Modern Trends in Non-Surgical
Modern Trends in Non-Surgical
Treatment of Brain Tumors
Essay Submitted For Partial Fulfillment of the Master Degree in
Neuropsychiatry
By
Hesham Mohammad Ibrahim El Adrousy
M.B., B.CH. (2004)
Supervised by
Prof. Dr. Mohammad Yasser Metwally
Professor of Neuropsychiatry ()
Faculty of Medicine - Ain Shams University
Dr. Amr Abdel Moniem Mohammad
Lecturer of Neuropsychiatry
Faculty of Medicine – Ain Shams University
Ain Shams University
Faculty of Medicine
2010
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Contents
• Acknowledgement ...……................................ II
• List of Figures ………………………….….…...... III
• List of Tables …………………………..……….... V
• Introduction ……………………………………….. 1
• Aim of The Work ……………………………..…... 8
• Review of Literature:
- Chapter 1: Molecular Pathogenesis of Brain Tumors ............ 9
- Chapter 2: Targeting Critical Points .................................... 31
- Chapter 3: Immunotherapy................................................. 47
- Chapter 4: Anti-angiogenic Therapy ................................... 63
- Chapter 5: Stereotactic Radiosurgery ................................. 81
- Chapter 6: Chemotherapy .................................................. 97
- Chapter 7: Endocrinal Therapy.......................................... 111
- Chapter 8: Gene and Viral Therapies ................................. 129
• Discussion .................................................................145
• Summary ................................................................... 161
• Recommendations .................................................. 165
• References ................................................................ 167
• Arabic Summary ...................................................... 213
Acknowledgement
First and foremost, thanks to God to whom I owe my self, existence and life.
Words are not enough to express my deepest thanks and gratitude to Prof. Dr. Mohammad Yasser Metwally for all of his guidance and support in this work. I'll never forget his generous advice and kind supervision.
I would like to express also, my deepest thanks to Dr. Amr Abdel Moniem for his support, valuable observations and friendly criticism.
Finally, I would like to thank my parents for their great love and support.
Hesham El Adrousy
List of Figures
|Figure NO. |Title |Page |
|1 |The p53 and retinoblastoma cell cycle and cell death signaling pathways. |12 |
|2 |Sonic hedgehog signaling pathway. |20 |
|3 |Wingless signaling pathway. |21 |
|4 |Targeting growth factors & their receptors, and downstream intracellular |40 |
| |effector molecules. | |
|5 |Therapies directed against cancer stem cells. |41 |
|6 |Peptide-Based Vaccines. |54 |
|7 |Fusion of dendritic cells with tumor cells. |57 |
|8 |Recurrent glioblastoma treated with bevacizumab and irinotecan. |66 |
|9 |Recurrent glioblastoma treated with cediranib. |69 |
|10 |Gamma-Knife principle. |82 |
|11 |Photograph of the world’s first PerfeXion. Gamma Knife. |83 |
|12 |The CyberKnife. |85 |
|13 |Mechanism of vector-mediated gene therapy. |132 |
|14 |General mechanism of oncolytic virus selectivity. |138 |
List of Tables
|Table NO. |Title |Page |
|1 |A comparison of Gamma Knife and CyberKnife Radiosurgery |84 |
Introduction
&
Aim of the Work
Introduction
Two large epidemiologic studies, one from the Mayo Clinic and the second from the Central Brain Tumor Registry of the United States (CBTRUS) gave a remarkably similar incidence of symptomatic brain tumors with a rate of about 12 per 100,000 populations per year. Given the current United States population, this comes to about 35,000 new patients with symptomatic brain tumors who are diagnosed each year (De Angelis, 2005).
Brain tumors are the fourth most common solid malignancy in the under 45 age group, and the eighth most common in the under 65 age group. Overall, brain tumors are the second most common cause of death from neurological disease, after stroke (Hart and Grant, 2007).
Brain Metastasis is the most common intracranial tumor, with an estimated annual incidence of more than 100,000 cases. In 20 to 40% of patients with cancer, metastatic lesions travel to the brain (Sawaya et al., 1994). Gliomas are the most common primary brain tumors (Belda-Iniesta et al., 2006).
In children, brain tumors are the most common solid tumor of childhood and are second only to leukemia in their overall incidence of malignancies in the pediatric population. In children, low grade astrocytomas and medulloblastomas predominate. In adults, malignant astrocytoma and meningioma are the most common tumors (De Angelis, 2005).
Collected data on symptoms before and after surgical resection report that 32% had an improvement in their symptoms, 58–76% were not different, and 9–26% had a worsening. Neurosurgery can improve some symptoms, but it can also create new ones. Neurological complications following surgery include focal haematoma, abscess and seizures. Systemic complications include pneumonia and thromboembolic disease. Morbidity rates range from 11% to 32%, with a mortality rate of 0–20% (Hart and Grant, 2007).
High-grade primary and metastatic brain tumors are common, deadly, and refractory to conventional therapy and have median survival duration of less than one year (Heimberger and Priebe, 2008).
The diffuse infiltrative nature of gliomas makes resection rarely complete and recurrence inevitable, so resection is rarely curative (Hart and Grant, 2007).
Despite advances in radiation and chemotherapy along with surgical resection, the prognosis of patients with malignant glioma is poor. Therefore, the development of a new treatment modality is extremely important. Biotherapy for brain tumors will open a novel reality now (Yamanaka and Itoh, 2007).
Medulloblastoma is the most common malignant brain tumor of childhood. Surgery, radiation therapy, and chemotherapy cure many patients, but survivors can suffer long-term toxicities affecting their neurocognitive and growth potential; furthermore, there is no curative therapy in up to 30% of cases, mainly because of our incomplete understanding of many of the underlying molecular and cellular processes (Grizzi et al., 2008).
There has been substantial progress in understanding the molecular pathogenesis of these tumors, especially in the critical role of tumor stem cells. In addition, there have been important technologic advances in surgery and radiation therapy that have significantly improved the safety of these therapies, and these advances have allowed the widespread application of techniques, such as stereotactic radiosurgery, to treat brain metastases and some primary brain tumors that cannot be removed surgically. Most excitingly, improved understanding of the biology of brain tumors finally is being translated into novel therapies using targeted molecular agents, inhibitors of angiogenesis, and immunotherapies. The preliminary results with these therapies are encouraging (Wen and Schiff, 2007).
Immunotherapy is an appealing therapeutic modality for brain tumors because of its potential to selectively target residual tumor cells that have invaded the normal brain. Most immunotherapeutic studies are designed to exploit the capacity of dendritic cells for inducing cell-mediated effects as well as immune memory responses for destroying residual tumor cells and preventing recurrence (Parajuli et al., 2007). Recent reports demonstrate that systemic immunotherapy using dendritic cells or peptide vaccines successfully induce an antitumor immune response and prolong survival in those patients without major side effects (Yamanaka, 2008).
Malignant tumors of the central nervous system are difficult to cure, despite advances made in the fields of neurosurgery and radiation oncology. These tumors are generally resistant to standard chemotherapeutic agents, and new strategies are needed to overcome these tumors. Tumors of the brain demonstrate various features of angiogenesis. Correlation has been made between the degree of increased vascularity and outcome, making these tumors enticing targets for anti-angiogenic agents. Important advances in utilizing anti-angiogenic agents as an additional therapeutic modality for patients with central nervous system tumors have been identified. Rapid developments in understanding the molecular basis of angiogenesis and brain tumors have been made over the past decade, and application of this knowledge is currently being brought to the clinic (Warren and Fine, 2008).
Overactivation of epidermal growth factor receptor signaling has been recognized as an important step in the pathogenesis and progression of multiple forms of cancer of epithelial origin. The important role of aberrant epidermal growth factor receptor signaling in the progression of malignant gliomas makes epidermal growth factor receptor-targeted therapies of particular interest in this form of cancer. The use of anti-epidermal growth factor receptor therapies against malignant brain tumors, although in its infancy, promises to yield exciting results as these new drugs probably will enhance the usefulness of existing therapies (Nathoo et al., 2004).
