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Essay: Dissertation: Brain tumours

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Abstract: Brain tumor is abnormal growth within the brain in which the cells divide uncontrollably this growth invades the brain and causes a variety of complications some forms like glioblastoma multiforme grows more aggressively than others. Brain metastases are the primary intracranial tumors and their occurrence is growing with time, some of these tumors are difficult to cure and thus represents poor prognosis. The use of various techniques like surgery, chemotherapy and radiotherapy has provided some insightful knowledge but no efficient option has been available that can be used for the treatment of all types of tumors. Chemotherapy has generally shown detrimental side effects thus limiting its use. The dawn of new technologies in the field of medicine has led to the discovery of novel therapeutic molecules and the resulting targeted therapies like Sorafenib, Lepatinib.Cediranib and Trastuzumab etc that are showing some promising results in the treatment of brain tumors in this review we will look at all these different therapeutic techniques.
1.1 Brain
Brain is the portion of central nervous system that is located within the skull. It is a soft spongy mass of tissues and it is protected by bones of skull and three thin membranes called meninges (Kamble and Rane, 2013).
1.1.1 Anatomy of the brain
Commonly the nervous system is divided into two parts, namely the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS is composed of the brain and its cranial nerves plus the spinal cord. In this section we concisely study the structures of the cells and the anatomy of the brain. The brain is primarily made up of two types of tissue, the Gray Matter (GM) and the White Matter (WM). Gray matter is constituted of neuronal and glial cells, also known as the neuroglia or the glia, which account for the control of brain activity. The cortex on the other hand is a coating of gray matter that entirely covers the brain and the basal nuclei are the gray matter nuclei located deep inside the white matter. The basal nuclei are made up of the caudate nucleus, pallidum, putamen and claustrum. The cerebral cortex is connected with the rest of the brain regions through white matter fibers knows as myelinated axons while the left and right brain hemispheres are connected through a thick band of white fibres known as the corpus callosum. (Narendran et al., 2012).
Figure 1: Anatomy of the brain (Narendran et al., 2012).
As can be seen (Figure 1) the brain is mainly comprised of the cerebrum, the cerebellum and the brain stem. Longitudinal fissures divide the right and left hemispheres which are each further fractioned into 4 areas known as lobes. The frontal lobe lies in the front of the brain behind which can be found the parietal lobe, the occipital lobe can be found at the back of the brain and each side of the brain is composed of the temporal lobe.
1.2 Brain tumor
A brain tumor is an abnormal growth of tissue in the brain. Unlike other tumors, brain tumors spread by local extension and rarely metastasize (spread) outside the brain. Brain Tumors can be either benign or (non-cancerous),or malignant, meaning they may be cancerous. It is estimated that between 30000 and 35000 new cases of primary brain tumors (PBT) will be diagnosed in the upcoming year in the USA (Newton, 2006).In India near about 80,271 people are affected by various type of tumor (2007 estimates).Brain tumor segmentation in Magnetic Resonance Imaging (MRI) is a complex problem in the field of medical imaging. Swarm intelligence is a popularity gaining area in the field of optimization and researchers have developed various by modeling the behaviors of different swarm of animals and insects such as ants, termites, bees, birds, fishes (Kamble and Rane, 2013).With the aid of swarm intelligence it is possible to create computer simulations of biological concepts. The reliable segmentation in magnetic resonance imaging is greatly important for surgical plans and the assessment of therapies.
Figure 2: One axial slice of a MR image of the brain showing tumor areas. (Narendaran et al., 2012).
As can be observed in Figure 2, in addition to the solid portion of the tumor each primary tumor may be associated towards other areas such as Necrosis and Edema. Edema is the increase of brain volume arising from an increase in sodium and water content, it is also one of the leading factors towards mortalities suffered through brain tumors.
1.2.1 Benign vs. Malignant
Neoplasms of the brain are normally referred to as tumors and not brain cancers even when they are malignant. This is because unlike neoplasms occurring somewhere else in the body, unique behaviors can be seen while observing brain tumors, mainly because their symptoms arise due to localized growth within the brain and that they rarely ever spread to the rest of the body. (Bauman and Macdonald, 2007).
Brain tumors which grow in a controllable fashion and do not spread to surrounding tissues and structures are known as Benign brain tumors. Contrary to how they sound benign tumors can also be fatal or functionally deterring, especially when found at the base of the skull where their effects can spill over into structures of the brainstem, the eyes or the cranial nerves, places where their surgical or radioactive treatment becomes difficult. Typical types of benign brain tumors found are Acoustic Neuroma, Craniopharyngioma, Meningioma and Pituary Adenoma. On the other side tumors with a disposition for rapid growth, spreading to other structures and/or to the other parts of the neuroaxis are known as Malignant brain tumors. Some types of Malignant tumors found within the brain are the Anaplastic Astocytoma and the Glioblastoma, Primary CNS Lymphoma and Medulloblastoma. Low grade gliomas are normally taken as slow growing neoplasms but in many case they recur even after conventional treatments, developing a malignant conversion over the passage of time.
