic lesions (17, 25, 27, 30, 51, 73), sometimes characterized by intra- or extraneuraxis

risks remain to be tackled. Quoting some of the most intriguing:

Anaplastic (Gr. 3) Meningioma

coating.


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**4** 

*Korea* 

**Gamma Knife Radiosurgery for the Vestibular** 

Vestibular schwannomas are slow-growing, benign tumours. Microsurgery has been the standard treatment for vestibular schwannoma over the past 30 years. Following the introduction of stereotactic radiosurgery for the treatment of vestibular schwannoma in 1969, its increasing use worldwide had led to its acceptance by many as a safe and efficient alternative to microsurgery. The primary advantages of stereotactic radiosurgery are its

Because the cerebello-pontine angle is composed of many important cranial nerves and vessels, planning quality is expressed as various indices such as conformity or homogeneity that are regarded as being related to the development of complications. Improved technology and the development of the new gamma knife radiosurgery units—such as the automatic positioning system and the fusion technique in the gamma plan—increase the planning accuracy of the irradiated target area. However, the relationship with the course of the response of the tumour and the complication rate remains poorly understood. In this chapter, we will review how the high conformity indices contribute to the post-radiosurgery

With regard to the complications of stereotactic radiosurgery (despite the many benefits that allow it replace microsurgery as a primary treatment modality), additional research is needed to reduce the complications that are associated with stereotactic radiosurgery in order to improve patient quality of life. Complications that are associated with stereotactic radiosurgery for vestibular schwannoma include hearing deficits, facial palsy, hydrocephalus, and brain stem damage, although the incidence of some of these conditions is much lower than with microscopic open surgery. We reviewed complications and their risk factors (with a particular emphasis on hydrocephalus) from our experience of gamma

Regarding hydrocephalus, this complication can occur at various stages during the natural course of a vestibular schwannoma. The reported incidence ranges from 3.7% to 15% of cases (Atlas et al., 1996; Litvack et al., 2003). Large vestibular schwannomas sometimes cause obstructive hydrocephalus; however, CSF malabsorption may be the cause of communicating-

safety in terms of morbidity and its high tumour control rate.

knife radiosurgery for the treatment of vestibular schwannoma.

course of the disease by analysing the literature.

**1. Introduction** 

**Schwannomas, Technical Considerations** 

**and Hydrocephalus as a Complication** 

Seong Hyun Park, Jaechan Park and Jeong Hyun Hwang *Department of Neurosurgery, Kyungpook National University Hospital* 

Sung Kyoo Hwang, Kisoo Park, Dong Hyun Lee,