Combined inhibition of vascular endothelial growth factor and platelet derived growth factor signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. So, dual inhibition of vascular endothelial growth factor and platelet derived growth factor signaling significantly increased tumor growth delay versus each monotherapy (Timke et al., 2008).
Combination of radiotherapy with vascular endothelial growth factor and platelet derived growth factor anti-angiogenic agents has the potential to improve the clinical outcome in cancer patients (Timke et al., 2008). Recent studies incorporating cytotoxic therapy plus anti-vascular endothelial growth factor agents among recurrent glioma patients have achieved unprecedented improvements in radiographic response, time to progression and survival (Reardon et al., 2008).
In prolactin secreting pituitary adenomas, dopamine agonists are considered the first-line of treatment. Dopamine agonists (bromocriptine and cabergoline) effectively normalize prolactin levels in as many as 89% of patients and decrease tumor volume by at least 50% in more than two thirds of patients within the first several months of therapy. Recent reports highlight impressive advancements in the pharmacologic treatment of growth hormone-secreting adenomas. Traditionally, the two options for medical therapy for these tumors have been dopamine agonists and somatostatin analogues. Dopamine agonists provide symptomatic relief in the majority of patients but normalize insulin like growth factor I levels only in approximately 20% to 40% of cases. Somatostatin analogues (octreotide and lanreotide) can normalize insulin like growth factor I levels in up to 60% of patients and have a more favorable side-effect profile compared with dopamine agonists agonists. The recently introduced growth hormone receptor antagonist (pegvisomant) has normalized insulin like growth factor I levels in 90% to 100% of patients who have refractory disease (Jagannathan et al., 2007).
Somatostatin and its analogues have the potential to be effective in a wider group of pituitary and other tumors. More potent and broader-spectrum somatostatins are likely to play an increasing role in the treatment of tumors (Hubina et al., 2006). Somatostatin and its analogues have direct anti-proliferative effect and anti-angiogenic effect (Grozinsky-Glasberg et al., 2008). A frequent finding in meningiomas is expression of progesterone receptors. So, anti-progesterone treatment can be considered in recurrent unresectable benign meningiomas (Sioka and Kyritsis, 2009).
Until recently, the use of systemic chemotherapy was restricted and ineffective, due to the fact that the blood brain barrier inhibits the adequate therapeutic concentrations of most chemotherapeutic agents into the tumor and peritumoral area (Argyriou et al., 2009). Objective benefit from the temozolomide treatment (stabilization or remission) was observed in 49% of patients irrespective of histological diagnosis. Tolerability of treatment with temozolomide in patients with high-grade gliomas is good (Ziobro et al., 2008). Temozolomide can also enhance tumor cell radiosensitivity in vitro and in vivo and this effect involves an inhibition of DNA repair (Kil et al., 2008).
Radiosurgery is a procedure in which spatially accurate and highly conformal doses of radiation are targeted at well-defined structures with an ablative intent. It has been used increasingly as a primary or adjuvant treatment for various brain diseases, including primary brain tumors, secondary metastatic tumors, and arterio-venous malformations. Radiosurgery is used to treat much smaller volumes of tissue and has traditionally used a high dose of precisely focused radiation delivered in a single session (Oh et al., 2007).
Gamma Knife Radiosurgery provides safe and effective alternative treatment that is less invasive and has fewer side effects (Nesbitt, 2007). Gamma Knife Radiosurgery for brain metastases from conventionally radioresistant primary cancers provides better local control of the brain disease and improves survival time (Sin et al., 2009). Gamma Knife Radiosurgery for brain metastases without prophylactic whole brain radiation therapy prevents neurological death and allows a patient to maintain good brain condition (Serizawa et al., 2008). Gamma Knife Radiosurgery also provides excellent control of pineal region brain tumors when it is used in conjunction with surgery, conventional radiation therapy, or both (Lekovic et al., 2007). Gamma Knife Radiosurgery can control hemangioblastomas for as many as 10 years (Tago et al., 2005).
One of the novel strategies for treatment of brain tumors is gene therapy that includes the use of diverse viral and non-viral vectors and different genes to treat these tumors (Benítez et al., 2008).
The development of new approaches for the treatment of these tumors has led to the emergence of oncolytic virotherapy, with the use of conditionally replicating viruses, as a potential new intervention. Herpes simplex virus type 1 has emerged as the leading candidate oncolytic virus (Markert et al., 2006). These oncolytic viruses can specifically replicate and lyse in cancers, without spreading to normal tissues (Cutter et al., 2008).
Aim of the Work
The aim of this review is to highlight the modern trends in non-surgical treatment of brain tumors for better management and prognosis of those patients.
Chapter (1)
Molecular Pathogenesis
Of
Brain Tumors
Molecular Pathogenesis of Brain Tumors
Primary brain tumors are a genetically and phenotypically heterogenous group of neoplasms that vary prognostically as a function of location, pathologic features, and molecular genetics (Levin et al., 2001). They are comprised of tumors that originate from within the brain and from structures associated intimately with brain as meninges and ependymal tissues. Understanding of molecular and genetic changes causing tumorigenesis is critical for development of new therapeutic strategies for brain tumors (Sauvageot et al., 2007).
Gliomas:
Gliomas are the most common type of primary brain tumor and are grouped into three major categories astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas based on their histologic similarity to normal astrocytes or oligodendrocytes. Gliomas are subgrouped by WHO into grades based on histologic factors, such as nuclear atypia, mitotic activity, vascular proliferation, and necrosis. Tumor grade is predictive of patient survival (Sauvageot et al., 2007).
Astrocytomas:
Astrocytomas account for more than 60% of all primary brain tumors (Cavenee et al., 2000). They are classified into four grades. Grade I pilocytic astrocytomas are essentially benign. Grade II diffuse astrocytomas are characterized by nuclear atypia. Grade III anaplastic astrocytomas show high mitotic activity and nuclear atypia. Grade IV glioblastomas are highly infiltrative, proliferative, and necrotic. Glioblastomas are the most common form of gliomas, accounting for more than half of all primary gliomas and representing more than 75% of astrocytomas (CBTRUS, 2006).
Glioblastoma subtypes:
Malignant transformation results from the accumulation of genetic abnormalities, including chromosomal loss, mutations, and gene amplifications and rearrangements. Two subtypes of glioblastomas are identified that are indistinguishable clinically but that have different genetic profiles. Primary glioblastomas typically appear in older patients who have no previous history of the disease, whereas secondary glioblastomas usually manifest themselves in younger patients as low-grade astrocytomas that transform within 5 to 10 years into glioblastomas (Sauvageot et al., 2007).
Defects in the p53 Apoptotic and Cell Cycle Pathway:
P53 is a tumor suppressor gene that plays a critical role in apoptosis and cell cycle arrest. Loss of function-mutations in the p53 protein are found in more than 65% of low-grade astrocytomas, anaplastic astrocytomas, and secondary glioblastomas, suggesting that this is an early event in formation of these tumors. Unlike secondary glioblastomas, primary glioblastomas infrequently display mutations in p53 (less than 10%), although this pathway is deregulated at other levels (Sauvageot et al., 2007). Approximately 75% of glioblastomas exhibit functional inactivation of the p53 pathway, which results in defects in apoptosis and increased cell cycle progression (Fig. 1) (Ichimura et al., 2000).