1.3 History
The history of brain tumor surgery is central to the development of neurosurgery as a specialty. William Macewen is considered to have performed the first successful brain tumor removal in 1879 in a young woman. In his article he stated that he removed “the usual fungous tumor of the dura mater, likely a meningioma, after localizing the tumor to the region of the left central area. His comments imply that he had some experience with such tumors, although he does not mention prior successful surgical removals. In the late 19th century accounts began to be published on attempts to remove brain tumors (meningiomas). Macewen, Victor Horsley, and William W. Keen began to perform aggressive maneuvers in attempting brain tumor removal. Nevertheless, they describe limited systematic diagnostic processes beyond localization by clinical examination. Harvey Cushing is usually credited with making the greatest early strides toward brain tumor removal (Preul, 2005). Certainly, he did advance operative techniques with his
adoption of new anesthetic methods and his use of “motor driven suction” and “electrosurgical devices.” Cushing did not, however, take advantage of new technology for diagnosis in some critical instances. For example, he was slow to adopt Walter Dandy’s ventriculography procedure. Al- though Dandy claimed that at least one third of brain masses could be readily localized using his air injection method, still in 1927 Cushing only advocated the method in “obscure cases.” Other practitioners were rapidly adopting new technology for use in neurosurgery. At least by the first decade of the 20th century, only a few years after the introduction to the world of x-rays in late 1895, Fedor Krause was using x- rays routinely for assistance in localizing intracranial tu- mors. In Cushing’s 1913 chapter of W. W. Keen’s textbook on surgery, the word “x-rays” is used only once. In contrast, by 1911 Krause had written an entire chapter devoted to “Radiography,” in which he promoted the benefits of x- rays for diagnosis of masses and tumors that had changed the contours of the skull or that had left osseous deposits, and in cases in which the neurological examination was “mute.” The history of brain tumor surgery makes for fascinating reading. Advancements in technologies directly affected the ability of neurosurgeons to remove tumors and at the same time decreased operative risk. As well, the personalities of the first and second generations of neurosurgeons helped to forge through what were often discouraging surgical outcomes. At times their personalities mingled, pro- viding for even more drama. Although we have made much progress in technological and diagnostic developments for neurosurgery, we still face the challenge of substantially increasing the survival rates for patients with many types of brain tumors
1.4 Types and grades of brain tumor
1.4.1 Tumor Grade
Brain tumors are graded by doctors according to the appearance of their cells beneath a microscope. (NCI all you need to know about tumors).
Grade I: Benign Tissue. The cells exhibit normal growth and look very similar to normal brain cells.
Grade II: Malignant Tissue. The cells exhibit a further warped appearance compared to that observed in the first grade.
Grade III: The malignant tissue cells exhibit active anaplastic growth and appear much different than the normal cells.
Grade IV: By this stage the malignant tissue cells exhibit rapid growth and appear severely abnormal.
Concerning appearance lower grade tumor cells, cells from the first two grades are closer to normal while also exhibiting slower growth in comparison to the higher grade tumor cells of the third and fourth grade. Even though it is more common among adults compared to children, low grade tumors may gradually transform into high grade tumors over time.
1.4.2 Types of Primary Brain Tumors
There are several forms of primary brain tumors, they are named according to the type of cells/the part of the brain where they first form (NCI all you need to know about tumors). A Glioma is an example as most primary brain tumors begin in glial cells. It’s most common forms among adults are;’
Astrocytoma:
Named for the star-shaped glial cells Astrocytes, they can be found in any grade and most often arise in the cerebrum of adults.
Grade I or II: Commonly referred to as a low-grade glioma
Grade III: Anaplastic Astrocytoma. High grade.
Grade IV: Commonly referred to as a Glioblastoma or a malignant Astrocytic Glioma.
Meningioma:
Named aptly as it arises in the Meninges, it usually starts of benign but may grow from grade I, grade II to grade III
Oligodendroglioma:
Arising from cells which comprise of the fatty substances responsible for covering and protecting nerves the Oligidendroglioma is usually found in the cerebrum in middle aged adults. It is commonly observed in grade II and III.
Medulloblastoma:
A grade IV tumor usually arising in the cerebellum it is also referred to as a primitive neuroectodermal tumor.
Grade I or II astrocytoma:
While the most common type is the grade I Pilocytic Astrocytoma this tumor may occur anywhere in a child’s brain.
Ependymoma:
Commonly found in children and young adults, it arises from the cells of the ventricle linings or the spinal cord’s central canal. It can be observed in Grades I, II and III.
Brain stem glioma:
Appearing in the lowest part of the brain this tumor can be low or high grade. It’s most common type is the Diffuse Intrinsic Pontine Glioma.
1.5 Prevalence
Brain tumor incidence rate in the USA according to a (1985-1994) survey was used to estimate the number of individuals living with the disease for the year 2000 the results were 13.8 per 100,000 with 2, 5, and 10 year survival rates of 58%, 49%, and 38%, respectively (Freels et al., 1999). The prevalence rate for all primary brain tumors was 130.8 per 100,000 with approximately 350,000 individuals estimated to be living with the diagnosis in the US in 2000. The prevalence rate for malignant tumors, 29.5 per 100,000, was similar to previous surveys. The prevalence rate for benign tumors, 97.5 per 100,000, is current (Freels et al., 1999).
1.6 Causes
Primary brain tumors almost always occur spontaneously in the brain itself without no known cause while secondary tumors have some of the following causes
‘ Genetic Changes
‘ Hereditary
‘ Errors in fetal development
‘ Ionizing radiation
‘ Electromagnetic fields (including cellular phones)
‘ Environmental hazards (including diet)
‘ Viruses
‘ Injury to brain
‘ Immunosuppression
1.7 Brain Tumor Symptoms (NCI all you need to know about tumors)
‘ Headaches:
Possibility it may be severe and may be aggravated in the morning or with activity.
‘ Seizures:
Convulsions, also known as motor seizures are uncontrollable spasms of someone’s muscles. Various sorts of documented seizures include Myclonic and Tonic Clonic seizures (Grand Mal).
The variations between the two types are;
o Myclonic:
‘ Single or Multiple events of muscle spasms and rapid contractions.
o Tonic Clonic (Grand Mal):
‘ Unconsciousness followed by spasms and relaxation of muscles
‘ Loss of control over body functions
‘ Short period without breath and a blue discoloration throughout the body
‘ Sensory:
o No unconsciousness but a change in the senses of sight, smell or hearing.
