Brain Metastases: Biology and Comprehensive Strategy from Radiotherapy to Metabolic Inhibitors and Hyperthermia

is increasing. Associated to radiotherapy and chemotherapy we suggest and discuss the biological reasons for adding hyperthermia and glycolysis metabolic inhibitors with the aim to obtain a better control of brain metastases


Introduction
Metastases to the brain is one of the most feared complication of systemic cancer and its incidence is rising for several reasons. The two most important reasons are the improvement in treatment, with a longer patient life; and the advance in diagnostic and imaging means Magnetic Resonance Image (MRI) and Computed Tomography (CT), Positron Emission Tomography [PET]) that have permitted to detect smaller lesions in asymptomatic patients. These improvement in radiology allows earlier diagnosis and result in better treatment management (Kamar et al., 2010, Rao et al, 2007, Patchell et al. 2003. Single metastases are detected in greater proportion. For example, in the case of ovarian tumors brain metastases are solitary in 43% of the cases (Pectasides et al. 2006). Single metastases appear approximately in one quarter of all patients with brain metastases (Rao et al. 2007). Norden et al. 2005 recently reported that breast, colon and renal cell carcinoma tend to produce single metastases, whereas melanoma and lung cancer have a greater tendency to produce multiple metastases. Single metastases can be treated surgically or by high precise radiotherapy modalities such as Gamma knife and StereoTactic Radiotherapy (SRT) or Conformal Radiotherapy (CRT). SRT was initially used for substituting surgical approach in patients with inaccessible tumor location or with comorbid medical conditions, now is used in many institutions as first approach, peculiarly from breast colon and renal carcinoma. Actually, many patients, refuse surgical approach so the use of SRT or CRT in combination with whole brain irradiation (WBRT) or SRT as a boosting method after WBRT is increasing. Associated to radiotherapy and chemotherapy we suggest and discuss the biological reasons for adding hyperthermia and glycolysis metabolic inhibitors with the aim to obtain a better control of brain metastases.

Epidemiology, pathology and prognosis of patients with brain metastasis
Brain metastases occur in 20% to 40% of cancer patients. Chernik, from 1970 to 1976 at the Memorial Sloan-Kettering Cancer Center, autopsied 3219 cancer patients. They found that 24% of these patients had intracranial metastases and the 20% had leptomeningeal metastases (Posner and Chernik 1978). Other studies reported similar percentage even if the methodology is slightly different (Baker et al. 1942, Chason et al 1963, Nussbaum 1996. In decreasing frequency, lung cancer, unknown primary, breast, melanoma, renal, and colon cancers are the most common tumors to metastasize to the brain (Pectasides et al. 2006, Norden et al. 2005, Posner and Chernic 1978, Chason et al 1963, Nussbaum et al. 1996.

Localization of brain metastases
Another important aspect is the precise localization of the metastases in the brain (Globus et al. 1942, Tom et al. 1946, Zimm et al. 1981, Tikhtman et al 1995. Approximately the 80% of metastases are localized in the cerebral hemisphere, 17% in the cerebellum and 3% in the brain stem (Tikhtman et al 1995). Delattre and contributors have also analyzed the localization of metastases in the specific regions of the cerebral hemisphere (Delattre et al. 1988). They found that brain metastases involved the frontal area for 21%, the parietal and the temporoparietal-occipital for 19%. These authors have also outlined that metastasis located preferentially at the junction of gray and white matter. Hwang et al. recently reexamined the importance of the vascular border zone and the gray and white matter junction in the distribution of brain metastases and agreed with Delattre and contributors (Hwang et al. 1988). They found in 302 metastatic brain lesions studied, that gray and white matter junction was the preferred site for 64 % of the brain metastases and the vascular border zones were the site of predilection for the 62%. These results support the notion that metastatic emboli tend to lodge in an area of sudden reduction of vascular caliber (gray/white matter junction) and in the most distal vascular field area (Border zone) (Hwang et al. 1988).

Shape of brain metastases
Most metastases appear round well-demarcated lesions that displace rather than invade the surrounding brain parenchyma. The lesions can vary in size ranging from microscopic to masses of 1-4 centimeters in diameter. The histopathologic features are similar to that of tumor of origin. Microinvasion is present although the majority of metastatic lesions appear well demarcated and sometimes with reactive astrocytosis surrounding the metastatic area . A new vasculature can appear at peripheral zones and is part of the edema. In central areas, necrotic areas are present (Nathoo et al. 2005). Meningeal metastases diffuse into the subarachnoid space with accumulation around blood vessels ).