Defects in the Retinoblastoma Cell Cycle Pathway:
Retinoblastoma is a critical gatekeeper of cell cycle progression by its ability to restrict or allow a cell to progress through the G1 phase of the cell cycle pathway. Hypophosphorylation of retinoblastoma maintains the cell in a quiescent state by preventing the transcription of genes important in mitosis. Retinoblastoma can be phosphorylated by cyclin-dependent kinases 4 and 6, which are regulated negatively by cyclin-dependent kinase inhibitors, including p16Ink4a and p21Cip1. The transition from low-grade to high-grade astrocytoma is associated with allelic losses on chromosomes 9p and 13q and with amplification of 12q, which are chromosomal loci that house genes associated with the retinoblastoma pathway (Fig. 1). More specifically, approximately 25% of high-grade gliomas have mutations in retinoblastoma and 15% exhibit gene amplification of cyclin-dependent kinase 4, whereas inactivation of the p16Ink4a cyclin-dependent kinase inhibitor occurs in 50% to 70% of these tumors (Sauvageot et al., 2007).
Olig2 is a transcriptional repressor that is involved in lineage specification in the nervous system (Novitch et al., 2001). It is expressed in astrocytomas regardless of grade, suggesting it is an early oncogenic event (Ligon et al., 2004).
An article has revealed that Olig2 is required for glioma formation and that it is a direct repressor of the cyclin-dependent kinase inhibitor gene, p21Cip1 (Ligon et al., 2007).
Defects in Growth Factor Signaling:
Excessive signaling resulting from the overexpression of either the growth factor ligand or the receptor gives a proliferative and survival advantage to the cells leading to their transformation and progression. The most common defects in growth factor signaling involve the platelet-derived growth factor and epidermal growth factor signaling pathways (Sauvageot et al., 2007).
[pic]
Fig. 1. The p53 and retinoblastoma cell cycle and cell death signaling pathways: double arrows indicate multistep stimulation. Rb: retinoblastoma. p14ARF: p14 alternate reading from, MDM2: murine double minute–2, Bax: BCL2-associated X protein, cdc2: cell division cycle 2 (Sauvageot et al., 2007).
Overexpression of both platelet-derived growth factor receptors and ligands within the same cells lead to autocrine loops, which can drive cell proliferation (Sauvageot et al., 2007). Platelet-derived growth factor activation promotes the upregulation of vascular endothelial growth factor, which enhances angiogenesis (Guo et al., 2003). Platelet-derived growth factor ligands and receptors are found in low-grade and high-grade astrocytomas, suggesting that this is an early oncogenic event in secondary glioblastomas. Platelet-derived growth factor receptors gene amplification is associated with loss of function of p53, placing these two genetic lesions as hallmarks of secondary glioblastomas (Sauvageot et al., 2007).
Defects in epidermal growth factor receptors occur almost exclusively in primary glioblastomas, where approximately 40% of these tumors show amplification of the region in chromosome 7 that encodes the epidermal growth factor receptor gene (Sauvageot et al., 2007). Overactivity of this receptor results in cellular proliferation, tumor invasiveness, increased angiogenesis and motility, and inhibition of apoptosis (Shinojima et al., 2003). Within tumors exhibiting epidermal growth factor receptors amplification, 40% also express a constitutively autophosphorylated variant of the epidermal growth factor receptors that lacks the extracellular ligand-binding domain, known as epidermal growth factor receptor mutant version III. This truncated receptor enhances tumorigenicity by increasing tumor proliferation and invasiveness and decreasing apoptosis (Lal et al., 2002).
Phosphatase and tensin homolog deleted on chromosome 10 is a tumor suppressor gene that is mutated or deleted in gliomas. Inactivating mutations in phosphatase and tensin homolog deleted on chromosome 10 results in increased survival, proliferation, and tumor invasion. Approximately 30% to 40% of glioblastomas exhibit mutations within the phosphatase and tensin homolog deleted on chromosome 10, which occur almost exclusively in primary glioblastomas (Sauvageot et al., 2007).
Oligodendrogliomas:
Oligodendrogliomas are diffusely infiltrating tumors whose cells resemble immature oligodendrocytes. They account for more than 4% of all primary brain tumors and represent approximately 20% of all glial tumors (DeAngelis, 2001). Oligodendrocytomas are classified into two grades, grade II oligodendroglioma and grade III anaplastic oligodendroglioma (Sauvageot et al., 2007).
Genetic alterations:
The main genetic abnormalities associated with oligodendrogliomas are loss of chromosomes 1p and 19q, which occur in approximately 50% to 90% of grade II and grade III tumors, suggesting that this is an early oncogenic event in the formation of oligodendrogliomas (Jenkins et al., 2006). In addition, Olig2 is expressed in grade II and grade III tumors (Ligon et al., 2004). The retinoblastoma cell cycle pathway is altered in 65% of oligodendrogliomas at the level of cyclin-dependent kinases 4 amplification, mutations in retinoblastoma, or deletions of p16Ink4a (Watanabe et al., 2001). p53 gene mutations are seen in approximately 10% to 20% of all oligodendrogliomas (Sauvageot et al., 2007).
Finally, similar to high-grade astrocytomas, approximately 9% of anaplastic oligodendrogliomas exhibit mutations in phosphatase and tensin homolog deleted on chromosome 10, and more than 20% exhibit loss of the 10q locus which houses phosphatase and tensin homolog deleted on chromosome 10 (Sasaki et al., 2001). Such mutations, combined with growth factor abnormalities, would result in increased proliferation of cells (Sauvageot et al., 2007).
Defects in Growth Factor Signaling:
Oligodendrogliomas also exhibit abnormalities within the epidermal growth factor receptors and platelet derived growth factor receptors signal transduction pathways. Unlike astrocytomas, which exhibit epidermal growth factor receptors amplification and overexpression only in high-grade tumors, overexpression of this protein occurs in approximately 50% of low-grade and high-grade oligodendrogliomas. Coexpression of platelet derived growth factor ligands and receptors occur in almost all oligodendrogliomas (Sauvageot et al., 2007). Abnormalities within epidermal growth factor receptors and platelet derived growth factor receptors signaling indicate that this is an early oncogenic event in the formation of these tumors (Weiss et al., 2003).
Oligoastrocytomas:
As their name implies, oligoastrocytomas are composed of a heterogeneous population of cells that have characteristics of astrocytomas and oligodendrogliomas. Oligoastrocytomas are divided into two grades, grade II oligoastrocytomas and grade III anaplastic oligoastrocytomas which are clinically aggressive and characterized by high mitotic activity, nuclear atypia, and necrosis (Sauvageot et al., 2007).
The cellular heterogeneity seen in oligoastrocytomas is reflected in the genetic heterogeneity of these tumors. Approximately 30% to 50% of oligoastrocytomas exhibit 1p and 19q deletions reminiscent of oligodendrogliomas, whereas a separate 30% of these tumors house genetic anomalies similar to astrocytomas, including mutations in p53. Microdissection of the astrocytoma versus oligodendroglioma components of these tumors have revealed common genetic changes in all components of a given tumor, suggesting that these histologically mixed tumors may arise from a single transforming event (Sauvageot et al., 2007).
Meningiomas:
Meningiomas originate from the transformation of meningothelial cells and account for approximately 13% to 26% of all primary brain tumors (Louis et al., 2000). The large majorities of meningiomas are benign and classified as WHO grade I tumors, although 5% to 7% of all meningiomas are grade II atypical meningiomas, and 1% to 3% are grade III anaplastic meningiomas (Sauvageot et al., 2007). Atypical meningiomas are characterized by an increased mitotic index and sheeting architecture, macronucleoli, hypercellularity, or necrosis, whereas anaplastic meningiomas exhibit high mitotic index and frank anaplasia (Perry et al., 2004).
Genetic alterations:
The most common change in meningiomas is loss of heterozygosity of chromosome 22, which houses the neurofibromatosis type 2 gene (Sauvageot et al., 2007). Loss of function of neurofibromatosis type 2 is an early event in approximately 60% of meningiomas and occurs in almost all neurofibromatosis type 2 associated meningiomas. The neurofibromatosis type 2 gene encodes a protein known as merlin which is part of the protein 4.1 family (Perry et al., 2004). Loss of merlin in vivo is associated with increased cell growth and formation of highly motile and metastatic tumors (Giovannini et al., 2000). Another protein 4.1 family member known as DAL-1 has a growth suppressive effect. It is lost in up to 76% of benign and atypical meningiomas and 87% of malignant meningiomas (Gutmann et al., 2000). Loss of protein 4.1R occurs in 40% of meningiomas (Robb et al., 2003). These data suggest that the protein 4.1 family of proteins plays a critical role in meningioma formation (Sauvageot et al., 2007).