‘ Complex Partial:
o Might be attributed towards a loss of awareness as well as a partial or total loss of consciousness and it can also be associated with repeated unintentional movements such as twitches, memory reformation, nausea and vomiting.
1.7.1 Symptoms that may be specific to the location of the tumor include:
‘ Pressure or headache in the vicinity of the tumor,
‘ Loss of balance and degradation of fine motor skills. Linked with tumors found in the cerebellum.
‘ Changes in personality and judgment including sluggishness, lack of initiative, muscles weakness or even paralysis. Linked with tumors found in the frontal lobe in the cerebrum.
‘ Complete or Partial loss of sight. Linked with tumors in the occipital or temporal love in the cerebrum
‘ Alteration in the perception of touch or pressure of touch, limb weakness on a single side of the body, confusion between left and right sides of the body. It is linked to a tumor in the frontal or parietal lobe in the cerebrum.
‘ Loss of vision, including partial loss and double vision. Linked to a tumor in the temporal, occipital lobe or the brain stem.
‘ Changes in speech, hearing, memory or emotional behavior state such as problems in comprehension and addition in aggression. Linked with a tumor in the frontal and temporal lobes of the cerebrum.
‘ Lactation and altered periods of menstruation in women, and abnormal growth in adult limbs. Linked with a pituitary tumor.
‘ Weakness or numbness of the facial muscles, difficulty in swallowing and double vision. Linked with a tumor within the brain stem.
‘ Inability to look upward. Linked to a Pineal Gland Tumor.
1.8 Brain Tumor Diagnosis
Identifying a brain tumor usually involves a neurological examination, brain scans, and/or an analysis of the brain tissue (Priyanka and Singh, 2013). A neurological examination is a series of tests to measure the function of the patient is nervous system and physical and mental alertness. A brain scan is a picture of the internal structures in the brain. A specialized machine takes a scan in much the same way a digital camera takes a photograph. The most common scans used for diagnosis are as follows:
1.8.1 MRI (Magnetic Resonance Imaging)
MRI is a scanning device that uses magnetic fields and computers to capture images of the brain on film. It does not use x-rays. It provides pictures from various planes, which permit doctors to create a three-dimensional image of the tumor (Logeshwari and Karnan, 2010).The MRI detects signals emitted from normal and abnormal tissue, providing clear images of most tumors.
1.8.2 CT or CAT scan (Computed Tomography)
CT scan combines sophisticated x-ray and computer technology. CT scan shows a combination of soft tissue, bone, and blood vessels (National Brain Tumor Society).CT images can determine some types of tumors, as well as help detect swelling, bleeding, and bone and tissue calcification. Usually, iodine is the contrast agent used during a CT scan.
1.8.3 Biopsy
A biopsy is a surgical procedure in which a sample of tissue is taken from the tumor site and examined under a microscope (National Brain Tumor Society).The biopsy will provide information on types of abnormal cells present in the tumor. The purpose of a biopsy is to discover the type and grade of a tumor. A biopsy is the most accurate method of obtaining a diagnosis.
1.9 Brain Segmentation
Several methods have been employed to perform brain segmentation and some of them are available through computer softwares such as Brain-Visa, FSL and Brain suite.
Although a problem faced with these softwares is that most of them break down if a tumor is present in the brain, particularly if it is present on the border of the brain, refer to Figure 5. (Narendran et al., 2012) performed a symmetry analysis along the assumption that tumors are normally not symmetrically located in both hemispheres, even though the whole brain is approximately symmetrical. They first segmented the brain through a histogram analysis and morphological operations. This lead to a partial segmentation, where a part corresponding to the tumor may have had been missing. The algorithm was applied on the gray level image of the head to ascertain the value of the symmetry plane due to the nonsymmetrical nature of the brain. The calculated symmetry planes of the head and of the segmented brain in typical cases are approximately equal and this approximation is acceptable in pathological cases for the purpose of detecting tumors.
(a) (b)
(c) (d)
Figure 3: Pathological brain segmentation through existing methodology
(a) One slice of the original image on two examples
(b) Segmented brain by histogram analysis and morphological operations using Brain Visa.
(c) Segmented brain by BET using FSL.
(d) Segmented brain by BSE using Brain suite.
1.10 Different therapeutic Techniques for Brain Tumor
1.10.1 Radiotherapy
Whole brain radiotherapy (WBRT) has been imperative in the treatment of metastatic brain tumors for over fifty years. Historically the average survival of patients carrying brain metastases with supportive care alone is only one year while the WBRT extends the survival to almost 3 years (Peacock and Lesser, 2006). Considering all the primary types of tumors found the Melanoma tumor is the most resistant to radiotherapy. (Barranco et al., 1971). Melanoma is also mostly underrepresented in the currently grounded WBRT literature (Komarnicky et al., 1991). The role of WBRT in the treatment of melanoma brain metastasis remains to be proved. The overall reported average survival of patients, with the WBRT, is around 2 years and this puts a stain on the perceived benefits of WBRT application for the Melanoma Metastases.
