**3. Current methods of treatment of brain metastases**

The treatment of brain metastasis is multidisciplinary and different medical (surgeons, radiotherapists, chemotherapists) and non-medical figures (specialized nurses, health physicists, and radiotherapy technics) are interested. The clinical treatment consists in a combination of surgery, radiotherapy and chemotherapy.

For describing the current therapies of brain metastases we have followed the suggestions of the "American College of Surgical oncology CNS Working Group" (2005) and some recent reviews on the argument (Shaffrey et al. 2004, Eichler A. F. and Loeffler J. S 2007, Ngguyen and De Angelis 2004). The criteria used by the American college of Surgical Oncology are the following: age, Karnofsky Index, presence or absence of non-Central Nervous System (CNS) metastasis. Using these criteria and the predictive study [RPA] of Gaspar et al. (1997, 2000) it is possible to calculate the median survival. For patients falling in the RPA 1 with median survival = 7.1 months, an aggressive approach is suggested. It is out of doubt that the improvement in imaging techniques has changed the treatment options, and that the survival of patients with brain metastasis is dependent on the status of their systemic disease (Kamar et al. 2010, Rao et al. 2007, Patchell 2003, Eichler A. F. and Loeffler J. S 2007).

#### **3.1 Surgery**

Surgical approach has changed the survival and the quality of life of many patients. The most convincing evidence of this benefit is reported for Non-Small Lung Cancer (NSLC) patients with a single brain metastasis. Different authors have reported a 5-years survival ranging from 0% to 45% (Hankins et al. 1988, Wronski et al. 1995). As outlined by Nguyen and De Angelis (2004) this variation on survival is accounted by two factors: a) variation on treatment aggressiveness of primary lung tumor, b) variation on the incidence of systemic disease burden among those series.

Surgical resection is generally followed by Whole - Brain Radiation Therapy (WBRT). WBRT has demonstrated palliation of neurologic symptoms and extension on survival (see studies of Patchell et al. 1990 and Vecht et al. 1993). Surgery for single metastases has shown benefit for melanoma (Buchsbaum et al. 2002), prostate cancer (McCutcheon et al. 1999), colorectal cancer (Hammoud et al. 1996), ovarian ( Cormio et al. 2003) and cervical cancer (Tajran et al. 2003).

Surgery for multiple brain metastases is a relatively new approach supported by the important retrospective study of University of Texas M.D. Anderson Cancer Center. In this study were treated 56 patients with no more than 3 metastases. No more than 3 craniotomies were performed and the group was divided in two subgroups according to the extension of the surgical resection. For one group [A] of 30 patients the complete resection was not possible, for a second group [B] of 26 patients the multiple metastases were completely resected. In a third Group [C], 26 patients were resected for single metastasis and this group was used as control. From the comparison of the various subgroups the following results emerged: Group C and Group B obtained the same survival time and a multivariate analysis demonstrated that the only variables significantly affecting the survival were the groups of patients and the extent of the primary tumor (Bindal et al. 1993). The recurrence was similar in group B and C suggesting that an aggressive surgical approach may be useful. This approach has been confirmed by another study on 138 patients (Iwadate et al 2000). This study included other two variables: age and Karnofsky index. Age >60 years and Karnofsky < 70 and incomplete removal were significant factors.

### **3.2 Radiation therapy**

166 Advances in Cancer Therapy

ability to suppress metastases *in vivo*. Proteins that regulate different functions such as adhesion, migration, growth and differentiation are coded by these MSGs. These genes have been described for breast carcinoma (Seraj et al. 2000), melanoma (Leone et al. 1991) and

Notwithstanding all these progresses the entire process of brain colonization remains actually poorly understood and better human and animal models are to be tried. It is our hypothesis that the peculiar metabolism of the normal brain with its high glucose uptake

The treatment of brain metastasis is multidisciplinary and different medical (surgeons, radiotherapists, chemotherapists) and non-medical figures (specialized nurses, health physicists, and radiotherapy technics) are interested. The clinical treatment consists in a

