**Stereotactic Radiosurgery for Gliomas**

Mehmet Tönge and Gökhan Kurt

*Gazi University, Department of Neurosurgery Turkey* 

#### **1. Introduction**

The idea of stereotactic radiosurgery (SRS) was first conceived in 1951 by Swedish neurosurgeon Lars Leksell. Focus of his idea was to destroy the surgically inaccessible intracranial tissues or lesions with single fraction high-dose radiation obtained from multiple radiation beams directed to target by stereotactic instruments. He designed the first prototype of gamma knife with Larsson in the light of this idea and performed on his first patient in a nuclear building in 1967. Device was installed at Sophiahemmet hospital in Karolinska – Sweden in the following year. Although only a limited number of patients were treated with gamma knife until 80's, the technique became more popular afterwards and pervaded all around the world. By the time, different radiosurgical devices were developed (Pollock & Brown, 2005; Stieber & Ellis, 2005).

SRS was also used in the management of gliomas as well as many other intracranial lesions for years. Some data acquired despite the lack of reported large case series and long term follow up results. Gliomas are believed to arise from neuroglial cells which encounter the most frequent intracranial tumors in different series, constitute 45-60% of all intracranial tumors. Gliomas have astrocytic, oligodendroglial, ependymal and mixed subtypes. They are also graded I to IV according to histological and clinical behavior. Whereas the grade I and II are accepted as "low grade", the grade III and IV are "high grade" gliomas (Louis et al., 2007). However a portion of low grade gliomas (LGG) are curable by means of current multimodal treatment techniques, the main goal in high grade gliomas (HGG) is the prolongation of survival with a high quality of life as much as possible. Besides, the malignant transformation of LGGs is a well-known issue. Extensive surgical resection followed by radiation therapy (RT) and chemotherapy is the golden standard within most of the treatment protocols; particularly for HGGs. Currently, there are many ongoing clinical studies focused on the role of SRS in the management of gliomas. In most cases, the treatment protocols should be individualized.

#### **1.1 Radiotherapy versus radiosurgery**

The term "radiotherapy" refers to the treatment of malignant neoplasms and some benign situations by ionizing radiation. The history of RT goes back almost to the exploration of radiation. Many techniques have been developed for performing RT over time which made the RT more accurate and lesion targeted. Recently, techniques such as 3D conformal RT provided by multileaf-collimators and intensity modulated RT are available in addition to conventional RT. External beam radiotherapy (EBRT) is frequently performed in multiple low-dose fractions for post-surgical residuals or recurrences in the management of gliomas.

Stereotactic Radiosurgery for Gliomas 277

Radiosurgical devices may be divided into two main groups according to working principles: a) Photon based systems b) Particle based systems. X or gamma rays are used in photon based systems which are substantially capable to penetrate sufficiently into cranium and to generate energy deposition. While X rays are obtained from crashing accelerated electrons on a metallic surface, the gamma rays occur during subatomic particle interactions. They are commonly obtained by courtesy of the natural decay of cobalt60 to nickel60. Techniques like unifying multiple beams at a target point or intensity modulation are performed to achieve the maximal effect on target due to the potential of these beams to

Main components of a gamma knife are; a gamma knife device with a Co60 source, a stereotactic head frame and a software to make calculations of dose planning. Technology of the device has been developed concurrent with the developments in neuroimaging and computer technology since its first introduction in 1968. In current version of gamma knife, patient undergoes brain imaging following the fixation of a stereotactic head frame onto head. Then, the images are processed with the software and dose planning is performed. Finally, the patient is irradiated by the device. Radiation originating from Co60 source is divided into 201 beams through a hemispheric helmet and targeted into lesion. Beams can be shaped into 4, 8, 14 or 18 mm in diameter radiation balls by using different helmets. Also the shape of the radiation shots can be modified through plugging and shielding techniques thus the eloquent structures like cornea, optic nerves and brainstem can be prevented against adverse radiation effects. Rigid fixation of the head frame by four screws into the outer table of calvarium results in high accuracy with less than 1 mm deviation at dose planning. Automatic positioning system (APS) enables the computer controlled treatment session without interruption (Pollock & Brown, 2005). Furthermore, the superimposition of CT, MR, functional MR, MR tractography, PET scan and angiography images increases the accuracy and efficacy of dose planning (Pantelis et al., 2010). A commonly used term for dose planning is the "marginal dose" which refers to dosage of the radiation measured at peripheral margin of the lesion. For example, the marginal dose of 12 Gy within 50% isodose means the central dose lesion received is 24 Gy. A dose planning image is shown in figure 1.