Prognosis of brain metastases
Untreated brain metastases have a dismal prognosis, generally no greater than 1-5 months. Gaspar et al. 2000, studying a RTOG (Radiation Therapy Oncology Group) data base, performed a Recursive -Partitioning Analysis [RPA] on 1200 patients. They identified the factors able to influence the prognosis of these patients (Gaspar et al. 2000, D'Ambrosio et al. 2007). Among the several prognostic factors, Karnofsky Performance Status (KPS) has been identified as the most important. The other important factors were: status of primary tumor, age and the presence or absence of systemic metastases. Stratifying the patients according these criteria they have been able to obtain the following prognostic factors. Patients with KPS = 70%, with age = 65 with controlled primary tumor and absence of systemic metastases had a median survival of 7.1 months, whereas the survival was reduced to 2.3 months for patients with KPS < 70. The presence of uncontrolled tumor and systemic metastases even if with a KPS = 70% reduced the median survival to 4.2 months (Gaspar et al. 1997(Gaspar et al. , 2000. The survival was not different between patients with undiagnosed primary lesion and thosewith diagnosed primary tumor (6 and 4.5 months, respectively; p = 0.097) as reported in a recent study by D'Ambrosio (D'Ambrosio et al. 2007).

Brain metastases biology
Researchers have gained insight into the mechanisms by which metastatic cells arise from certain primary tumors (i.e. breast, melanoma) and metastasize to brain. These findings have been obtained in a mouse model (Kang et al. 2004, Nicolson 1993, Beasley et al. 2011). These authors have outlined that metastases formation are not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of metastatic tumor cells to grow in that environment, this in agreement with the Paget hypothesis of seed and soil. In other words, the formation of metastasis requires the right cells with the compatible environment , Deichman 1998. Metastatic process is a high selective non-random process consisting in a series of linked sequential steps. In a heterogeneous population of primitive tumor cells only some are able to survive and to lodge at distant sites ). The outcome of cancer metastases depends on multiple interactions between metastatic cells and homeostatic mechanisms. Each metastatic step is selective and if the various steps are not completed, the metastatic process may fail. This is probably why only 0.01% of the cells that reach the circulation form a metastatic colony , Kang et al 2004. For tutorial purpose we can divide the metastatic process to the brain in the following steps (Fidler 2010, Deichman 1998): A) process of selection among the heterogeneous tumor cells of origin into an aggressive and able to mobilize subpopulation; B) penetration of this selected subpopulation into the host circulation; C) localization into the microvasculature of the brain; D) crossing of Blood Brain Barrier (BBB); D) migration and growth in the brain structure. The process of selection (A) is the result of different pressures exerted by the tumor microenvironment and the genetic instability intrinsic to the tumor cells living in that environment. For different pressures we intend: tumor hypoxia, different metabolic advantageous tumor micro-area, immunologic pressure, presence or absence of an angiogenesis process. These different pressures can select among cells genetically unstable, cells able to survive in a different environment, to mobilize and to reach the blood stream (Deichman 1998). To gain access to the general circulation and to colonize to distant organs metastatic cells must invade tumor associated vasculature. The molecular mechanisms controlling the penetration of blood vessels are not completely understood (Beasley et al 2011, Deichman 1998. Once these cells have reached the blood vessels, various mechanisms are needed to survive both the immune system and the shear stress. To avoid the identification the immune cells, metastatic cells shielded under an agglomerate of platelets and red blood cells (Deichman 1998)]. Other important mechanisms are the resistances by metastatic cells to the apoptotic effects of reactive oxygen radicals produced www.intechopen.com by macrophages and neutrophils and the production of prostaglandins of E type . Furthermore the adhesion of the platelets on the metastatic cells induces a hypercoagulable state that increases the metastatic potential. In fact this adhesion increases the resistance to both the immune system and the shear stress (Kehrli 1999). The most common metastatization to brain occurs by hematogenous route. One route is via the general circulation. In fact in the resting state, the brain receives 15% to 20% of the body's blood flow, thus making it likely that circulating tumor cells will reach the brain. The second, via the vertebral venous system (Batson's plexus) which explains the absence of lung metastases found in certain patients with lung cancer. This spreading way is disputed and not confirmed by all authors (Deeken et al. 2007). Once metastatic cells have survived the circulatory stream, they may adhere to the endothelium, extravasate into the organ and then begin to proliferate in the new parenchyma. The arrest in the microcirculatory system is regulated by several factors, among them the multiple vascular adhesion molecules and the size of circulating emboli. Among adhesion molecules two families seem to be implicated: the selectins and the products of Immunoglobulin (Ig) genes and the integrins (Deeken et al. 2007). Integrins are major adhesion and signaling receptors that mediate cell migration and invasion ). In the case of human non small lung cancer (NSLC) the block of adhesion molecules integrin 3 1 has been demonstrated to significantly decrease the brain metastasis (Nathoo et al 2005). After reaching the brain capillaries, the metastatic cells must cross the BBB, degrade the brain Extracellular Matrix (ECM) and invade the brain parenchyma. This interaction is tight regulated by the paracrine and autocrine growth mechanisms present in the brain (Nicolson 1993). BBB is constituted by brain endothelial cells associated with pericytes and astrocyte foot processes. Brain endothelial cells have continuous tight junction, no fenestrations and is highly selective in its permeability (Perides et al. 2006). In experimental melanoma the fibrinolytic system facilitates tumor cell migration across the BBB as demonstrated by Perides and his group (Perides et al. 2006). For metastasis to the brain from breast tumor, the cooperation between metastatic cells and astrocyte is of importance (Weil et al. 2005).