For describing the current therapies of brain metastases we have followed the suggestions of the "American College of Surgical oncology CNS Working Group" (2005) and some recent reviews on the argument (Shaffrey et al. 2004, Eichler A. F. and Loeffler J. S 2007, Ngguyen and De Angelis 2004). The criteria used by the American college of Surgical Oncology are the following: age, Karnofsky Index, presence or absence of non-Central Nervous System (CNS) metastasis. Using these criteria and the predictive study [RPA] of Gaspar et al. (1997, 2000) it is possible to calculate the median survival. For patients falling in the RPA 1 with median survival = 7.1 months, an aggressive approach is suggested. It is out of doubt that the improvement in imaging techniques has changed the treatment options, and that the survival of patients with brain metastasis is dependent on the status of their systemic disease (Kamar et al. 2010, Rao et al. 2007, Patchell 2003, Eichler A. F. and Loeffler J. S 2007).

Surgical approach has changed the survival and the quality of life of many patients. The most convincing evidence of this benefit is reported for Non-Small Lung Cancer (NSLC) patients with a single brain metastasis. Different authors have reported a 5-years survival ranging from 0% to 45% (Hankins et al. 1988, Wronski et al. 1995). As outlined by Nguyen and De Angelis (2004) this variation on survival is accounted by two factors: a) variation on treatment aggressiveness of primary lung tumor, b) variation on the incidence of systemic

Surgical resection is generally followed by Whole - Brain Radiation Therapy (WBRT). WBRT has demonstrated palliation of neurologic symptoms and extension on survival (see studies of Patchell et al. 1990 and Vecht et al. 1993). Surgery for single metastases has shown benefit for melanoma (Buchsbaum et al. 2002), prostate cancer (McCutcheon et al. 1999), colorectal cancer (Hammoud et al. 1996), ovarian ( Cormio et al. 2003) and cervical cancer (Tajran et al.

Surgery for multiple brain metastases is a relatively new approach supported by the important retrospective study of University of Texas M.D. Anderson Cancer Center. In this study were treated 56 patients with no more than 3 metastases. No more than 3 craniotomies were performed and the group was divided in two subgroups according to the extension of the surgical resection. For one group [A] of 30 patients the complete resection was not possible, for a second group [B] of 26 patients the multiple metastases were completely

prostate cancer (Dong et al. 1995).

**3.1 Surgery** 

2003).

disease burden among those series.

may explain the large incidence of metastases.

**3. Current methods of treatment of brain metastases** 

combination of surgery, radiotherapy and chemotherapy.

Radiotherapy is the mainstay therapy of brain metastases. Currently there are three major categories of radio therapeutic treatments of brain metastasis: WBRT, radiosurgery, stereotactic radiotherapy. There are two options for radiosurgery: Gamma knife, Linac – based radiosurgery.

*WBRT* has been demonstrated by Patchell 1990 and Vecht 1993 to increase life survival in association with surgery. The WBRT is a palliative procedure which aim is to achieve life prolongation, local control and improvement in quality of life. WBRT has been also used prophylactically, aimed to treat malignancies having high brain metastasizing affinity, such as small cell lung carcinoma (SCLC), leukemia and lymphoma (Meert et al. 2001, Brown et al. 2005). The most frequently applied doses range from 20 Gy to 30 Gy in 5-10 sessions. Doses from 30 to 36 Gy are used as prophylaxis in the case of SLC and from 12-18 for hematologic diseases (Alexander et al. 1995, Brown et al. 2005). The combination of WBRT with radiosurgery will be discussed later.

**Radiosurgery** is now possible because of the availability of CT and MRI and computer planning makes possible the delivery of high dose of radiation to a precise target tumor area. This delivering of precise high dose of radiation energy to a tumor is called radiosurgery. It can be achieved combining 3 elements: 1) stereotactic localization of metastatic lesion; 2) precise collimation of the radiation energy and 3) administration of the total dose coming from different points in space and intersected in a single target volume. The peculiarity of radiosurgery is the fall of dose at the target edges, this permit to concentrate the dose to the target tumor area sparing everything possible the healthy tissue surrounding the tumor (Lunsford et al. 1990). Two radiosurgical treatment facilities exist: **Gamma Knife**, **Linac radiosurgery**.

Historically, LeKsell in Sweden was the first to apply radiosurgery. Initially low energy xrays (280 kV) were used and concentrated stereotactically to the intracranial target. The technique was first accepted with skepticism; however after the initial studies by Lunsford et al. (1990) (University of Pittsburgh), radiosurgery has gained a considerable acceptance. Lately in 1967, Leksell, in collaboration with Larsson, developed according to the same principle of radiosurgery the first cobalt - 60 gamma unit (Gamma Knife).