Even though WBRT is typically considered a safe and noninvasive method, some emerging research has suggested notable drawbacks, including fatigue, drowsiness and neurocognitive sequelae (Peacock and Lesser, 2006). These could greatly impair the quality of the patients lives being treated with WBRT. In a recent randomized controlled trial, through specific neuropsychological assessment methods, it was ascertained that patients receiving WBRT suffered from a significantly grander decline in memory and learning in comparison with patients receiving localized radiation with stereotactic radiosurgery (SRS) (Chang et al., 2009). Taking these into consideration, when considering WBRT as a treatment option, the risks and benefits associated with it should therefore be carefully analysed in each individual patient’s case and preference should be shown to other more effective treatment alternatives when they are made available. In special palliative cases a more accelerated course with 400 cGy fractionated dose up to 20 Gy of total dose may be considered. According to the available evidence, surgical resection followed by a WBRT is an effective means of treatment for patients with single, surgically accessible, Brain metastasis exhibiting control over extra cranial disease and a good general condition (Gaspar et al., 2010)
Multiple brain metastasis, in seventy to ninety percent cases WBRT permits the control of presenting neurological symptoms without enabling acute neurological adverse effects (Hoegler, 1997). Prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been deemed as a strategy to prevent dissemination to the brain. PCI resulted in a reduction in the incidence of BM from eighteen to eight percent, but did not impact overall survival (Sun et al., 2011). Importantly, PCI leads to lower rates of both immediate and delayed recall, implying that the use of PCI impairs memory function in treated patients (Sun et al., 2011).
 
1.10.2 Stereotactic Radiosurgery
Delivering a single but large dose of focused radiation to destroy lesions localized by stereotaxy Stereotactic Radiosurgery (SRS) minimizes radiation exposure to normal brain parenchyma by crossfiring from several directions, resulting in rapid radiation falloff in the surrounding tissues. The tumoricidal mechanism of SRS, believed to mediate through changes in tumor vasculature, is different from WBRT and thus tumors traditionally regarded as radioresistant such as melanoma, renal cell carcinoma and sarcoma has shown susceptibility to SRS (Niranjan et al., 2004). SRS as a primary treatment method, has shown to be effective for melanoma metastases (Mehta et al., 1992). Multiple retrospective series have shown a median survival of 61-0 months following treatment of SRS for patients with either single or multiple brain metastases (Brown et al., 2002). These results mathc up with results obtained from numerous surgical series for melanoma brain metastases of 51-0 months (Wronski and Arbit, 2000). Although such retrospective data comparison is filled with the danger of relating to inherent selection and follow-up biases, plus the fundamental difference in the patient population sample, attempts to conduct potential randomized studies to compare the role of surgery against that of SRS in the management of cerebral metastases in general has not been successful due to significant obstacles in patient accrual (Muacevic et al., 2008). Current practice therefore has to rely on judicious evaluation of
available retrospective data.
A few advantages over conventional surgeries are that first, SRS can treat inaccessible tumor minus the increased risks of surgical resection, especially when eloquent brain has to be transgressed to reach the lesions. It is considered less invasive, requires shorter hospital stayovers because only a single-fraction of radiation is given, and is open for patients with major cardiac, renal, pulmonary, or hematologic diseases and for those phobic of surgeries. Some major drawbacks of SRS include first, the restriction in treating only small tumors (generally <3 cm) and the lack of apparent immediate treatment effects mainly due to a limit in conformity that can be achieved in a large tumor volume (>3 cm) and thus, treatment of such tumors with SRS could result in an unaaceptably high integral radiation dose to the surrounding brain parenchyma (Smith and Lee, 2007). This occurs because the tumoricidal effect of SRS relies on the disruption of normal cellular activity and proliferation and cell death which evolves gradually over a period of weeks to months. Keeping all this in mind, a collaborative approach between neurosurgeons and radiation oncologists is therefore imperative in providing a complementary and efficient utilization of both modalities. For example, a patient carrying multiple small deep-seated tumors with a dominantly large symptomatic lesion would benefit most from a combined treatment with SRS for the smaller lesions and surgery for the dominant symptomatic lesion. Such a mix and match approach presumably provides the best local disease control and for melanoma patients right now with an increasing propensity for developing multiple brain metastases is particularly desirable as a substitute, global therapies including WBRT often lacks treatment efficiency as discussed above (Delattre et al., 1988).
In the past, WBRT has been used as a standard adjuvant therapy following local treatment with surgery or SRS. This is based on evidence from randomized controlled studies that indicate tumor relapse rates to be higher when WBRT was forgone (Aoyama et al., 2006). However, as melanoma is again largely underrepresented and understated in these studies, the true efficiency and use of WBRT in preventing melanoma metastasis relapse cannot be conclusively established based on current evidence. On the other hand, a recent randomized study from MD Anderson Cancer Center which demonstrates patients with cerebral metastases having more significant deterioration in
their neurocognitve functions after adjuvant WBRT than their no-WBRT counterparts affirms the speculation concerning the harmful neurological sequelae of WBRT (Chang et al., 2009).
In view of these, many authors have suggested an alternative to the application of WBRT, SRS could be considered as a boost treatment to the tumor resection cavity for the purpose of minimizing local tumor recurrence, especially for patients with radioresistant tumors like melanoma (Mathieu et al., 2008). With this premise, at MD Anderson Cancer Center, a phase III randomized controlled trial was opened in August 2009 to evaluate the efficacy of postoperative SRS on the resection bed of cerebral metastases in reducing the risk of local tumor recurrence at six months. This trial, expected to complete in 2014, will provide important data to clarify the proper use of this adjunctive treatment.