However the LINAC based RT has been used since 1950s; LINAC was applied to radiosurgery in 80s. Typical current version of a LINAC device consists of a stereotactic head frame, floor stand, 6 megavolts linear accelerator, collimators and high precision attachments. A stream of electrons is accelerated almost to light speed and crash onto a metallic surface which results in production of mainly heat and lesser X rays. These rays are transferred to target point following modulation by multileaf collimators. Multileaf collimators allow to integration of multiple rays coming from different directions at a

CyberKnife® technology (Accuray, Sunnyvale, CA) was developed by Adler & colleagues, and was approved by FDA (Food and Drug Administration) for radiation treatment in 2001

**1.2 Radiosurgical devices** 

**1.2.1 Gamma knife** 

affect the normal tissues on their way.

**1.2.2 Linear accelerator (LINAC)** 

**1.2.3 CyberKnife** 

definite target point (Pollock & Brown, 2005).

A typical RT session is performed with approximately 30 day fractions by a cumulative ~60 Gy dose except the hypofractioned RT for HGGs. Radiation has prominent effects on tumor tissue like cytotoxicity via early and late DNA damage; inflammatory reactions and edema. Radiosensitivity of the tissue is substantially related with the tissue's proliferation index. Because the normal brain cells are more constant than the tumor cells, the radiation doses between specific ranges tend to effect more on tumor cells. Currently, more conformal and intensity modulated irradiation is preferred to whole brain irradiation in RT protocols.

SRS efforts to effect only to the target lesion while protecting surrounding tissues in a single fractioned high-dose radiation. In contrast to conventional RT, radiosurgery doesn't rely on the increased radiation sensitivity of the target compared with the normal brain. One of the key elements in stereotactic radiosurgery is the use of many radiation fields distributed over space all focusing on a target. This feature minimizes the effect to surrounding normal tissue. Besides, the applied re-irradiation dose and cumulative normalized total doses increase with a change in irradiation technique from conventional RT to radiosurgery retreatment without increasing the probability of normal brain necrosis (Mayer & Sminia, 2008; Niyazi et al., 2011). The goal of radiosurgery is to arrest the cell division capability of target cells, regardless of the individual cell's mitotic activity and radiosensitivity. Radiosurgery also allows for delayed intratumoral vascular obliteration (Hadjipanayis et al., 2002a). Mechanisms of cell damage are sudden cell death via apoptosis in acute stage; and endothelial proliferation, luminal narrowing and thrombosis in the late stage (Witham et al., 2005). Deliverance of radiation dose in single fraction increases the biological effect of the radiation 2.5 to 3 times compared with multi-fractioned RT which allows decreasing the total treatment dose (Crowley et al., 2006). This means a radiation dose of 15 Gy has similar biological efficacy with approximately 40-45 Gy dose delivered by fractioned RT. However, the edema and radionecrosis caused by irradiation is more relevant in high-dose single fraction deliverance. For that reason, it's not applicable on large intracranial volumes. SRS is almost always a one-day treatment protocol. However SRS has different application protocols, basic steps are the same:


Main differences between conventional RT and SRS are shown in table 1.


Table 1. Differences between conventional RT and SRS.