The **Gamma Knife** contains 201 cobalt sources of gamma rays arrayed in a hemisphere within a shielded structure. A primary collimator, forces all the emitted sources to a common focal area, then a secondary collimator adapts this primary focal beam to sizes from 4 to 18 mm, through computer software, to target to the corresponding size of brain metastasis. In this case the limiting size of this device are brain metastases with a major

Brain Metastases: Biology and Comprehensive

drugs is illustrated in Fig.1.

**X-rays collimation**.

Strategy from Radiotherapy to Metabolic Inhibitors and Hyperthermia 169

(Valk and Dillon 1991). The leakier endothelium determines an increment in the quantity of fluid in the interstitium, an excessive production of free radicals due to the iron loss by red blood cells and an increased production of proinflammatory prostaglandins and cytokines (see Fig.1) (Michalowsky 1986, St Clair and Given 2003, Wong and Van der Kogel 2004). An interesting study by Kureshi et al. (1994) on frozen specimen obtained by patients with radionecrosis has shown that all specimen were infiltrated with both CD4+ and CD8+ cells and activated macrophages (CD11c+, HLA-DR+). Furthermore they analyzed a panel of cytokines and found that Tumor Necrosis Factor- α (TNF-α) and Interleukin-6 immunoreactivity was prominent in majority of the specimen (75%) and were predominately produced by macrophages. TGF-[beta] astrocytic and macrophage immunoreactivity was present at moderate levels in all cases. Other authors have outlined that radiation injury is not only maintained by the inflammatory reaction elicited by radiation but is self maintained by the induction of apoptosis of endothelial cells (Wong and Van der Kogel 2004). These authors have also outlined the importance of hypoxia and VEGF production and of increased release of nitric oxide (NO) (Wong and Van der Kogel 2004). Belka et al. 2001, in agreement with us have outlined that radiation injury is the result of a complex alterations and that no single mechanism is responsible of the event. At least four factors contribute to central nervous system toxicity: (1) damage to vessel structures, (2) deletion of oligodendrocytes, (3) deletion of neural stem cells, (4) generalized alterations of cytokine expression (Kureshi et al. 1994). Actually no definitive therapies exist for radionecrosis (Valk and Dillon 1991, Belka et al 2001, Nieder et al 2007), however high dosage of corticosteroids, stem cell transplantation or erythropoietin (EPO) have been suggested. Pleiotropic functions of EPO on CNS have been recognized such as: inhibition of apoptosis, anti-inflammatory anti oxidative effects, prevention of glutamate-induced toxicity and stimulation of angiogenesis (Wong and Van der Kogel 2004). Other authors have proposed melatonin as radioprotective agent (Vijayalaxmi et al. 2004). Hyperbaric oxygen has been also proposed, however as outlined by Wong and Van der Kogel (2004), has not demonstrated a benefit. Since 1999, for brain metastases, a radioprotector formed by an association between bioflavonoids (silymarin) and omega three fatty acids has been suggested by an Italian group to decrease the risk ratio of developing brain necrosis and to improve significantly survival time (Gramaglia et al 1999). Omega 3 fatty acids have demonstrated to decrease the synthesis of proinflammatory prostaglandins (Fig.1) and cytokines, to have antitumoral activity and to change many tumor environmental parameters (Baronzio et al. 1994) whereas bioflavonoids have elicited protection of neuronal cells from oxidative stress and glutamate (Ishige et al 2001). A recent review on silymarin by Agarwaal et al. (2006) has outlined that this bioflavonoid has important anti-inflammatory and antiangiogenic activity. A vision of the various point of activity of these two natural

As previous described, **Linac radiosurgery** technology delivers high doses of ionizing radiation to small intracranial targets. SRT or CFRT requires: adequate a) **patient immobilization**, b) accurate **three – dimension dose calculation TP** (treatment planning); c)

a. **The patient immobilization.** SRT is done using a frame fixed to patient's skull using four pins. These pins are anchored into the periosteum and afford an excellent immobilization. The method is not devoid of side effects such infections and pain. Anesthetic is used during the procedure to control this last side effect. For treatment

diameter = 18 mm or tumor volume ranged from 0.5 to 33 cm3 (Alexander et al. 1995, Lunsford et al. 1990).