Telomerase enzyme is associated with tumor progression, with infrequent expression in benign meningiomas (approximately 8%) and higher levels in atypical and anaplastic meningiomas (approximately 60% and approximately 90%, respectively) (Falchetti et al., 2002). Progesterone receptors are present in more than 80% of meningiomas. Progesterone receptors expression is inversely proportional to tumor proliferation and histologic grade, with expression occurring in 96% of benign tumors compared with 40% in malignant tumors. Progesterone receptors expression is a favorable prognostic factor for meningiomas (Sauvageot et al., 2007).
Defects in Growth Factor Signaling:
Growth factors may play a role in meningioma initiation and progression. Coexpression of Platelet derived growth factor ligands and receptors occurs in the majority of meningiomas (Sauvageot et al., 2007), with higher expression correlating with increasing tumor grade (Yang et al., 2001). Epidermal growth factor receptors and their ligands; epidermal growth factor and transforming growth factor α, are expressed in almost all meningiomas but not in normal meninges. Increased transforming growth factor α expression is associated with aggressive meningioma growth. Insulin-like growth factor II, its receptor, and insulin-like growth factor binding protein are expressed in meningiomas, where a high ligand/receptor ratio is associated with malignant progression (Sauvageot et al., 2007).
Medulloblastomas:
Medulloblastomas are an invasive embryonal tumor of the cerebellum that show tendency to metastasize. Although medulloblastomas occur most frequently during childhood, approximately 30% of cases arise in adults (Sauvageot et al., 2007). Medulloblastomas are considered WHO grade IV tumors because of their invasive and malignant phenotypes and are grouped into four subtypes consisting of: classic, desmoplastic, extensive nodularity and large-cell medulloblastomas. The histologic subtype is associated with the clinical outcome (Eberhart et al., 2002).
Adult medulloblastomas differ from pediatric medulloblastomas in terms of histology, localization, and relapse frequencies (Carrie et al., 1994). Unlike pediatric medulloblastomas, which are localized in the midline cerebellar vermis and extend into the fourth ventricle, approximately 50% of adult medulloblastomas are located laterally within the cerebellar hemispheres (Prados et al., 1995).
Genetic alterations:
The most common genetic abnormality in medulloblastoma consists of an isochromosome of chromosome 17, which arises in approximately 50% of cases, and which occurs with a higher frequency in classic than in desmoplastic medulloblastomas. Deletions of the short arm of chromosome 17p also occur in 30% to 45% of cases. Although the tumor suppressor gene, p53, is located on 17p and is mutated in many cancer types, only rare mutations in this gene are found in medulloblastomas. Also deletions on chromosomes 1q and 10q are found in 20% to 40% of medulloblastomas (Sauvageot et al., 2007).
Defects in Growth factor Signaling:
The main growth factor pathways that are defective in medulloblastomas are (Fuccillo et al., 2006):
1) Sonic hedgehog pathway.
2) ErbB pathway.
3) Wingless pathway.
Signaling within Sonic hedgehog pathway is initiated by binding of the ligand Sonic hedgehog to its receptor PTC that normally inhibits the activity of a protein known as Smoothened. This binding removes inhibition of Smoothened leading to release of glioma-associated oncogene homolog-1 that enters the nucleus to activate gene transcription (Fig. 2). Hence, PTC can play the role of a tumor suppressor, whereas Sonic hedgehog and Smoothened are putative oncogenes (McMahon et al., 2003). Inactivating mutations of PTC was identified in approximately 8% of medulloblastomas whereas activating mutations within Sonic hedgehog and Smoothened was identified in rare cases (Sauvageot et al., 2007).
ErbB2 is a receptor tyrosine kinase. Overexpression of ErbB2 or a single point mutation in the transmembrane domain of this receptor can induce tumor formation (Yarden and Sliwkowski, 2001). 80% of medulloblastomas show overexpression of ErbB2 which is associated with a worse prognosis (Gajjar et al., 2004). The tendency of these tumors to metastisize may be mediated in part by aberrant ErbB2 activation, as ErbB2 overexpression in medulloblastomas increases cell migration and promotes the upregulation of prometastatic genes (Hernan et al., 2003).
[pic]
Fig. 2. Sonic hedgehog signaling pathway: Shh: Sonic hedgehog, SMO: Smoothened, GLI1: glioma-associated oncogene homolog-1, SuF: suppressor of fused (Sauvageot et al., 2007).
Wingless activation of the frizzled transmembrane receptor inhibits β-catenin degradation by the GSK-3/APC/axin complex (Baeza et al., 2003). The resulting increases in β-catenin levels enable it to enter the nucleus and activate proliferation genes such as MYC and cyclin D1 (Fig. 3) (Henderson and Fagotto, 2002). Approximately 15% of sporadic medulloblastomas exhibit mutations within Wingless pathway (Baeza et al., 2003).
[pic]
Fig. 3. Wingless signaling pathway: Wnt: Wingless, Dsh: disheveled, LEF: lymphoid enhancer bindin factor, TCF: transcription factor protein, UUUU: ubiquitination (Sauvageot et al., 2007).
Pathogenesis of Brain Tumors Spread:
In a mathematical model it has been calculated that the velocity of expansion is linear with time and varies from about 4 mm/year for low-grade gliomas and 3 mm/month for high grade gliomas (Swanson et al., 2003). Motility and invasion of glioma cells are due to events involving extracellular matrix, adhesion molecules and properties of the cells themselves (Schiffer, 2006).
Several genes involved in glioma invasiveness have been identified and include members of the family of metalloproteases. Expression of metalloprotease 2 and, to a lesser extent, metalloprotease 9 correlates with invasiveness, proliferation and prognosis in astrocytomas (Wang et al. 2003).
Other non-metalloprotease proteases, including urokinase-type plasminogen activator and cysteine proteases (e.g. cathepsin B), are elevated in high-grade gliomas. Invasion inhibitory protein 45, a potential tumor suppressor gene on chromosome 1p36, its product inhibits invasion and it is frequently down-regulated in glioblastomas. Other invasion- and migration-associated genes have been identified including P311, death-associated protein 3, and FN14 (Furnari et al., 2007). Other proteins are overexpressed in invasive areas of glioblastoma, such as angiopoietin-2, which in addition to its involvement in angiogenesis also plays a role in inducing tumor cell infiltration by activating metalloprotease 2 (Hu et al. 2003).
Many factors intervene in regulating cell migration and invasion, first of all epidermal growth factor. Highly amplified cells for epidermal growth factor receptors are found at the invading edge of the tumor. Another very important factor in regulation of glioma cell motility is phosphatase and tensin homolog deleted on chromosome 10; its phosphatase-independent domains reduce the invasive potential of glioma cells (Schiffer, 2006). Phosphatase and tensin homolog deleted on chromosome 10 mutation has been implicated in an invasive phenotype due to its ability to stabilize E-cadherin and modulate cell matrix adhesion complexes (Furnari et al., 2007).
Integrins variously occur on glioma cells and mediate cell adhesion to extracellular matrix (Tysnes and Mahesparan, 2001). Integrins, especially αVβ3 complexes, are elevated in glioblastomas and appear to be relevant to processes of glioma invasion and angiogenesis (Kanamori et al. 2004). Integrins also play a role in glioma cell growth and proliferation. Other factors involved in controlling cell motility are scatter factor/hepatocyte growth factor and transforming growth factor β1 (Schiffer, 2006).