#### **1.2 Radiosurgical devices**

276 Advances in the Biology, Imaging and Therapies for Glioblastoma

A typical RT session is performed with approximately 30 day fractions by a cumulative ~60 Gy dose except the hypofractioned RT for HGGs. Radiation has prominent effects on tumor tissue like cytotoxicity via early and late DNA damage; inflammatory reactions and edema. Radiosensitivity of the tissue is substantially related with the tissue's proliferation index. Because the normal brain cells are more constant than the tumor cells, the radiation doses between specific ranges tend to effect more on tumor cells. Currently, more conformal and intensity modulated irradiation is preferred to whole brain irradiation in RT protocols. SRS efforts to effect only to the target lesion while protecting surrounding tissues in a single fractioned high-dose radiation. In contrast to conventional RT, radiosurgery doesn't rely on the increased radiation sensitivity of the target compared with the normal brain. One of the key elements in stereotactic radiosurgery is the use of many radiation fields distributed over space all focusing on a target. This feature minimizes the effect to surrounding normal tissue. Besides, the applied re-irradiation dose and cumulative normalized total doses increase with a change in irradiation technique from conventional RT to radiosurgery retreatment without increasing the probability of normal brain necrosis (Mayer & Sminia, 2008; Niyazi et al., 2011). The goal of radiosurgery is to arrest the cell division capability of target cells, regardless of the individual cell's mitotic activity and radiosensitivity. Radiosurgery also allows for delayed intratumoral vascular obliteration (Hadjipanayis et al., 2002a). Mechanisms of cell damage are sudden cell death via apoptosis in acute stage; and endothelial proliferation, luminal narrowing and thrombosis in the late stage (Witham et al., 2005). Deliverance of radiation dose in single fraction increases the biological effect of the radiation 2.5 to 3 times compared with multi-fractioned RT which allows decreasing the total treatment dose (Crowley et al., 2006). This means a radiation dose of 15 Gy has similar biological efficacy with approximately 40-45 Gy dose delivered by fractioned RT. However, the edema and radionecrosis caused by irradiation is more relevant in high-dose single fraction deliverance. For that reason, it's not applicable on large intracranial volumes. SRS is almost always a one-day treatment protocol. However SRS has different application

protocols, basic steps are the same:

 Stereotactic imaging Dosimetric planning

Irradiation

**Tissue selectivity** 

Establishment of a fiducial system for targeting

Table 1. Differences between conventional RT and SRS.

Main differences between conventional RT and SRS are shown in table 1.

tissue

**Total dose of the treatment** High (45-70 Gy) Low (10-20 Gy) **Fractions** Multiple Single or few

**Duration of the treatment** Weeks Single day or few days **Tumor size** Not a criteria <3-3.5 cm in diameter

**Radiation beam** X ray X ray, gamma ray or

Regarding mitotic activity and radiosensitivity of the

**RT SRS** 

charged particles

activity and

tissue

Regardless of the mitotic

radiosensitivity of the

Radiosurgical devices may be divided into two main groups according to working principles: a) Photon based systems b) Particle based systems. X or gamma rays are used in photon based systems which are substantially capable to penetrate sufficiently into cranium and to generate energy deposition. While X rays are obtained from crashing accelerated electrons on a metallic surface, the gamma rays occur during subatomic particle interactions. They are commonly obtained by courtesy of the natural decay of cobalt60 to nickel60. Techniques like unifying multiple beams at a target point or intensity modulation are performed to achieve the maximal effect on target due to the potential of these beams to affect the normal tissues on their way.

#### **1.2.1 Gamma knife**

Main components of a gamma knife are; a gamma knife device with a Co60 source, a stereotactic head frame and a software to make calculations of dose planning. Technology of the device has been developed concurrent with the developments in neuroimaging and computer technology since its first introduction in 1968. In current version of gamma knife, patient undergoes brain imaging following the fixation of a stereotactic head frame onto head. Then, the images are processed with the software and dose planning is performed. Finally, the patient is irradiated by the device. Radiation originating from Co60 source is divided into 201 beams through a hemispheric helmet and targeted into lesion. Beams can be shaped into 4, 8, 14 or 18 mm in diameter radiation balls by using different helmets. Also the shape of the radiation shots can be modified through plugging and shielding techniques thus the eloquent structures like cornea, optic nerves and brainstem can be prevented against adverse radiation effects. Rigid fixation of the head frame by four screws into the outer table of calvarium results in high accuracy with less than 1 mm deviation at dose planning. Automatic positioning system (APS) enables the computer controlled treatment session without interruption (Pollock & Brown, 2005). Furthermore, the superimposition of CT, MR, functional MR, MR tractography, PET scan and angiography images increases the accuracy and efficacy of dose planning (Pantelis et al., 2010). A commonly used term for dose planning is the "marginal dose" which refers to dosage of the radiation measured at peripheral margin of the lesion. For example, the marginal dose of 12 Gy within 50% isodose means the central dose lesion received is 24 Gy. A dose planning image is shown in figure 1.