Following the same principle several authors (Betti et al. 1991, Colombo et al. 1985, Hartman et al. 1985, Giller and Berger 2005, Shoshan et al. 2005, Sperduto 2003, Valk and Dillon 1991) in the late 1980 developed **LINAC** based radiosurgical method. Linac radiosurgical treatment relies upon the following aspects: a) a collimated X-ray is directed stereotactically to the target area; b) the gentry of the linear accelerator rotates over the patient producing an arc of radiation oriented on the target. In this manner different arc or multiple non-coplanar intersecting arcs of radiation are used. Some important aspects of Linac therapeutic methodology are to be evidenced, they are: size, dose, toxicity.

#### **3.2.1 Size of target tumor volume**

Brain metastases have been considered ideal targets for radiosurgery and stereotactic radiotherapy due to their small spherical size, non-infiltrative borders, and location in noneloquent areas of the brain. In terms of stereotactic radiosurgery, the superiority of one energy source over another depends primarily on the dose distribution capabilities, which in turn depend on the target's volume, location, and shape. For small lesions (= 5 cm3), the dose distributions produced by the gamma knife are essentially identical to those achievable with LINAC units. When the target lesion is non -spherical or of intermediate size ( =5 or = 25 cm3), LINAC units may have an advantage over Gamma Knife units, due to their ability to treat larger lesions without requiring multiple isocenters (which makes treatment planning difficult), and the ability to shape the dose using collimated fields (Giller and Berger 2005).

#### **3.2.2 Dose fractionation**

Standard radiobiological principles suggest that fractionating radiation therapy (i.e., delivery in multiple sessions) will reduce both early and late toxicities to surrounding normal tissues. Radiotherapy can be delivered in a single session and is called radiosurgery, or in different sessions and is called: Stereotactic radiotherapy (SRT) or Conformal RadioTherapy (CRT) (Giller and Berger 2005, Shoshan et al. 2005, Sperduto 2003, Valk and Dillon 1991).

#### **3.2.3 Toxicity (radioprotection)**

Radiosurgery, notwithstanding its precision is not devoid of severe side effects on brain parenchyma, the worse being radionecrosis.CNS damage occurs in three different stages. The acute post radiation stage is usually well tolerated and consists in headache, nausea and somnolence. These symptoms are related to the cerebral edema and can be controlled with corticosteroids. A sub-acute stage caused by transient demyelization mediated damage to oligodendrocytes. This demyelization is clinically manifested by numbness, irritability, anorexia, somnolence and sometimes dysfunction of electric conduction. These symptoms occur approximately 10 weeks after cranial irradiation. Late effects (radionecrosis) become manifest from 6 to 9 months later and can evolve for a number of years following cranial irradiation. The process is associated with glia proliferation, mononuclear cell / astrocyte activation, and astrocyte secreted protein loss and cytokines production (Baker and Krochak 1989, Michalowsky 1986). The endothelium damage is the principal target of irradiation, is irreversible and progressive and determines an increase in the blood brain permeability

diameter = 18 mm or tumor volume ranged from 0.5 to 33 cm3 (Alexander et al. 1995,

Following the same principle several authors (Betti et al. 1991, Colombo et al. 1985, Hartman et al. 1985, Giller and Berger 2005, Shoshan et al. 2005, Sperduto 2003, Valk and Dillon 1991) in the late 1980 developed **LINAC** based radiosurgical method. Linac radiosurgical treatment relies upon the following aspects: a) a collimated X-ray is directed stereotactically to the target area; b) the gentry of the linear accelerator rotates over the patient producing an arc of radiation oriented on the target. In this manner different arc or multiple non-coplanar intersecting arcs of radiation are used. Some important aspects of Linac therapeutic

Brain metastases have been considered ideal targets for radiosurgery and stereotactic radiotherapy due to their small spherical size, non-infiltrative borders, and location in noneloquent areas of the brain. In terms of stereotactic radiosurgery, the superiority of one energy source over another depends primarily on the dose distribution capabilities, which in turn depend on the target's volume, location, and shape. For small lesions (= 5 cm3), the dose distributions produced by the gamma knife are essentially identical to those achievable with LINAC units. When the target lesion is non -spherical or of intermediate size ( =5 or = 25 cm3), LINAC units may have an advantage over Gamma Knife units, due to their ability to treat larger lesions without requiring multiple isocenters (which makes treatment planning difficult), and the ability to shape the dose using collimated fields (Giller and