To determine why certain tumors produce site-specific metastases to the brain, Fidler and collaborators studied cellsfrom K-175 melanoma syngeneic to C3H/HeN mice and the B16 melanoma syngeneic to C57 Bl/6 mice (Fidler , 2007. Regardless of the route of injection (internal carotid arteries-or directly into the cerebrum) K-175 produced melanocytic metastases in the brain parenchyma, whereas B16 cells produced lesions in the meninges and ventricles. These researches tried to understand which factors were responsible for the growth the melanoma cells in the specific areas (brain parenchyma, meninges). Some important aspects have been elucidated. For example B16 cells did not produce measurable gelatinase A activity whereas K-175 cells did. The presence of gelatinase theoretically can facilitate cells extravasation and the growth into the parenchyma. However studies with hybrids of B16 and K-1735 able to produce gelatinase A, failed to grow into brain parenchyma. Fidler switched his research on the different growth factors present in the brain. He studied growth factors such as Epidermal Growth Factor (EGF), basic Fibroblast Growth Factor (bFGF), Platelet Derived Growth Factor (PDGF), however only Transforming Growth Factor-beta 2 (TGF-2 )showed a greater concentration in the brain and was able to inhibit the growth of B16 and B16/K-1735 hybrid cells explaining the incapacity of these hybrids in producing intraparenchymal brain metastases .
Whether the progressive growth of brain metastases depends on neovascularisation is also unclear. As outlined by Bucana: "immunohistochemical and morphometric analyses show that the density of blood vessels within experimental metastases in the brains of nude mice, or within brain metastases derived from human lung cancer, is lower than in the adjacent, tumor-free brain parenchyma. However, blood vessels associated with brain metastases are dilated and contain many dividing endothelial cells. Immunohistochemical analysis also reveals that tumor cells located less than 100 micrometer from a blood vessel are viable, whereas more distant tumor cells undergo apoptosis. The blood-brain barrier is intact in and around experimental brain metastases smaller than 0.25 mm in diameter, but is leaky in larger metastases " (Bucana et al. 1999). Regarding melanoma other authors have found that neurotrophins (NTs) can promote brain metastases. NTs enhance the production of ECM degradation enzymes such as heparanases. Heparanases do not only degrade ECM but also the basement membrane of BBB Nathoo et al 2005, Menter et al 1994, Marchetti et al 2003, Denkins et al. 2004). The potential of angiogenesis in breast metastases has been further been studied. VEGF has been reported to increase the penetration of metastatic MDA-MB-231 breast carcinoma and to play a role in brain metastases dormancy in the absence of inhibitory antiangiogenic factors (Kim et al. 2004, Santarelli et al 2007, Palmieri et al. 2007, Yano et al,. 2000, Kaplan et al. 2005, Chen et al. 2007). Yano and collaborators however do not agree regarding the importance of VEGF on brain metastases and in an experimental mouse model using six different human cancer cell lines has reported that VEGF expression was necessary but not sufficient for the production of brain metastasis (Yano et al. 2000). Recently, the idea of premetastatic niche is leading the way (Kaplan et al 2006). Some authors support that the arrival of bone marrow-derived hematopoietic progenitors cells in distant sites represent early changes in the local environment (premetastatic niche) that dictates the pattern of metastatic spread and explains tumor dormancy (Kaplan et al. 2005(Kaplan et al. ,2006. Santarelli et al. 2007, outline that the reactive monocytosis and activated microglia present in the premetastatic niche increase the local inflammatory response and can induce the growth of tumor cells transplanted to the brain. Furthermore these authors outline that it is plausible that the brain is able to generate the adequate environment in anticipation and preparation of the ensuing metastatic colonization (Santarelli et al. 2007). Other studies have evidenced new mechanistic insights regarding some kind of tumors such as breast cancer and melanoma. Her-2 receptor. Overexpression of Her-2 receptor in breast carcinoma seems not only correlated to a poor prognosis but also to an increased colonization to the brain as demonstrated by Palmieri et al. (2007). Metabolic factors. Regarding only breast carcinoma, Chen et al (2007) have evidenced by proteomic analysis, that brain-metastasizing cancer cells over expressed enzymes involved in aerobic glycolysis and tricarboxylic acid cycle (TCA) cycle. From this study the authors outline that breast cancer that colonize the brain are able to adapt to the energy metabolism of the brain or develop metabolism able to survive in that specific environment. Stat3. In melanoma, the activation and over expression of Stat3 (Signal Transducer and Activator of Transcription 3), as reported by Tong-Xin is associated to brain metastases and might be considered a new potential target in this clinical situation (Tong et al 2006).