#### **1.2.2 Linear accelerator (LINAC)**

However the LINAC based RT has been used since 1950s; LINAC was applied to radiosurgery in 80s. Typical current version of a LINAC device consists of a stereotactic head frame, floor stand, 6 megavolts linear accelerator, collimators and high precision attachments. A stream of electrons is accelerated almost to light speed and crash onto a metallic surface which results in production of mainly heat and lesser X rays. These rays are transferred to target point following modulation by multileaf collimators. Multileaf collimators allow to integration of multiple rays coming from different directions at a definite target point (Pollock & Brown, 2005).

#### **1.2.3 CyberKnife**

CyberKnife® technology (Accuray, Sunnyvale, CA) was developed by Adler & colleagues, and was approved by FDA (Food and Drug Administration) for radiation treatment in 2001

Stereotactic Radiosurgery for Gliomas 279

near zero. This feature provides a moderate entrance dose on the surface structures; a uniform high dose within the target point; and a zero dose beyond the target. A single monoenergetic proton beam irradiates a volume of approximately 1 cc. superimposing of multiple beams allows to irradiation of larger lesions. The proton therapy is tended to be

 Because the relatively longer planning procedure, patient undergoes imaging and treatment on separate days. Beads are implanted into the outer table of the patient's skull and the head of the patient is fixed by a rigid head frame prior to treatment (Chen et al., 2007). Proton beam therapy is performed by only limited number of centers around the world because of the complexity of particle-beam treatment planning, the need for a cyclotron to generate the

However the SRS is a relatively young treatment modality, over 400.000 patients were treated with gamma knife all around the world. Currently, there are sufficient data proving the efficacy of SRS on lesions such as arterio-venous malformations, acoustic schwannomas, trigeminal neuralgia and skull base meningiomas. Indications for SRS in gliomas are not definite yet because of the lack of large randomized clinical trials, and multiplicity of

High grade astrocytoma (HGA) includes anaplastic astrocytoma (AA), glioblastome multiforme (GBM), giant cell GBM and gliosarcoma according to WHO (World Health Organization) classification system (Louis et al., 2007). Whilst AA is grade III, rests are grade IV tumors. AA and GBM account for 60-65% of all gliomas (Sloan et al., 2005). The overall survival for untreated GBM is only 2-3 months which increases to mean 9-12 months with addition of gross total resection and RT. Addition of chemotherapy to this modality brings approximately 5 more months. Currently, overall survival for GBM following surgical resection and RT increased to 14-19 months by addition of a latterly popularized chemotherapeutic agent temazolamide (Combs et al, 2005). Median survival for AA is about 2- 3 years with surgical resection, RT and chemotherapy. 5 years survival rate for AA is reported 18%. Most of the AA cases transform into GBM during the course of disease. The treatment approaches for HGA remains palliative, not curative. There is a general consensus for a classification system for evaluating the response of the tumor to SRS treatment (Table 2).

Complete response (CR) Complete disappearance of enhancing or nonenhancing tumor

No change (NC) Less than 50% reduction or 25% increase in tumor volume (stable disease)

Progressive disease (PD) >25% increase in volume of the enhancing or nonenhancing tumor

Partial response (PR) >50% shrinkage of the tumor

Table 2. Classification of responsiveness of the tumor to SRS treatment.

performed for larger and more complex lesions in comparison with photon therapy.

protons and the expense of these units (Pollock & Brown, 2005).

gliomas subtypes despite the widespread use (Rejis, 2009).