Standard radiobiological principles suggest that fractionating radiation therapy (i.e., delivery in multiple sessions) will reduce both early and late toxicities to surrounding normal tissues. Radiotherapy can be delivered in a single session and is called radiosurgery, or in different sessions and is called: Stereotactic radiotherapy (SRT) or Conformal RadioTherapy (CRT) (Giller and Berger 2005, Shoshan et al. 2005, Sperduto 2003, Valk and

Radiosurgery, notwithstanding its precision is not devoid of severe side effects on brain parenchyma, the worse being radionecrosis.CNS damage occurs in three different stages. The acute post radiation stage is usually well tolerated and consists in headache, nausea and somnolence. These symptoms are related to the cerebral edema and can be controlled with corticosteroids. A sub-acute stage caused by transient demyelization mediated damage to oligodendrocytes. This demyelization is clinically manifested by numbness, irritability, anorexia, somnolence and sometimes dysfunction of electric conduction. These symptoms occur approximately 10 weeks after cranial irradiation. Late effects (radionecrosis) become manifest from 6 to 9 months later and can evolve for a number of years following cranial irradiation. The process is associated with glia proliferation, mononuclear cell / astrocyte activation, and astrocyte secreted protein loss and cytokines production (Baker and Krochak 1989, Michalowsky 1986). The endothelium damage is the principal target of irradiation, is irreversible and progressive and determines an increase in the blood brain permeability

methodology are to be evidenced, they are: size, dose, toxicity.

Lunsford et al. 1990).

Berger 2005).

Dillon 1991).

**3.2.2 Dose fractionation** 

**3.2.3 Toxicity (radioprotection)** 

**3.2.1 Size of target tumor volume** 

(Valk and Dillon 1991). The leakier endothelium determines an increment in the quantity of fluid in the interstitium, an excessive production of free radicals due to the iron loss by red blood cells and an increased production of proinflammatory prostaglandins and cytokines (see Fig.1) (Michalowsky 1986, St Clair and Given 2003, Wong and Van der Kogel 2004). An interesting study by Kureshi et al. (1994) on frozen specimen obtained by patients with radionecrosis has shown that all specimen were infiltrated with both CD4+ and CD8+ cells and activated macrophages (CD11c+, HLA-DR+). Furthermore they analyzed a panel of cytokines and found that Tumor Necrosis Factor- α (TNF-α) and Interleukin-6 immunoreactivity was prominent in majority of the specimen (75%) and were predominately produced by macrophages. TGF-[beta] astrocytic and macrophage immunoreactivity was present at moderate levels in all cases. Other authors have outlined that radiation injury is not only maintained by the inflammatory reaction elicited by radiation but is self maintained by the induction of apoptosis of endothelial cells (Wong and Van der Kogel 2004). These authors have also outlined the importance of hypoxia and VEGF production and of increased release of nitric oxide (NO) (Wong and Van der Kogel 2004). Belka et al. 2001, in agreement with us have outlined that radiation injury is the result of a complex alterations and that no single mechanism is responsible of the event. At least four factors contribute to central nervous system toxicity: (1) damage to vessel structures, (2) deletion of oligodendrocytes, (3) deletion of neural stem cells, (4) generalized alterations of cytokine expression (Kureshi et al. 1994). Actually no definitive therapies exist for radionecrosis (Valk and Dillon 1991, Belka et al 2001, Nieder et al 2007), however high dosage of corticosteroids, stem cell transplantation or erythropoietin (EPO) have been suggested. Pleiotropic functions of EPO on CNS have been recognized such as: inhibition of apoptosis, anti-inflammatory anti oxidative effects, prevention of glutamate-induced toxicity and stimulation of angiogenesis (Wong and Van der Kogel 2004). Other authors have proposed melatonin as radioprotective agent (Vijayalaxmi et al. 2004). Hyperbaric oxygen has been also proposed, however as outlined by Wong and Van der Kogel (2004), has not demonstrated a benefit. Since 1999, for brain metastases, a radioprotector formed by an association between bioflavonoids (silymarin) and omega three fatty acids has been suggested by an Italian group to decrease the risk ratio of developing brain necrosis and to improve significantly survival time (Gramaglia et al 1999). Omega 3 fatty acids have demonstrated to decrease the synthesis of proinflammatory prostaglandins (Fig.1) and cytokines, to have antitumoral activity and to change many tumor environmental parameters (Baronzio et al. 1994) whereas bioflavonoids have elicited protection of neuronal cells from oxidative stress and glutamate (Ishige et al 2001). A recent review on silymarin by Agarwaal et al. (2006) has outlined that this bioflavonoid has important anti-inflammatory and antiangiogenic activity. A vision of the various point of activity of these two natural drugs is illustrated in Fig.1.