1.10.3 Surgery
Metastatic brain tumors characteristically form circumscribed and rounded masses, rendering them highly amenable to surgical extirpation and the delivery of a local cure? following complete tumor excision. This has particularly been the case for patients harboring only a single metastasis as the results from three landmark surgical randomized controlled trials collectively demonstrate that patients survive longer with lower recurrence after combined treatment with surgical resection and WBRT than WBRT alone (Hart et al., 2005). For patients harboring multiple brain metastases, however, the survival benefits derivable from surgery are less clear, as data suggest that patient outcome is tied in more closely with the systemic tumor burden than the central nervous system (CNS) disease (Chang and Adler, 2000). In view of these, as patients with cerebral metastases represent a heterogeneous group of patients with less than 30% having only a single metastasis, a custom approach is therefore required to tailor the utilization of surgery to the clinical condition of each individual patient. It is undeniable that surgery can play an indispensable palliative role in alleviating neurological symptoms from the local mass effect of the tumor even for patients with advanced disseminating disease. Currently no other treatment modality can effect
immediate reduction of tumor mass effect, neural decompression, and restoration of CSF flow more efficiently than surgery. This is particularly the case when the tumor is located in the posterior fossa when expedient surgical resection could mean life or death in preventing fatal brainstem compression or herniation. With modern neurosurgical armamentarium including neuronagvigation, intraoperative imaging and functional mapping, surgery for brain metastases can be performed in unprecedentedly precise and controlled manner with minimal morbidity and mortality (Paek et al., 2005). It is therefore of paramount importance that all patients with cerebral metastases are assessed as candidates for surgical resection irrespective of their overall cancer status or the multiplicity of their CNS disease.One significant, but often unrecognized technical issue when performing surgery on cerebral metastases is the notion of en bloc versus piecemeal resection in minimizing intraoperative tumor spillage. Because brain metastases are circumscribed tumors, it has been postulated that the violation of tumor capsule and perturbation of tumor content during piecemeal resection could lead to dissemination of neoplastic substrates into the neuraxis whilst en bloc resection along a gliotic plane in the brain parenchyma could preserve the natural biological containment of the tumor cells (Suki et al., 2008). This speculation has been supported by some retrospective data in showing a higher rate of leptomeningeal disease observed in patients undergoing piecemeal metastatic tumor resection than patients having en bloc resection (Suki et al., 2008). For metastatic melanoma, however, as tumor hemorrhage often occurs, the importance of tumor seeding due to operative maneuvers may be played down by the fact that the pressure generated during the ictus of hemorrhage would inevitably rupture the tumor capsule, seeding a myriad of microscopic tumor foci into the locoregional milieu. Nevertheless it would still make good oncologic sense and be prudent, when feasible, to perform en bloc resection, particularly allowing for generous margin to eradicate local hemorrhagic seeding for melanoma to improve local disease control, reserving piecemeal resection in cases when the tumor is too large in size or when adjacent brain eloquence precludes safe en bloc resection. Further prospective data will help clarify these issues.
1.10.4 Chemotherapy
Chemotherapy has traditionally played a limited role in the treatment of brain tumor and has been reserved for patients who have failed other treatment modalities. Although blood brain barrier (BBB) is interrupted, brain therapeutic levels of many drugs do not remain long enough or at high enough concentrations to ensure cell apoptosis. Furthermore, the drug distribution is not uniform, with a preferential concentration in the necrotic area and a rapid diffusion into normal brain. Treatment efficacy is determined by the sensitivity of tumor cells to chemotherapeutic agents. Brain metastasis from Non-small-cell lung cancer (NSCLC) and breast cancer are less sensitive to chemotherapy. There is, therefore, a strict relation between metastatic and primary tumor chemosensitivity and the choice of chemotherapeutic regimen. In patients with BM from breast cancer, cisplatin and etoposide yielded a high objective response rate of 55% in CNS (Boogerd et al., 1992). Recently, a new class of chemotherapeutic agents that own the ability to cross the physiological BBB holds results for patients affected by BM. Topotecan is a semi-synthetic camptothecin derivative that selectively inhibits topoisomerase I in the S-phase of the cell cycle, interfering with the replication and transcription processes in the tumor cell, which eventually leads to cell death. In addition to its well-established activity against primary tumors, topotecan freely penetrates the BBB and measurable levels of topotecan and its metabolites can be detected in the cerebro-spinal fluid. Topotecan monotherapy was evaluated in 20 small cell lung cancer (SCLC) patients with asymptomatic brain metastasis after failure of first-line chemotherapy, but without radiation therapy, suggesting that topotecan can induce a high response rate in SCLC brain metastasis (Ardizzoni et al., 1997). Wong and Berkenblit affirm that topotecan, especially in patients with SCLC or breast cancer, has shown excellent response rates against BM and may effectively combine with WBRT and other chemotherapeutic drugs (Wong and Berkenblit, 2004). A recent study confirms the good efficacy of topotecan in SCLC but, in contrast with other studies, do not support the use of topotecan in brain metastases arising from other tumors. In addition, the ability of topotecan to cross the BBB suggests that it may also have a prophylactic role against brain metastases from SCLC (Lorusso et al., 2006). Temozolomide (TMZ) is a novel oral alkylating agent that has demonstrated efficacy in the treatment of a variety of solid tumors. Because of its small molecular weight, TMZ crosses the BBB and in addition can be administered orally. TMZ is also associated with a low incidence of severe adverse events. Based on the clinical pharmacology of TMZ, it has been suggested that TMZ may be effective in the prevention and treatment of brain metastases.(Paul et al., 2002) have reported that, among 40 patients with advanced melanoma treated with TMZ, the incidence of CNS relapse was lower in patients treated with TMZ. Only two patients of 19 (10%) treated with TMZ developed CNS metastasis.
1.10.5 Molecular Targeted Therapy
Elevated expression or mutation of receptors and intracellular downstream effectors has been demonstrated in metastatic progression. These pathways are controlled by the binding of growth factors to tyrosine kinase receptors. Specific targeting of these signaling pathways that lead to altered cellular proliferation and cell migration and invasion could provide new targets for brain tumor treatment. Targeted therapies block activation of oncogenic pathways, either at the ligand-receptor interaction level or by inhibiting downstream signal transduction pathways, thereby inhibiting growth and progression of disease (Table 2). Because of their specificity, targeted therapies should theoretically have better efficacy and safety profiles than systemic cytotoxic chemotherapyor radiotherapy.