**Terminology Description** 

*(CR+PR+NC = Tumor Control Rate (TCR), CR+PR = Effectiveness)* 

**2. Current SRS approaches for glioma** 

**2.1 High grade astrocytoma** 

(Adler et al., 1999). CyberKnife system consists of a lightweight LINAC device mounted on an industrial robotic arm and computer software. This structure provides multiaxial movement capability to the device. Real time X ray motion detector cameras monitor the patient's movements during treatment session which minimizes probable accuracy problems. Patient comfort and convenience are served by eliminating invasive frame replacement. In addition, because imaging and planning can occur any time before the radiosurgery procedure, the coordination of radiological resources, physician schedules and patient needs is simplified. Most patients undergo convenient outpatient treatment sessions that are completed within 1 hour, and they complete a treatment plan of two to five fractions in the same number of days (Kuo et al., 2003).

Fig. 1. Snapshot view of gamma knife dose planning on MRI. Orange circle indicates the borders of the tumor, yellow circle indicates the treatment dose of 15 Gy shot isocenter (within 50% isodose) and peripheral two green circles indicate 12 and 8 Gy isodose fields.

#### **1.2.4 Charged particle beam therapy**

Proton based SRS was pioneered by Kjellberg & colleagues in the 1960s. This discipline uses either charged protons or helium ions instead of photons. Protons are generated by stripping an atom of its electron and accelerating the residual proton in the magnetic field of a cyclotron or a synch-cyclotron. It's also known as "hadron therapy". A phenomenon called "Bragg peak effect" is very important for a better understanding of fundamentals of proton beam therapy. The pattern of energy distribution of a proton beam consists of an entrance region of a slowly rising dose, a rapid rise to a maximum (Bragg peak) and a rapid fall to

(Adler et al., 1999). CyberKnife system consists of a lightweight LINAC device mounted on an industrial robotic arm and computer software. This structure provides multiaxial movement capability to the device. Real time X ray motion detector cameras monitor the patient's movements during treatment session which minimizes probable accuracy problems. Patient comfort and convenience are served by eliminating invasive frame replacement. In addition, because imaging and planning can occur any time before the radiosurgery procedure, the coordination of radiological resources, physician schedules and patient needs is simplified. Most patients undergo convenient outpatient treatment sessions that are completed within 1 hour, and they complete a treatment plan of two to five

Fig. 1. Snapshot view of gamma knife dose planning on MRI. Orange circle indicates the borders of the tumor, yellow circle indicates the treatment dose of 15 Gy shot isocenter (within 50% isodose) and peripheral two green circles indicate 12 and 8 Gy isodose fields.

Proton based SRS was pioneered by Kjellberg & colleagues in the 1960s. This discipline uses either charged protons or helium ions instead of photons. Protons are generated by stripping an atom of its electron and accelerating the residual proton in the magnetic field of a cyclotron or a synch-cyclotron. It's also known as "hadron therapy". A phenomenon called "Bragg peak effect" is very important for a better understanding of fundamentals of proton beam therapy. The pattern of energy distribution of a proton beam consists of an entrance region of a slowly rising dose, a rapid rise to a maximum (Bragg peak) and a rapid fall to

fractions in the same number of days (Kuo et al., 2003).

**1.2.4 Charged particle beam therapy** 

near zero. This feature provides a moderate entrance dose on the surface structures; a uniform high dose within the target point; and a zero dose beyond the target. A single monoenergetic proton beam irradiates a volume of approximately 1 cc. superimposing of multiple beams allows to irradiation of larger lesions. The proton therapy is tended to be performed for larger and more complex lesions in comparison with photon therapy.

 Because the relatively longer planning procedure, patient undergoes imaging and treatment on separate days. Beads are implanted into the outer table of the patient's skull and the head of the patient is fixed by a rigid head frame prior to treatment (Chen et al., 2007). Proton beam therapy is performed by only limited number of centers around the world because of the complexity of particle-beam treatment planning, the need for a cyclotron to generate the protons and the expense of these units (Pollock & Brown, 2005).