As previous described, **Linac radiosurgery** technology delivers high doses of ionizing radiation to small intracranial targets. SRT or CFRT requires: adequate a) **patient immobilization**, b) accurate **three – dimension dose calculation TP** (treatment planning); c) **X-rays collimation**.

a. **The patient immobilization.** SRT is done using a frame fixed to patient's skull using four pins. These pins are anchored into the periosteum and afford an excellent immobilization. The method is not devoid of side effects such infections and pain. Anesthetic is used during the procedure to control this last side effect. For treatment

Brain Metastases: Biology and Comprehensive

Collimator

Strategy from Radiotherapy to Metabolic Inhibitors and Hyperthermia 171

c. **Collimator.** The major problem in radiosurgery is treating irregularly shaped lesions. The use of overlapping spherical treatments results in some shaping advantages but the increased time used to reproduce this technique determines a non-homogeneous dose deposition and an increase on side effects. Improved tumor dose homogeneity can be obtained using a field shaping device able to form an optimal field shape for each beam direction (Kurup et al 2007). To obtain the best dose distribution different devices have been set up (i.e. 3D line®, Radionics ®) (Gauer et al. 2008, urie et al. 2001). Generally, these collimator devices consist of two opposing banks tungsten leaves and allows shaping of a radiation field up to a size of 11 x 10 cm2 at the isocenter. Mechanical and dosimetric evaluations are performed to test the stability of the mechanical isocenter and to determine leaf leakage, penumbra width, and accuracy of leaf positions and uniformity of leaf speed. Several multileaf collimators are commercially available and differ from each other by many aspects such as: Leaf pairs, field size, leaf width, leaf transmission, maximum speed and total weight. As example, in table 1 we report some

Leaf pairs 31 24 Field size( cm2) 10x12 11x10 Leaf Width (mm) 4 4.5 Focused design Single Double Total weight (Kg) 35 35 Maximum speed (cm/s) 2.5 1 Table 1. Comparison of Some Characteristics of Radionics ® and 3Dline ® multileaf

An important question arises: is SRT efficacious as surgery in achieving local control (Rao et al. 2007)? As reviewed by Sperduto (2003), SRT is as good as or even better than surgical resection in term of local control. Another prospective study has addressed this question (Mucacevic et al. 2006). Mucacevic et al. 2006 found that local control was superior in SRT treated patients compared to surgery, and that SRT group had a greater improvement in

Another question is: can SRT be used only for multiple brain metastases? Previous studies suggested that use of radiosurgery for brain metastases should be limited to patients with three or fewer lesions (Gupta 2005, Andrews et al. 2004). A recent randomized trial, compared whole-brain radiation therapy (WBRT) plus radiosurgery boost to metastatic foci. This trial has demonstrated a significant advantage of radiosurgery boost over WBRT alone in terms of freedom from local failure, and that the result also present among patients with 2, 3, or 4 metastases (Andrews et al. 2004). Survival also did not depend on number of metastases. The drawback of this technique is the risk of radiation necrosis. Chang et al. (2000) found that radionecrosis occurred in the 5.4% of patient treated and only 7 tumors

Radionics 3Dline

of the characteristics of 3D line® and that of Radionics ®.

**4. Current debates on the best treatment options** 

quality of life even if a higher rate of distant brain failure was present.

that last several weeks the immobilization device should be reproducible and in this case an individual customized thermoplastic mould is built.