Metastasis suppressor genes.
Recently seven Metastasis Suppressor Genes (MSGs) have been identified. These genes have no effect on the growth of primary tumors but have the www.intechopen.com 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 prostate cancer (Dong et al. 1995). 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 may explain the large incidence of metastases.

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 , 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. (1997Gaspar et al. ( , 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.

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 andVecht 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.

Radiation therapy
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, Linacbased radiosurgery. WBRT has been demonstrated by Patchell 1990 andVecht 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 diameter = 18 mm or tumor volume ranged from 0.5 to 33 cm 3 (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.

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 cm 3 ), 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 cm 3 ), 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).

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.

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 andKrochak 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 www.intechopen.com (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-(TNF-) 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 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 .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.
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(Gauer et al. , 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 cm 2 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 ®.

Current debates on the best treatment options
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 quality of life even if a higher rate of distant brain failure was present. 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 www.intechopen.com required subsequent surgical resection. Regarding toxicity by adding SRT + WBRT however, Aoyama et al. (2006) found no difference between the group treated with SRT alone or the group treated with SRT + WBRT. Furthermore they found that the patients in whom WBRT was omitted had a higher rate of failure in the brain (76%vs. 48%) and required salvage therapy more often for recurrent brain metastases. Study by Hidefumi et al. 2006, has clearly evidenced that WBRT associated to SRT improve the survival of patients with 1 to 4 brain metastases. Furthermore these authors outlined that intracranial relapse occurred more frequently in patients who did not receive WBRT. A recent study however indicate that SRT boost after WBRT for single brain metastases improves survival in select patients, whereas for patients up to four metastases the association improves local control not overall survival (Eichler and Loeffler 2007). Patchell et al. (1998) and Sneed et al. (2002) however disagree and from their retrospective and prospective data suggest that omitting WBRT does not result in shorter survival. They outline that the status of systemic disease is the predominant determinant of patient's prognosis. To our opinion WBRT can omitted on selected patients with high risk of radionecrosis (increased accumulation of gadolinium in tumor area, neuro cognitive deterioration, persistence of headache and peritumoral edema) or if a close follow-up can be ensured to the patients treated with SRT. If patients do not show increased risk of radionecrosis, have a Karnofsky index > 70% and the systemic disease is minimal WBRT is however mandatory.