1.10.5.1 Trastuzumab
The incidence of brain metastasis is particularly high in patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer (Park et al., 2009).With the exception of HER2 that does not have a ligand-binding domain, the rest of the HER family receptors, upon ligand binding to their extracellular domain, forms either homodimers or heterodimers that initiate their intrinsic tyrosine kinase activity controlling the activation of various downstream effectors pathways. Intracardiac injection of the control and HER2-transfected 231BR cells produced similar numbers of brain micrometastases, but the HER2 transfectants produced 2.5- to 3-fold greater numbers of large BM (Palmieri et al., 2007). These data provide the evidence that HER2 over expression changes the natural history of breast cancer to promote outgrowth of tumor cells in the brain (Palmieri et al., 2007).Trastuzumab is a
humanized monoclonal antibody that targets the extracellular domain of HER2. It has been approved for the treatment of metastatic breast cancer, alone or in combination with chemotherapy, for patients with tumors that over express the HER2 receptor. In a retrospective study with patients affected by HER2-positive breast cancer that developed BM, (Nam et al., 2008) reported a median OS of 13 months in patients who received trastuzumab compared with 4 months in those who did not receive trastuzumab and 3 months in patients with HER2-negative tumors.(Bartsch el al., 2007) also evaluated the effect of the continuation of trastuzumab after diagnosis of BM for 17 patients, in comparison with a cohort of 36 patients with HER2 over expressing tumors not treated with trastuzumab after WBRT. In this study, potassium per sulfate (KPS) and trastuzumab were associated with better overall survival, with a trend towards longer time to in brain progression. The results demonstrated that trastuzumab may act synergistically with radiation in a HER2 level-dependent manner encouraging further assessment in combination with WBRT. However, a met analysis by (Bria et al., 2008) used the data from 3 large phase III trials in the adjuvant setting, the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Herceptin Adjuvant trial (HERA), and the North Central Cancer Treatment Group (NCCTG0 N9831, indicating that the incidence of CNS disease was significantly higher in the trastuzumab-treated patients when compared to the non-trastuzamab-treated patients. To evaluate the potential of effects on the CNS, a four-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved in the current study exceeded those reported in patients after intrathecal administration. The results support future studies for intrathecal application of trastuzumab in patients with brain metastases in HER2-positive breast cancer (Braen et al., 2010). Recent studies have examined the influence of patient characteristics on survival and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to rationalize the design, stratification and interpretation of clinical trials. The Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification based on clinical factors (KPS, age, and control of extracerebral disease) the prognostic indicator for patients with BM (Gaspar et al., 1997).
1.10.5.2 Lapatinib
Lapatinib is a small-molecule tyrosine kinase inhibitor that inhibits the epidermal growth factor receptor ( EGFR) and human epidermal growth factor receptor 2 (HER2) and has the potential to be used when trastuzumab resistance develops. In mice with BM, treatment with lapatinib results in a statistically significant decrease in phosphorylated HER2, suggesting that pharmacologically relevant levels are achieved in CNS metastatic lesions (Gril et al., 2008). Interestingly, lapatinib can cross the BBB and has modest activity in breast cancer metastases in the CNS (Geyer et al., 2006). A recent study demonstrated that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with BM after cranial radiation (Iwata et al., 2010). In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream-signaling proteins, cell proliferation, and migration in 231-BR cells. Mice bearing HER2 overexpressing xenographs which received lapatinib developed less frequent BM compared to control (Iwata et al., 2010). Several trials have demonstrated the safety and efficacy of lapatinib alone and in combination with capecitabine, paclitaxel or endocrine therapy in patients with advanced HER2-positive breast cancer (Geyer et al., 2006). In the EGF105084 study, 242 patients with HER2 overexpressing breast cancer with CNS disease received lapatinib after cranial radiotherapy (Lin et al., 2009). Clinically significant CNS objective responses were observed in 20% of patients treated with lapatinib plus capecitabine after disease progression on single-agent lapatinib. Overall, 40% of patients achieved a 20% or greater reduction in the volume of CNS lesions. Lapatinib seems to be associated with regressions of BM in patients who have progressed despite trastuzumab and radiotherapy (Lin et al., 2009).