Fig. 1. In this figure, the effects of Radiotherapy on Brain structure, the reactions produced and the targets of radioprotectors such as Sylimarin \*\* and omega 3 fatty acids (W-3) \* are illustrated.

b. **Treatment Planning.** After careful positioning the patient, is immobilized with thermoplastic moulds or with stereotactic frame undergoes to a contrast enhanced brain Computed Tomography (CT) or to a Brain Magnetic Resonance (MRI) scans with 2-5 mm slice thickness and 2-5 mm separation. Once obtained the CT/MR data, these are processed using a computerized treatment planning. CT/MRI images are fused using image fusion software and the Gross Tumor Volume (GTV) is defined and contoured manually. In some departments an integration of images with metabolic information such as Single Photon Emission Computed Tomography (SPECT) is also used (Mongioj et al 1999).This permits sometimes to obtain more accurate tumor visualization. The fusion of images is obtained by commercial software (i.e. package SRS PLATO®) consisting of three principal algorithms: (1) a module dedicated to the localization of each tomographic section on stereotactic space; (2) a CT/MR dedicated module for the creation of regions of interest (ROIs) for each slice and (3) a 3D- visualization module. Once the GTV is obtained, a margin over these countered borders must be defined to take into account the possible microscopic extension of the tumor not evidenced on the CT/MR scans. These margins are generally 10-20 mm around the GTV obtaining the Planned Target Volume (PTV). After PTV determination, a new contour is done ensuring PTV coverage by 95% isodose line with the aim for obtaining uniform dose homogeneity.

Fig. 1. In this figure, the effects of Radiotherapy on Brain structure, the reactions produced and the targets of radioprotectors such as Sylimarin \*\* and omega 3 fatty acids (W-3) \* are

b. **Treatment Planning.** After careful positioning the patient, is immobilized with thermoplastic moulds or with stereotactic frame undergoes to a contrast enhanced brain Computed Tomography (CT) or to a Brain Magnetic Resonance (MRI) scans with 2-5 mm slice thickness and 2-5 mm separation. Once obtained the CT/MR data, these are processed using a computerized treatment planning. CT/MRI images are fused using image fusion software and the Gross Tumor Volume (GTV) is defined and contoured manually. In some departments an integration of images with metabolic information such as Single Photon Emission Computed Tomography (SPECT) is also used (Mongioj et al 1999).This permits sometimes to obtain more accurate tumor visualization. The fusion of images is obtained by commercial software (i.e. package SRS PLATO®) consisting of three principal algorithms: (1) a module dedicated to the localization of each tomographic section on stereotactic space; (2) a CT/MR dedicated module for the creation of regions of interest (ROIs) for each slice and (3) a 3D- visualization module. Once the GTV is obtained, a margin over these countered borders must be defined to take into account the possible microscopic extension of the tumor not evidenced on the CT/MR scans. These margins are generally 10-20 mm around the GTV obtaining the Planned Target Volume (PTV). After PTV determination, a new contour is done ensuring PTV coverage by 95% isodose line with the aim for obtaining uniform dose

illustrated.

homogeneity.

case an individual customized thermoplastic mould is built.

that last several weeks the immobilization device should be reproducible and in this

c. **Collimator.** The major problem in radiosurgery is treating irregularly shaped lesions. The use of overlapping spherical treatments results in some shaping advantages but the increased time used to reproduce this technique determines a non-homogeneous dose deposition and an increase on side effects. Improved tumor dose homogeneity can be obtained using a field shaping device able to form an optimal field shape for each beam direction (Kurup et al 2007). To obtain the best dose distribution different devices have been set up (i.e. 3D line®, Radionics ®) (Gauer et al. 2008, urie et al. 2001). Generally, these collimator devices consist of two opposing banks tungsten leaves and allows shaping of a radiation field up to a size of 11 x 10 cm2 at the isocenter. Mechanical and dosimetric evaluations are performed to test the stability of the mechanical isocenter and to determine leaf leakage, penumbra width, and accuracy of leaf positions and uniformity of leaf speed. Several multileaf collimators are commercially available and differ from each other by many aspects such as: Leaf pairs, field size, leaf width, leaf transmission, maximum speed and total weight. As example, in table 1 we report some of the characteristics of 3D line® and that of Radionics ®.


Table 1. Comparison of Some Characteristics of Radionics ® and 3Dline ® multileaf Collimator