Chemotherapy
As outlined by Nguyen and De Angelis 2004, chemotherapy has a limited role in treating brain metastases and is used after failure of surgery and or radiation therapy. Many chemotherapy drugs do not cross the blood-brain barrier but can reach malignant tumors in the brain, presumably through a local breakdown in the blood-brain barrier. In some chemotherapy-sensitive tumors like, lymphoma, small cell lung cancer (SCLC) and breast cancer (Eichler and Loeffler 2007), chemotherapy can induce remissions, but its routine use is still under evaluation. But for most tumors, chemotherapy for brain metastases is ineffective, may be because of the existence of the BBB. In fact, many drugs do not cross easily BBB, and do not remain in the brain long enough or at high concentration to ensure adequate cancer killing effect (Tosoni et al. 2004). Drugs active on primary tumors may not be as active on metastases (Chang et al. 2007, Cavaliere andShiff 2007). On the contrary other authors outline that brain metastases are as responsive as primary systemic cancer. This has been demonstrated by numerous phase II studies (Tosoni et al. 2004). Different chemotherapeutic regimens have been used for treating brain metastases from SCLC [52,101]. Drugs have been used as single agent or combined to other drugs or associated with WBRT or SRT. The most active single drugs are cisplatinum (CCP), and temozolomide (TMZ) (Nguyen and De Angelis 2004). Cisplatinum alone has shown a response rate (RR) of 30% (Tosoni et al. 2004). A better response of 50% rate has been obtained combining to cisplatinum, etoposide, cyclophosphamide, methotrexate, and 5 fluouracil (Tosoni et al. 2004). The association with WBRT was better in term of overall survival and in treatment response (57% vs 22%) compared to patients who had received only WBRT (Postmus et al. 2000).
Breast cancer is sensitive to chemotherapy (Cavaliere and Shiff 2007). Rosner et al (1986) have shown a 50% response rate among 100 women treated with different regimens. The most common agents are: cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, and vincristine. All these agents do not cross BBB notwithstanding a response by metastatic foci have been obtained. This outlines that BBB is not so important and that the appropriate regimen and the chemosensitivity of the metastases are more important. Boogerd et al. 1992, reported a 59% RR, and according to Rosner et al. (1986), suggest that chemotherapeutics may cross BBB at a sufficient concentration to achieve a clinical effect. Another interesting and a standard drug on breast cancer is doxorubicin. Doxorubicin does not cross easily BBB however when encapsulated in liposomes its penetration can increase (Siegal et al. 1995). Caraglia et al. (2006) used liposomal doxorubicin and temozolomide (TMZ) in 19 patients with brain metastases. This association resulted in a RR of 37%; furthermore 8 patients had complete response and 2 a partial response. Temozolamide has limited activity against breast cancer so the majority of the response may be attributed to doxorubicin (Cavaliere and Shiff 2007). The incidence of metastases in breast cancer increases with the increase in HER2 overexpression. HER2 is an 185KDa transmembrane tyrosine kinase with extensive homology to the epidermal growth factor receptor. Trastuzumab is a monoclonal antibody (MOaBs) now approved as a first line chemotherapy in patients with positivity for HER2 receptors. After its introduction however an increased incidence in brain metastases has been noted. Retrospective studies documented an incidence between the 25% and the 40%, suggesting that HER-2 positive tumors have a biological predisposition to metastasize to brain (Lin and Winer 2007). The reasons for this increased incidence, as reported by Lin and Winer (2007), are multifactorial and include biological and treatment related factors. This last factor seems linked to the low penetration across BBB of Trastuzumab. Recently, to overcome this problem, Lapatinib has been suggested. Lapatinib has a dual inhibitor activity on epidermal growth factor and on HER2 and in preliminary has shown an objective response in two patients among 39 treated . Other studies with lapatinib and other HER2 inhibitors are currently been tested (Lin and Winer 2007). The incidence of brain metastases in melanoma is high and can reach the 43%. Melanoma is relatively chemoresistant. The various biological treatments such as interferon or interleukin-2 and chemotherapeutics (dacarbazine) have shown a limited activity. Temozolomide (TMZ) has demonstrated a relatively important response against brain metastases from melanoma. TMZ is a third generation alkylating agent that can be taken orally. Its small size and lipophilic properties, allows TMZ to cross easily BBB. CNS concentrations can reach 30% of the plasma concentrations. When it has reached the CNS, TMZ is converted to the active metabolite (MTIC). TMZ has been used as a single agent or combined with WBRT (Cavaliere and Shiff 2007