Cell-of-Origin of Brain Tumors:
Primary malignant brain tumors have a high rate of recurrence after treatment. Studies have led to the hypothesis that the root of the recurrence may be brain tumor stem cells, stem-like subpopulation of cells that are responsible for propagating the tumor. Current treatments combining surgery and chemoradiotherapy could not eliminate brain tumor stem cells because these cells are highly infiltrative and have several properties that can reduce the damages caused by radiation or anti-cancer drugs. Brain tumor stem cells are similar to the neural stem cells. Furthermore, data from various models of malignant brain tumors have provided evidence that multipotent neural stem cells and neural progenitor cells could be the cell origin of brain tumors. Thus, the first event of brain tumorigenesis might be the occurrence of oncogenic mutations in the neural stem cells or neural progenitor cells. These mutations convert a neural stem cell or neural progenitor cell to brain tumor stem cells, which then initiates and sustains the growth of the tumor (Xie, 2009).
What are Stem Cells?
Stem cells are defined as cells capable of self-renewal and multipotency. Self-renewal refers to the ability of a cell to generate an identical copy of it, whereas multipotency refers to the ability to give rise to all the differentiated cell types within a given tissue. Stem cells are able to divide asymmetrically to produce mother and daughter cells. The mother cell has equivalent self-renewal and multipotency capabilities as the original stem cell, whereas the daughter cell (a progenitor cell) has a more limited set of developmental options and are able to transiently divide before giving terminally differentiated cells (Sauvageot et al., 2007).
Stem Cells in the Nervous System and in Brain Tumors:
Historically, it has been believed that the cell-of-origin of gliomas must be a mature glial cell. More recently, neural stem cells have been identified within the adult brain, providing an alternate source of cycling cells capable of transformation. Neural stem cells capable of self-renewal and multipotency were identified in germinal areas of the adult nervous system within the subventricular zone and the dentate gyrus of the hippocampus (Sanai et al., 2004).
Evidence suggests that tumorigenic stem cells also exist within brain tumors. Initial reports showed that neural stem cells could be isolated from glioblastomas and medulloblastomas (Singh et al., 2003). Subsequent experiments revealed that xenotransplantion of neurospheres derived from human brain tumors could form neoplasms that have the morphology and lineage characteristics of the original tumors (Singh et al., 2004).
Implantation of as few as 100 of these cells that were shown to express the stem cell surface marker, cluster destination 133 (CD133), suffices to generate a tumor compared with implantation of 10,000 cluster destination 133 negative cells, which are not able to form a tumor. Several studies have indicated the presence of cluster destination 133 positive brain tumor stem-like cells within the human glioblastomas (Anhua et al., 2008). These studies do not exclude the possibility that cycling progenitor cells, or even more differentiated cells, also may play a role in contributing the growth and malignancy of these tumors (Sauvageot et al., 2007). The neural progenitor cells are one source of gliomas as the marker phenotypes, morphologies, and migratory properties of cells in gliomas strongly resemble neural progenitor cells in many ways (Canoll and Goldman, 2008).
Mouse Models:
Mouse models of gliomas, in which different transforming events are targeted to specific subpopulations of cells within the nervous system, have been created to help clarify the cell-of-origin of gliomas. Although these experiments have shown that tumors can arise from progenitor cells and from more differentiated cells, they reveal that progenitor cells are more permissive to oncogenic transformation (Holland et al., 2000). This idea is supported by data showing that the transforming epidermal growth factor receptors mutant version III gene induces glial tumors more readily when introduced into progenitor cells than in differentiated ones (Bachoo et al., 2002).
These data reveal that malignant transformation occurs more readily in progenitor cells, but that multiple oncogenic pressures can drive more differentiated cells to reacquire progenitor cell phenotypes, which subsequently also can drive tumorigenesis (Sauvageot et al., 2007).
Functional Similarities between Stem Cells and Tumor Cells:
Several similarities exist between stem cells and tumor cells, including 1) extensive proliferation, 2) heterogeneity of progeny, and 3) high motility (Sauvageot et al., 2007).
Neural stem cells and gliomas are highly proliferative, and the epidermal growth factor receptors are involved in this response in both cell types. It plays a prominent role in promoting proliferation of gliomas, both as a result of epidermal growth factor receptors amplification, as well as expression of the constitutively active epidermal growth factor receptor mutant version III (Sauvageot et al., 2007).
Neural stem cells and gliomas show a diversity of progeny. Neural stem cells can give rise to heterogeneous population of cells. Likewise, gliomas are a heterogeneous population of cells that arise from a much localized transformation event, most likely occurring in a multipotent tumor stem cell. In cases where clonality cannot be established, this may suggest that independent transformation events in different cells of origin. Recent evidence reveals that some of the heterogeneity may arise from progenitors that are recruited to the tumor mass after the original transformation event occurred (Assanah et al., 2006).
A cardinal feature of malignant gliomas is their ability to migrate and infiltrate into adjacent regions. Similarly, neural stem cells and neural progenitors exhibit a migratory capacity in the normal adult brain (Lois and Alvarez-Buylla, 1994). After injury, the progenitor cells migrate from the subventricular zone to the site of injury (Hayashi et al., 2005). Once again, this shared phenotype may result from epidermal growth factor activity and epidermal growth factor receptor mutant version III which upregulates factors of tumor invasion (Lal et al., 2002).
Molecular Similarities between Stem Cells and Tumor Cells:
Several proteins that are normally involved in neural stem cells development also are present in gliomas, including platelet derived growth factor, phosphatase and tensin homolog deleted on chromosome 10, Oolig2, and Sonic hedgehog, providing further support for the notion that the origin of gliomas may be neural stem cells and their progenitors (Sauvageot et al., 2007).
Coexpression of platelet derived growth factor ligands and receptors are a common occurrence in brain tumors. Platelet derived growth factor also plays an important role in regulating glial progenitor proliferation (Sauvageot et al., 2007). In the adult brain, platelet derived growth factor receptor expression is restricted to the germinal zone of the brain and, more specifically, is expressed in a subset of subventricular neural stem cells capable of differentiating into neurons and oligodendrocytes. Infusion of platelet derived growth factor into the lateral ventricles induces the formation of atypical hyperplastic cells that resemble gliomas (Jackson et al., 2006).
Phosphatase and tensin homolog deleted on chromosome 10 also is involved in the growth of neural stem cells and gliomas. It is inactivated in a high percentage of brain tumors, and this inactivation results in increased cell migration, invasion, survival, and proliferation. Correspondingly, phosphatase and tensin homolog deleted on chromosome 10 plays a critical role in neural stem cells maintenance and function (Li et al., 2002).
Expression of Olig2 further extends the connection between normal neural stem cells and gliomas. Olig2 expression found in all malignant gliomas is required for glioma formation (ligon et al., 2007). During normal development, Olig2 is expressed in precursor cells within germinal areas of the brain (Menn et al., 2006), and is necessary for normal and tumorigenic progenitor cell growth (ligon et al., 2007).
Finally, the Sonic hedgehog and glioma-associated oncogene homolog-1 signaling pathway controls the proliferation of precursor cells within the adult germinal zones (Sauvageot et al., 2007). A variety of primary brain tumors express glioma-associated oncogene homolog-1, and inhibition of this pathway inhibits tumor growth (Dahmane et al., 2001).
In addition, targeted disruption of the Sonic hedgehog receptor results in medulloblastoma formation. The parallels between these developmental programs and tumorigenesis lend further evidence that tumor formation results from aberrations of developmental programs normally active in normal neural stem cells and their progenitors (Sauvageot et al., 2007).
