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

Baronzio Gianfranco1, Fiorentini Giammaria2 Guais Adeline3 and Schwartz Laurent4

*1"Metabloc Cancer Center", c/o Centro Medico Kines Castano primo, (Mi) 2Oncology Unit, Hospital San Salvatore, Pesaro 3Biorébus, Paris 4Hôpital Raymond Poincaré, Garches 1.2Italy 3.4France* 

### **1. Introduction**

160 Advances in Cancer Therapy

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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.

Brain Metastases: Biology and Comprehensive

**2.4 Brain metastases biology** 

(Fidler 2002, 2010, Deichman 1998).

(Fidler 2010, Deichman 1998):

Strategy from Radiotherapy to Metabolic Inhibitors and Hyperthermia 163

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, 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

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

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 (Shaffrey et al. 2004). 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

For tutorial purpose we can divide the metastatic process to the brain in the following steps

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

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, Fidler 2002, 2010, 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

circulation form a metastatic colony (Shaffrey et al. 2004, Kang et al 2004).

Brain Barrier (BBB); D) migration and growth in the brain structure.

reported in a recent study by D'Ambrosio (D'Ambrosio et al. 2007).