Hyperthermia and metabolic inhibitors, the future?
Multiple attempts have been made to improve the results of WBRT alone or combined with SRT/CFRT, by adding radiosensitizing agents. All the trials failed to demonstrate any www.intechopen.com benefit either in local control or in survival (Eichler and Loeffler 2007). When brain metastases reach a critical mass > 1-2 mm 3 (10 6 cells) and a distance from host nutritive vessel > of 100-200 μm develop area of hypoxia and angiogenesis. Hypoxia results in radioresistance (Wouters et al. 2007). Actually, no definitive clinical therapies exist for overcoming tumour hypoxia out of hyperthermia (HT) (Pontiggia et al. 1990, Baronzio et al. 2006. HT is a treatment raising the temperature of tumor -loaded tissue to 40-43 degrees C. It is deprived of important side effects and has shown to enhance the effects of radiotherapy and to potentiate the efficacy of certain drugs, such as nitrosurea, cisplatinum, metothrexate (Baronzio et al. 2006, Dewey et al 1977. HT combined with radiation has been reported to yield higher complete and durable responses than radiation alone in superficial tumors. Despite difficulties in increasing human tumor temperatures, recent clinical trials have shown that a combination of hyperthermia with radiation is superior to radiation alone in controlling many human tumors (Dewey et al. 1977, Gabriele andRoca 2006). The increased effect seen by combining cytotoxic agents with hyperthermia is complex, but may be due to altered drug pharmacokinetics such as increased solubility (e.g. nitrosureas and alkylating agents), altered plasma protein binding (e.g. cisplatinum) and activation of enzymatic processes (e.g. anthracyclines) (Luk andHulse 1980, Gerweek 1985). Hyperthermia does not usually cause marked increase in radiation side effects. Regarding brain, Seegenschmiedt et al. (1995), in their review affirmed that treatment toxicity to brain, is relatively low and longterm side effects are similar to that observed to RT alone. Ikeda et al. (1994), studied the toxicity of radiofrequency interstitial HT in dog and found alteration of Blood Brain Barrier (BBB). Other authors outlined that the maximum tolerated heat dose to CNS lies in the range of 40-60 min at 42-42.5°C or 10-30 min at 43°C (Gerweek 1985). A recent review by Sharma and Hoopes (2003) has reported that HT specifically alters the mammalian CNS. The morphological alterations for temperature in the range 40°C to 42 °C for 4 hours has been demonstrated for the axons, the glial cells and the vascular endothelium. Sneed and Stea 1995, demonstrated in a randomized study that HT has an acceptable toxicity, in fact no grade 5 toxicity was found outside 4 patients on 112 ( 3.5% ) with grade 2 and 7 (Sneed et al. 1995).
There are only a small number of studies on brain metastases with HT. In an interesting study reported by Pontiggia on 17 patients with lung cancer,the patients were treated with nitrosurea and capacitive HT for 60'. Sixteen patients out of 17 responded with clinical improvement and radiological regression of the disease. The survival time was in median 12.7 months (Pontiggia et al. 1995).
Hyperthermia is a useful adjunct to chemotherapy and radiotherapy; however, new therapeutic strategies easily applicable in many institutions are to be developed. The search for functional characteristics that allow cancer cells to spread to brain and development of new animal models will open new opportunities in target and drug discovery (Gril et al. 2010). Metabolic profiles of cells with metastatic propensity to brain may be one of these targets. In fact, studies by proteomics have demonstrated that breast cancer cells that metastasize to brain , have a unique protein profile consistent with increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways, permitting to these cells to have an enhanced proliferation and adaptation (Chen et al. 2007). Studies by Blasberg et al. (1985), using 14Cdeoxyglucose and quantitative autoradiography in metastatic walker 256 brain tumors confirm that glucose utilization is of primary importance in metastatic cells and that brain www.intechopen.com metastases consume glucose in presence of a low oxygen tension, the so called aerobic glycolysis or "Warburg effect" (Warburg 1956). Palmieri et al. 2009 have confirmed the "Warburg effect" analyzing resected human brain metastases of breast cancer through real time PCR. They demonstrated an upregulation of hexokinase-2, an enzyme that mediates the first step of glucose metabolism, its upregulation is associated with a poor prognosis (Palmieri et al.2009). Hennipman et al. (1988) suggested an association of an increasing rate of enzymes implicated in glycolysis in breast cancer metastases and that their activities were higher in metastases compared to the primary tumors (Richardson et al. 2008). Another study on MCF10 model of mammary carcinoma by Richardson, confirms the major shift toward aerobic glycolysis (Gambhir et al. 2001). Increased glycolysis at metastatic site has been confirmed by [18F] 2-fluoro-2-deoxy-Dglucose positron emission tomography (PET) (Richardson et al. 2008, Gambhir et al. 2001, Gillies et al. 2008, and Lee et al. 2008). Our group ) has developed a drugs combination able to alter two different steps of tumor metabolism (pyruvate dehydrogenase and ATP citrate lyase). The first drug is -lipoic acid (ALA), which, as is the case for dichloroacetate, inhibits the enzyme Pyruvate Dehydrogenase Kinase-1 (PDHK1). Inhibition of PDHK1 can restore the activity of pyruvate dehydrogenase, thus possibly redirecting aerobic glycolysis to respiration and thus decreasing the amount of lactate produced. The second drug is hydroxycitrate (HCA), which inhibits ATP citrate lyase. The efficacy of this combination appears in animals to be similar to conventional chemotherapy (cisplatin or 5-FU), as it results in both significant tumor growth inhibition and enhanced survival ). Similar results have been obtained in one case of pancreatic patient metastatic to liver ). An unpublished result, of a patient with head and neck cancer with brain metastases treated with ALA and HCA and chemotherapy has shown a complete disappearance of brain metastases (personal communication). Immunohistochemistry studies on several specimens of primitive and metastatic human cancers, such as colon, breast, lung, ovarian and pancreas, have, also revealed an overexpression of hypoxia-inducible factor 1 (HIF) (Zhong et al. 1999). This overexpression supports two basic biological behavior of cancer and its metastases, an altered glucose transport and a limited diffusion of O 2 , glucose and nutrients (Liu et al. 2002). Hypoxic tumor cells become hypersensitized to glycolytic inhibitors (Liu et al. 2002) and to hyperthermia (Baronzio et al. 2006), reinforcing our hypotheses on metabolic treatment of metastatic cancer.