 
1.10.5.3 Erlotinib and Gefitinib
Erlotinib and gefitinib are small molecules, reversible inhibitors of the tyrosine kinase domain of the EGFR resulting in the loss of autophosphorylation and subsequent downstream signaling through the The Ras/Raf/Mitogen-activated protein kinase MEK (RAS-RAF-MEK pathway). These small molecules have demonstrated efficacy in patients with relapsed NSCLC and as initial therapy for patients with advanced NSCLC and sensitizing EGFR mutations. Specific activating mutations within the tyrosine kinase domain of EGFR have been identified. The missense mutation L858R in exon 21 and the in-frame deletion in exon 19, nested around the amino acid residues 747 to 750 of the EGFR polypeptide, account for >85% of all clinically important mutations related to tyrosine kinase inhibitors (TKI) sensitivity. The detection of EGFR mutations in tumor tissues has been applied for predicting the response of TKI treatment and hence guiding the treatment for advanced NSCLC. However, brain tissue is the only available tissue for the determination of EGFR status, and the question of concordance between primary and metastatic EGFR status becomes crucial for therapy (Burel-Vandenbons et al., 2013). Studies on paired brain metastases/NSCLC suggest a possible discordance, but they are too few and are essentially insufficient to clarify this problem. A panel of 30 EGFR kinase domain mutations that were recently reported in NSCLC patients was cloned and expressed for analysis of kinase activity, transforming potential, and drug sensitivity. Most somatic mutations of EGFR are associated with 60%-80% response rates in patients treated with gefitinib or erlotinib (Rosell et al., 2009). Some initial case reports have showed activity of gefitinib and erlotinib on BM from NSCLC, suggesting a potential role of TKI in the treatment of NSCLC patients with metastatic CNS disease. (Ishida et al., 2004) administered gefinitib, in two women, affected by differentiated adenocarcinoma of the lung with BM without any previous systemic therapy. In both
patients, the metastatic brain lesions reduced notably after gefinitib treatment. Similarly, in two patients that received gefitinib orally, the disappearance or the reduction of the
BM has been demonstrated (Nishi et al., 2006). (Tang et al., 2011 reported the case of a woman with diffuse BM from lung cancer who experienced total regression of the metastases under gefitinib treatment. The tumor was positive for an EGFR exon 19 deletion mutation. She was treated with gefitinib 250 mg/day. One year later, the diffuse brain metastases had totally resolved. Recently, a case of NSCLC with CNS metastases harboring a rare EGFR double-activating mutation has been reported as showing a good clinical response to erlotinib (Masago et al,. 2010). In another case, a complete remission in brain disease from NSCLC using erlotinib was obtained (Lai et al., 2006). In this case, the presence of somatic mutation in EGFR gene has been associated with a higher responsiveness to erlotinib. The authors sequenced exons 18-21 of the EGFR gene using DNA extracted from tumor and normal lung tissue obtained at a previous resection: the L858R mutation was detected. This point mutation in the activation loop of the kinase domain is linked to erlotinib responses (Lai et al., 2006). In a phase II trial, Ceresoli and colleagues assessed the efficacy of gefitinib in 41 patients with NSCLC metastatic to the brain. In total, disease control rate was observed in 11 patients. The authors suggested that gefitinib, at the standard dose of 250 mg/day, can be active on brain disease in NSCLC patients (Ceresoli et al., 2006).
 
1.10.5.4 Multitarget Tyrosine Kinase Inhibitor
The MAPK pathway is a major intracellular signal transduction pathway that is responsible for cellular proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis. Sorafenib is an orally active multikinase inhibitor that blocks intracellular kinases in the Raf/MEK/ERK pathway that are involved in tumor proliferation, such as Raf-1, as well as those promoting angiogenesis, including VEGFR-2, VEGFR-3, FLT, PDGFR-b, FMA, RET, and c-KIT. In phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), sorafenib treatment was associated with a twofold increase in median PFS compared with placebo (Escudier et al., 2007). A recent study that reported five cases of intracerebral hemorrhage in metastatic renal cell carcinoma (RCC) patients with BM following treatment with either sorafenib or sunitinib raised the concern that antiangiogenic therapies, in patients with BM, may increase the risk for CNS hemorrhage (Pouessel and Culine, 2008). However, Massard and colleagues reported that patients that received sorafenib were less likely to develop BM when compared to the control group (3% vs. 12%, respectively) (Massard et al., 2010). Sorafenib may reduce metastases by suppressing the progression of visceral disease or by inhibiting brain metastasis angiogenesis. In a recent study, a patient affected by renal cell carcinoma with multiple BM was successfully treated with multimodal therapy including sorafenib (Walid and Johnston, 2009). Sorafenib has also shown promise in the treatment of patients with advanced or metastatic thyroid carcinoma. In a patient affected by follicular thyroid carcinoma and BM, symptoms and signs improved dramatically and continuously after initiation of sorafenib treatment (Shen et al., 2012). Activating mutations in the serine/threonine kinases BRAF, and NRAS were identified in 66% and 15% (Tsao et al., 2000) of melanoma cell lines, respectively, establishing MAPK signaling as a new therapeutic target in melanoma. Over 75% of BRAF mutations are characterized by the substitution of valine by glutamic acid at residue 600 (V600E) (Long et al., 2011). A phase I/II trial in which sorafenib was given in combination with carboplatin and paclitaxel reported a high response rate and longer PFS than with standard chemotherapy in metastatic melanoma patients (Flaherty et al., 2008). The most promising results in patients with BRAF mutation melanoma have been seen with drugs designed to selectively target the mutated and activated form of the BRAF kinase. The three drugs in clinical use or undergoing investigation in human clinical trials are LGX818, vemurafenib, and dabrafenib. These inhibitors are associated with specific toxicities and with the rapid development of resistance. Dabrafenib is a reversible and potent adenosine triphosphate-competitive inhibitor that selectively inhibits the BRAF V600E kinase. The phase I study showed dabrafenib to be safe and tolerable, to demonstrate activity in BRAF V600E and BRAF V600K melanoma, and to be the first drug to show activity in melanoma metastases in the brain (Menzies et al., 2012). The results of phase II BM trial
(BREAK-MB)11 (Davies et al., 2011) suggest that dabrafenib may be an effective adjunct for the treatment of BM, and that it warrants consideration as first-line therapy in patients with brain metastases, and with advanced extracranial disease. Additionally, dabrafenib was well tolerated, with the exception of intracranial hemorrhage, which occurred in 6% of patients (Menzies et al., 2012). Dabrafenib was also evaluated in a multicenter, open-label, phase 2 trial, in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. The results of this study show that dabrafenib is well tolerated and can represent a valid therapeutic strategy in patients with BRAF-mutant melanoma with BM either previously treated or not (Long et al., 2012). Sunitinib is a new, orally administered, small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs), including the VEGFRs types 1 and 2, PDGFR-? and PDGFR-?, the stem cell factor receptor c-KIT, the FLT3 and RET kinases. Sunitinib exhibits potent antiangiogenic and antitumor activity. Valid clinical activity has been observed in metastatic renal cell carcinomas and imatinib-resistant gastrointestinal stromal tumors, leading to regulatory approval in these two indications. Sunitinib or its metabolite penetrated the CNS of monkeys with rapid clearance, but does not appear to accumulate. In an open-label expanded study for the use of sunitinib in metastatic RCC, which included patients with BM, a positive response in intracranial disease was observed. In addition, 52% of patients had stable disease for at least three months (Gore et al., 2011). In a phase II study, antitumor activity and safety of sunitinib in patients with pretreated NSCLC and irradiated BM were evaluated (Novello et al., 2011). Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. Median progression-free survival was 9.4 weeks, and median overall survival was 25.1 weeks. Serious neurologic adverse events occurred in six patients (9%), and none were treatment-related. No cases of intracranial hemorrhage were reported (Novello et al., 2011).