Localization of Stem Cell–Derived Tumors:
If normal neural stem cells are the cell of origin of brain tumors, then it is expected that these neoplasms be localized preferentially in the germinal areas of the brain. Although this is not the case, much evidence suggests that they arise from these areas and then migrate out to their final locations (Zhu et al., 2005). This dissociation of transformed cells from germinal areas is consistent with current understanding of stem cell niches (Li and Neaves, 2006). The germinal areas in which stem cells reside are known as niches, and they maintain a homeostatic balance of factors that control the self-renewal and differentiation states of normal neural stem cells revealing these cells’ dependence on the niche for survival (Xie and Spradling, 2000). Tumorigenesis of normal neural stem cells reflect mutations that make the normal neural stem cells independent of the signals necessary for self-renewal and survival in the niche, thereby enabling it to grow at any location within the brain. The ability of niche-independent normal neural stem cells to migrate and grow in aberrant locations of the brain is suggestive of the highly infiltrative nature of brain tumors (Sauvageot et al., 2007).
Chapter (2)
Targeting Critical Points
Targeting Critical Points in Brain Tumors Pathogenesis
Knowledge of the relevant pathogenesis pathways aids selection of targets and agents. It is probable that, for any given molecular target, multiple pathways and multiple cell types can be affected. Different effects may reinforce or contradict each other (Wieduwilt and Moasser, 2008).
Before choosing a molecular target or pathway, it is necessary to select the cell, or cells, that will be the primary focus, and how directly they will be tied to tumor attack. Targeted therapy could be directed also at cells that participate in the antitumor immune response. Once a molecular target has been chosen, what agent should be selected to attack it, a small molecule inhibitor, an antibody, does one prefer to stimulate an immune response against the target (Lampson, 2009).
Despite the molecular heterogeneity of brain tumors, there exist common signal transduction pathways that are altered in many of these tumors. In malignancies, mutation or over-expression can occur in growth factor ligands and their receptors, as well as in intracellular effector molecules. Overexpression or mutations causing activation of these growth factors and their downstream effector molecules result in uncontrolled cell proliferation, survival, and invasion (Mercer et al., 2009). Targeting of these signaling pathways provides new molecularly targeted treatment options (Argyriou and Kalofonos, 2009).
Targeting the Growth Factors and their Receptors:
Growth factors bind to their receptors extracellularly and initiate an intracellular signal transduction cascade. Recent research has discovered many different monoclonal antibodies and small-molecule inhibitors that specifically target these ligands and receptors (Mercer et al., 2009).
Targeting the Epidermal Growth Factor Receptors:
Epidermal Growth Factor Receptor Inhibitors:
Epidermal growth factor receptor is amplified in 40–60% of glioblastomas, and approximately 30–50% of these tumors also possess the epidermal growth factor receptor mutant variant III, in which coding regions in the extracellular ligand domain are absent (Pelloski et al., 2007). Epidermal growth factor receptors play an integral role in the malignant phenotype of brain tumors, and it is a common hope among researchers that functional inhibition of epidermal growth factor receptor-mediated signaling will slow tumor growth (Sarkaria et al., 2007).
Treatment options that target epidermal growth factor receptors include erlotinib and gefitinib (Fig. 4). However, efficacy of these agents is modest (Argyriou and Kalofonos, 2009). Erlotinib was evaluated in a randomized phase II trial used in patients with recurrent glioblastoma multiforme. The 6-month progression-free survival was 12% (Mercer et al., 2009). Gefitinib was evaluated in a phase II clinical trial in patients with the first recurrence of a glioblastoma. The study showed a PFS-6 of 13% but no radiographic response was observed (Argyriou and Kalofonos, 2009). Overall survival rates in several phase I/II clinical trials for erlotinib and gefitinib treatment were similar, but erlotinib was more effective than gefitinib treatment in terms of objective radiographic responses (Argyriou and Kalofonos, 2009).
Epidermal Growth Factor Receptor Peptide Vaccines:
As mentioned previously, epidermal growth factor mutant variant III is an attractive target because it is not expressed in normal tissues but is expressed in a wide number of malignancies, including 31–50% of malignant gliomas (Heimberger et al., 2005). Initial preclinical studies targeting epidermal growth factor mutant variant III in rodents were promising. A peptide vaccine targeting epidermal growth factor mutant variant III was successful in extending the survival rate in vaccinated rats by 72%. The success of these preclinical studies led to several human trials that also produced promising results (Ciesielski et al., 2005).
In a phase I human trial, patients were treated with up to four peptide vaccines. The vaccine was well tolerated and the majority showed increased cellular and humoral responses. Clinical results were moderately favorable; 5 of 21 patients showed a partial radiographic response and 8 of 21 had stable disease. The median survival among patients with glioblastoma was 622 days (Yajima et al., 2005).
Phase I human trial involving epidermal growth factor mutant variant III the keyhole limpet vaccine showed that the vaccine was well tolerated and the clinical results were also promising in patients with malignant glioma. The vaccine was successful in stimulating cellular immunity. Among patients with grade III tumors, 2 of 3 patients had stable disease. Among patients with glioblastoma, the mean time to disease progression was 46.9 weeks. For the phase II trial, preliminary results have indicated that the vaccine is well tolerated and studies have demonstrated humoral and cellular immunity; the final results have not yet been reported (Sampson et al., 2008).
Targeting the Vascular Endothelial Growth Factor Receptors:
Vascular proliferation is a hallmark of tumor survival and growth. It was suggested that patients with highly vascularized tumors would have a poorer prognosis than patients with less neovascularization; however, this supposition requires further validation (DeGroot and Gilbert, 2007).
Glioma cells produce many different proangiogenic factors, including vascular endothelial growth factor. For these reasons, vascular endothelial growth factor ligands and receptors have been targeted for treatment of gliomas. Strategies for targeting this ligand and its receptor include using: 1) vascular endothelial growth factor antibodies, 2) vascular endothelial growth factor receptor tyrosine kinase inhibitors, and 3) protein kinase C inhibitors (Mercer et al., 2009).
Bevacizumab is, to date, the most promising vascular endothelial growth factor monoclonal antibody. Bevacizumab targets the vascular endothelial growth factor ligand with the goal of interfering with ligand-receptor signaling (Fig. 4). Although at first there was hesitation about using bevacizumab for the treatment of patients with brain tumors, because of its known history of intra-tumoral hemorrhage in patients with colorectal carcinoma (Mercer et al., 2009).
A phase II trial evaluated bevacizumab in combination with chemotherapy (irinotecan). The radiographic response rate was positive and 14 of 23 patients (61%) responded to therapy. The 6-month progression-free survival was 30% and the overall median survival time was 40 weeks (Vredenburgh et al., 2007).
It was suggested that bevacizumab as monotherapy may be the best way to maximize the efficacy of treatment while minimizing systemic toxicity. In a phase II trial of bevacizumab alone, the results showed that approximately 60% of patients who were treated with bevacizumab alone had objective radiographic responses, as well as a 6-month progression-free survival of 30% and a median progression-free survival of about 110 days (Fine, 2007).
Targeting the Platelet-Derived Growth Factor Receptors:
Platelet derived growth factor and its receptors play an important role in tumor interstitial pressure, tumor growth, and angiogenesis. Over-expression of platelet derived growth factor and its receptors in gliomas made them to be targets for anti-tumor treatments (Ostman, 2004).
The platelet derived growth factor receptor inhibitor for which most data have been obtained is imatinib mesylate. Imatinib is a small-molecule inhibitor of platelet derived growth factor receptors α and β (Fig. 4). However imatinib showed some anti-tumor effects in preclinical studies, minimal clinical benefit was seen using imatinib as monotherapy, with a radiographic response rate of 20% was obtained in 72% of the patients (Maiza et al., 2007). A very recent study has confirmed that, results obtained with lanreotide slow release and autogel and with octreotide long-acting repeatable are similar (Murray and Melmed, 2008).
In a study for 2 years of continuous treatment with octreotide long-acting repeatable, increased doses up to 40 mg every 28 days increased the chance to control growth hormone level and increased the rate of tumor shrinkage. A significant shrinkage (>25%) was found in 52.9% of patients after 12 months when they received 30 mg every 28 days and in all patients after 24 months when treated with 40 mg every 28 days. No data are currently available with lanreotide autogel. A preliminary experience in 26 patients treated first-line with this somatostatin analogue formulation had tumor shrinkage after 6 months of treatment (Colao et al., 2009).