Discussion and conclusions
Patients with brain metastases have usually a short survival. Historical studies have demonstrated that with no treatments the survival is of the order of one -two months, due to systemic progression in sites other than brain. Although brain metastases incidence is increasing, there is no consensus for their treatment. Currently, treatment options include WBRT, surgery, chemotherapy and SRT/CRT. WBRT has the advantage of being easily and widely available and is able to extend survival to three to six months. In the case of solitary metastases, the addition of surgical resection to WBRT has doubled the survival, in the range of 10 -12 months (Patchell et al. 1990, Heilbrun andAdler 2010). However, many patients have metastases in locations not amenable to surgical resection. STRT, for these patients has demonstrated in terms of survival and palliation to be a reliable clinical tool www.intechopen.com (Brown and Pollock 2005). For larger lesions surgery could be considered when feasible in alternative to STRT even though in our opinion the SRT as first attempt could avoid the risk of seeding and partial resection. Surgery, in our institution, showed its major role in two different settings, i.e. for solitary brain disease with a controlled disease outside the brain and for resection of large necrotic masses, as result of previous STRT (mainly for lesions of more than 45 mm of diameter). A recent work has confirmed that previous surgical treatments have a negative impact on survival, suggesting that intervention must follows SRT (Vijayalaxmi et al 2004). As outlined by De Angelis (1994), another biological aspect, favoring the use SRT compared to WBRT, relies on that, approximately half of patients have single metastases and 20% of patients have only two metastatic lesions at the moment of their diagnosis. This aspect suggests that metastases to brain must be considered and treated as a local disease process. We suggest that the correct approach to patients bearing brain metastases should have to consider palliation as first intent. SRT, which reach this need faster than WBRT, is to be considered the treatment of choice mainly for patients bearing up to 3 lesions at first diagnosis, reserving WBRT as adjuvant to SRT and for palliation attempt to those with more than 3 lesions. Surgery must be used for patients without evident primary tumor and for necrotic lesions following aggressive radiotherapy. Furthermore, the altered glucose metabolism of metastases, suggests that the metabolic treatment is a promising line of research that could have significant therapeutic applications in a near future.