1.10.5.5 Cediranib
Cediranib (AZD2171) is a potent oral, pan-VEGF (vascular endothelial growth factor) receptor tyrosine kinase inhibitor with activity against platelet-derived growth factor (PDGF) receptors and c-Kit. In an experimental study, BM-selected variant cells were recovered after three cycles of injection into the internal carotid artery of nude mice and harvest of BM, resulting in variants termed MDA-231 BR1, -BR2 and -BR3. Brain metastatic lesions of the selected variants contained significantly more CD31-positive blood vessels than metastases of the non-selected cell line. The variants selected from BM released significantly more VEGF-A and IL-8 into culture supernatants than the original cell line, and more VEGF-A RNA when cultured in normoxic conditions. Mice injected with MDA-231 BR3 into the carotid artery were treated with the VEGF-receptor tyrosine kinase inhibitor PTK787/Z 222584. Oral administration of the inhibitor resulted in a significant decrease in brain tumor burden, reduced CD31-positive vessels in the brain lesions and incidence of PCNA positive tumor cells, and increased apoptosis in the tumor (Folkman, 2007). In a phase II study, it has been demonstrated that AZD2171 induced vascular normalization and reduction of vasogenic brain edema in recurrent glioblastomas (Batchelor et al., 2007). In an experimental study, an hematogeneously-disseminated model of BM derived from a human androgen-independent prostate cancer, was used (JuanYin et al., 2010). BM in the DU145/RasB1 model occurs as large, expansive rounded lesions with marked peritumoral edema, as well as small infiltrative lesions. AZD2171 treatment resulted in a decreased blood volume within the center of the large tumors. Histological sections confirmed central necrosis of large tumors and that the blood vessels at the rim of the AZD2171-treated tumor were still dilated with hypertrophic endothelial cells (JuanYin et al., 2010). Similarly, with a model of advanced prostate cancer metastatic to skeleton and brain, it has been demonstrated that antiangiogenic treatment inhibited the growth of metastases in bone and brain, and reduced the morbidity and mortality of tumor-bearing mice (JuanYin et al., 2009).
 
1.10.5.6 Bevacizumab
Bevacizumab is a monoclonal antibody that binds VEGF-b, inhibiting angiogenesis. Inhibition of VEGF by bevacizumab will not only affect endothelial cells but also the tumor vasculature, suppressing new blood vessel growth and the existing vasculature. Concerns about the risk of intracranial hemorrhage initially precluded use in patients with brain metastases. A phase II trial of bevacizumab for NSCLC reported intracranial hemorrhage in patients developing cerebral metastasis during treatment, although the incidence was <1% (Sandler, 2007). However, successive studies with patients with various primary cancers demonstrated no significant increase in the risk of intracranial hemorrhage in patients with BM treated with bevacizumab (Besse et al., 2010). Findings from a multicenter prospective phase II trial showed that the addition of bevacizumab to various chemotherapy agents in patients with NSCLC and BM is safe, even though a low incidence of CNS hemorrhage was reported (Socinski et al., 2009). (De Braganca et al., 2010) suggests that bevacizumab administered with therapeutic intent for treatment of active CNS metastases may be effective safe and effective, especially for small lesions that are less likely to hemorrhage. In a new study, five patients with BM received bevacizumab combined with paclitaxel. The majority of adverse events were mild to moderate in intensity. Hypertension and proteinuria were common, and neuropathy was controlled with modification of the paclitaxel dose (Yamamoto et al., 2012).
1.10.5.7 Other Molecules
mTOR inhibitor rapamycin and its analogs are lipophilic, demonstrate BBB penetration, and have shown promising antitumor effects in several types of refractory tumors. The effects of different dose of mTOR inhibitors (rapamycin, Temsirolimus-CCI-779) on cell invasion in two brain metastatic breast cancer cell lines (MDA-MB231-BR and CN34-BrM2) were examined (Zhao et al., 2012). The two mTOR inhibitors, rapamycin and CCI-779, inhibited the invasion of brain metastatic cells only at a moderate concentration level, which was lost at higher concentrations secondary to activation of the MAPK signaling pathway. In vivo, a significant decrease was noted in the average number of micro and large metastatic lesions as well as the whole brain GFP
expression in the CCI-779. Combined with the brain MEK inhibitor SL327, high-dose CCI-779 significantly reduces the brain metastasis, and the combination treatment prohibited perivascular invasion of tumor cells and inhibits tumor angiogenesis in vivo (Zhao et al., 2012). In a patient with multiple brain lesions from non-small cell lung cancer, a weekly dose of 250 mg/m cetuximab was administered for 3 months. The target lesion showed enhancement of radiolabeled cetuximab on scintigraphy, demonstrating an accumulation of cetuximab in BM (Rades et al., 2010). Enzastaurin is a protein kinase C inhibitor with antitumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of WBRT in lung cancer patients with BM. Enzastaurin was well tolerated but did not improve overall survival or progression-free survival after WBRT in patients with BM (Gr?nberg et al., 2012).
 

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