It has been demonstrated that both somatostatin receptors and dopamine receptors are frequently coexpressed in adenomas from acromegalic patients and thus immunohistochemistry may determine receptor expression in pituitary adenomas to select patients responsive to different treatments (Ferone et al., 2008).
The combination treatment with somatostatin analogues and dopamine agonists could be beneficial to better suppress growth hormone level and also on tumor shrinkage but results on tumor shrinkage are lacking. The effect of somatostatin analogues on tumor shrinkage is reversible as demonstrated by tumor re-growth after stopping somatostatin analogues (Colao et al., 2009).
3. Thyroid Stimulating Hormone Secreting Adenomas:
This adenoma histotype is rare and frequently at diagnosis tumors are macros presenting with mass effect symptoms with variable symptoms of hyperthyroidism (Beck-Peccoz et al., 1996). The medical treatment of thyroid stimulating hormone secreting adenomas depends mainly on administration of somatostatin analogues, as dopamine agonists failed to persistently block hormone secretion in almost all patients and caused tumor shrinkage only in those with co-secretion of thyroid stimulating hormone and prolactin (Kienitz et al., 2007).
Somatostatin inhibits thyroid stimulating hormone secretion both in physiological conditions and in thyroid stimulating hormone secreting adenomas as well as thyroid stimulating hormone secreting adenomas express somatostatin receptors. So, somatostatin analogues are a very efficient treatment in patients with thyroid stimulating hormone secreting pituitary tumors to improve the clinical signs, the hormone levels and to produce tumor shrinkage (Fischler and Reinhart, 1999).
Octreotide given subcutaneously induced an acute thyroid stimulating suppression. In more than 90% of thyroid stimulating hormone secreting adenomas, octreotide subcutaneous suppressed thyroid stimulating hormone secretion and in about 50% of cases adenoma size was reduced (Chanson et al., 1993). Octreotide treatment was also considered useful preoperatively as it allowed an easier tumor removal as it produces tumor shrinkage (Beck-Peccoz et al., 1996).
Another multicenter study reported treatment with octreotide long-acting repeatable in thyroid stimulating hormone secreting adenomas. Eleven patients received octreotide subcutaneous (at dosages of 200–900 μg/daily) first and then octreotide long-acting repeatable (at 20 mg, every 28 days) after 4 weeks, both formulations significantly reduced thyroid stimulating hormone and thyroid hormone levels without causing significant side effects (Caron et al., 2001). The dose of octreotide needed to achieve thyroid stimulating hormone normalization was reported to be lower than that needed to suppress growth hormone in growth hormone secreting adenomas (Colao et al., 2003).
Lanreotide slow release treatment was similarly shown to suppress plasma thyroid stimulating hormone level and to normalize thyroid hormones with no significant change in adenoma size (Kuhn et al., 2000).
In five cases with thyroid stimulating hormone secreting pituitary adenomas, the hormone levels were successfully normalized and remained normal throughout the treatment period. The dosage of octreotide long-acting repeatable, or lanreotide slow release, required to normalize thyroid stimulating and thyroid hormone levels was indeed low (300 μg/day, 10 mg every 28 days, and 30 mg every 14 days, respectively) compared with dosages generally required in patients with growth hormone secreting adenomas, however, dosage should be titrated on the basis of individual patients’ responsiveness and tolerance (Colao et al., 2003).
4. Adrenocorticotrophic Hormone Secreting Adenomas:
The medical treatment of adrenocorticotrophic hormone secreting adenoma is reserved for patients with unsuccessful surgery (Pivonello et al., 2008) even after repeated pituitary surgery that is efficacious in approximately two-thirds (50–70%) of patients (Biller et al., 2008).
In long-term studies with bromocriptine, disease remission was confirmed in only a small minority of patients (Miller and Crapo, 1993).
A small, short-term study suggests that cabergoline at dosages of 2–3.5 mg/week may be effective (Pivonello et al., 2004). An extension study of this latter enrolling 20 patients after unsuccessful surgery, demonstrated that after 3 months of treatment, 75% of patients had normalization of free urinary cortisol that in 50% of them was maintained for 12 months (Colao et al., 2009). Tumor shrinkage after 6 months of cabergoline treatment was observed in 4 of 10 patients responsive to the treatment (Pivonello et al., 1999).
The use of cabergoline is still experimental and more data are required before proposing this treatment as an official therapy for adrenocorticotrophic hormone secreting tumors (Colao et al., 2009).
The possible role of somatostatin analogues has also been re-evaluated; pasireotide has been demonstrated to reduce adrenocorticotrophic hormone secretion in cell culture of corticotroph tumor (Hofland et al., 2005).
No definitive data are available on clinical trials, just a preliminary experience on very short-term treatment that looks encouraging (Boscaro et al., 2005). These data on the effectiveness of specific dopamine agonists and somatostatin analogues suggest that their combination may also be a possible therapeutic approach (Colao et al., 2009).
5. Non Functioning Adenomas:
Bromocriptine was used in non-functioning adenomas with disappointing results (Bevan et al., 1986). Quinagolide efficacy in the treatment of these tumors was tested in a few studies and significant tumor shrinkage was documented only in 4 out of 12 reported patients (Ferone et al., 1998).
Cabergoline was administered to 10 patients with non-functioning adenomas and significant adenoma shrinkage was found only in 2 out of 10 patients with non-functioning adenomas (Colao et al., 2000). In 18 patients with remnant non-functioning adenomas, 12 months of cabergoline treatment induced tumor shrinkage in 56%. Tumor shrinkage was associated with dopamine D2 receptor expression (Pivonello et al., 2004).
The results of chronic octreotide treatment were controversial; it was reported to induce a rapid improvement of headache and visual disturbances, without any change in tumor volume (Warnet et al., 1997). Decrease of tumor volume by 30±4% was reported in some patients with non-functioning adenomas treated with a combined octreotide + cabergoline treatment. There are no data on the effects of somatostatin analogues, octreotide or lanreotide slow release or autogel in non-functioning adenomas (Andersen et al., 2001).
Although first-line therapy of non-functioning adenomas is surgery, only 35.5% are considered cured after surgery. Conventional radiotherapy is reported to delay tumor regrowth and causes hypopituitarism in all patients after 10 years. Therefore, there is a need for an additional treatment in the majority of non-functioning adenomas patients. Both somatostatin analogues and dopamine agonists were found to be of some efficacy in selected patients with non-functioning adenomas, with the latter drugs being significantly more effective in reducing tumor volumes. However, no placebo-controlled long-term studies are available to suggest the use of somatostatin analogues or dopamine agonists or a combination of them (Colao et al., 2008).
Meningiomas:
It has been demonstrated that most of meningiomas express hormone receptors on their cell membranes (Marosi et al., 2008). Actually, up to 90% of meningiomas express progesterone receptors, while 30 to 48% express estrogen receptors (Korhonen et al., 2006).
It has been reported that the expression of the progesterone receptors alone in meningiomas indicates a favourable clinical and biological outcome. A lack of progesterone receptors or the presence of estrogen receptors correlates with an increasing potential for aggressive clinical behaviour, progression and recurrence of meningiomas (Pravdenkowa et al., 2006).
Epidemiological and immunohistochemical data have led to some attempts of treatment with anti-hormonal therapies for patients with progesterone receptors positive meningioma (Strik et al., 2002).
Mifepristone is oral anti-progesterone commonly used in treatment of estrogen receptors positive breast cancer with a significant benefit in global survival. Mifepristone inhibits the activity of progesterone receptors by complex mechanisms (Edwards et al. 2000). The use of progesterone antagonists in the palliation of meningioma has been discussed for more than 10 years (Strik et al., 2002).
The only prospective study on this topic was conducted on 160 patients in whom 80 patients were treated with mifepristone 200 mg and 80 patients were treated with placebo for a median duration of 10 months. The trial was prematurely closed. No difference was observed between the two arms in terms of time to progression, but 55% of patients had stable disease, 1% of patients had partial response and no patient achieved complete response (Newfield et al. 2001).
Feasibility of hormonal therapy was assessed in 28 patients with unresectable meningioma treated with oral mifepristone 200 mg/day and oral dexamethasone 1 mg/day for the first 14 days. With a median duration of therapy of 35 months, minor responses (improved visual field examination or improved CT or MRI scan) were noted in 8 patients, 7 of whom were male or premenopausal female, which can result in significant clinical benefit in this subgroup of patients (Grunberg et al., 2006).
In a phase II evaluation of hormonal therapy by tamoxifen (an orally active selective estrogen receptors modulator that competitively binds to estrogen receptors and inhibits oestrogen effects) in unresectable or refractory meningiomas, only 5% of patients achieved partial response, 10% had minor response that was of short duration, 32% remained stable for a median duration of more than 31 months while 53% demonstrated progression. A definite recommendation for the use of tamoxifen in refractory meningiomas could not be made (Goodwin et al. 1993).
Brain Tumors and Steroids:
A major cause of death in glioblastoma patients (more than 60% of cases) is brain herniation due to cerebral edema and increased intracranial pressure (Altaha, 2009).
Corticosteroids are usually indicated in any patient with brain tumor with symptomatic peri-tumoral edema. Dexamethasone is used most commonly as it has little mineralocorticoid activity and, possibly, a lower risk for infection and cognitive impairment compared with other corticosteroids (Batchelor and DeAngelis, 1996).
Vasogenic edema associated with brain tumors results from increased capillary permeability and causes neurologic dysfunction by exerting pressure on brain structures. This leads to headache with nausea, emesis and exacerbation of seizures; if severe, edema can result in herniation and death (Papadopoulos et al., 2001).
The mechanism of action of corticosteroids is not well understood. It has been argued that the anti-edema effect is due to reduction of the permeability of tumor capillaries by causing dephosphorylation of the tight junction component proteins (Drappatz et al., 2007).
Dexamethasone reduces the tumor-associated edema in patients with brain metastases or primary brain tumor as illustrated by CT studies (Sturdza et al., 2008). Dexamethasone produces symptomatic improvement within 24 to 72 hours. Generalized symptoms, such as headache and lethargy, tend to respond better than focal ones. Improvement on CT and MRI studies often lags behind clinical improvement (Drappatz et al., 2007).
Side effects of corticosteroids were dose-dependent, while the degree of neurologic improvement was independent of the dose. It is therefore generally accepted that corticosteroid dose should be titrated to the minimal dose needed to relieve symptoms. The usual starting dose is a 10 mg load, followed by 16 mg per day in patients who have significant symptomatic edema. Lower doses may be effective, especially for less severe edema. The dose may be increased up to 100 mg per day if necessary (Drappatz et al., 2007). The time to peak concentration for an oral tablet is 1-2 hours. The plasma half-life is about 2-4 hours but its biologic half-life is 36 to 54 hours (Sturdza et al., 2008).
Special care should be given to the tapering of the corticosteroid dose. Decreasing the dose by 25% every 4–5 days is a rational approach. In patients who have required corticosteroids for more than 2 weeks, the “steroid withdrawal syndrome” may occur (Rosenfeld and Pruitt, 2007). There is no standard recommendation regarding steroid dose used in patients with cerebral metastases, prior, during or following palliative radiotherapy (Sturdza et al., 2008).
A number of important aspects should be considered when prescribing steroids to maximize quality of life: (I) the lowest effective dose possible of corticosteroids should be used; (II) regarding peri-tumoral edema, treat the patient and not the MRI image (clinically asymptomatic edema does not require steroid treatment); (III) to reduce insomnia linked to steroids, avoid prescribing it in the evening; (IV) because of the risk of adrenal insufficiency following abrupt discontinuation, corticosteroids should be tapered progressively unless steroids have been administered for two weeks or less (Stupp et al., 2008).
Corticosteroid intake leads to a wide range of side effects. Side effects of corticosteroids include endocrine disorders such as Cushing’s syndrome and disturbances of the blood sugar level ranging up to diabetes mellitus, muscular weakness, increasing risk of infectious diseases, gastrointestinal complications such as ulcers or bleeding, atrophic changes of skin, and hematological and psychiatric disorders (Sturdza et al., 2008). Longer duration of treatment (more than 3 weeks), higher doses, and hypoalbuminemia are associated with greater toxicity (Drappatz et al., 2007).
The side effects associated with corticosteroids are the driving force to search for alternative therapies for cerebral edema. Corticotropin-releasing factor reduces peritumoral edema by a direct effect on blood vessels through Corticotropin-releasing factor 1 and 2 receptors. Phase I/II trials of this agent suggest that it is relatively well tolerated. Several phase III trials are in progress examining the efficacy of this drug in the treatment of acute and chronic peritumoral edema. Preliminary studies suggest that cyclooxygenase-2 (COX-2) inhibitors may be effective in treating cerebral edema but further clinical studies using cyclooxygenase-2 inhibitors have been delayed due to the cardiovascular complications of this class of drugs. Inhibitors of vascular endothelial growth factor or inhibitors of its receptors reduce tumor-related edema. These classes of drugs eventually may prove more effective and less toxic alternatives to corticosteroids (Drappatz et al., 2007).
Future Endocrinal Therapy:
Thyroid hormone plays a major role in normal brain maturation and affects the development of astrocytes. Increasing evidence has suggested that aberrant expression of thyroid hormone receptors isoforms could be associated with tumorigenesis. Thyroid hormone receptors expression was compared between low grade and high grade astrocytomas. A study demonstrated for the first time that thyroid hormone receptors isoforms are indeed expressed in human astrocytomas. The expression of thyroid hormone receptors isoforms is correlated to the malignancy grading of astrocytomas. The frequency of thyroid hormone receptors α1 or α2 expression significantly decreased with the grade of malignancy. However, the frequency of thyroid hormone receptors β1 expression significantly increased with the grade of malignancy. This result provides insight into the potential use of hormonal therapy for brain tumors that overexpress or underexpress thyroid hormone receptors (Hwang et al., 2008).
Chapter (8)
Gene & Viral Therapies
Gene and Viral Therapies
Advances in understanding and controlling genes and their expression have set the stage to alter genetic material to prevent or fight disease with brain tumors being among one of the first human malignancies to be targeted by gene therapy. All proteins are coded for by DNA and most neoplastic diseases ultimately result from the expression or lack of one or more proteins (e.g., coded by oncogenes or tumor suppressor genes, respectively). Therefore, diseases could be treated by expression of the appropriate protein in the affected cells (Asadi-Moghaddam and Chiocca, 2009).
Currently available treatments for brain tumors necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumors is promising as it can be delivered in situ and selectively targets tumor cells while sparing the adjacent normal brain tissue (Germano and Binello, 2009).
Gene therapy is an experimental treatment that involves introducing genetic material (DNA or RNA) into cells, and it has made important advances in the past decade. Within this short time span, it has moved from the conceptual laboratory research stage to clinical translational trials for brain tumors (Asadi-Moghaddam and Chiocca, 2009).
Two crucial considerations in gene therapy relate to: (1) what gene should be delivered for expression, and (2) how to deliver it. In its simplest form, gene therapy is the process by which either defective or missing genes are replaced, or new genes for new functions are introduced. For this purpose, the genetic material is coupled to additional regulatory sequences (e.g., promoters and enhancers) and is packaged inside a gene delivery vehicle to enable transfer and expression of the gene product inside the cell (Fig. 13) (Asadi-Moghaddam and Chiocca, 2009).
The first step of gene therapy involves gene delivery to facilitate the expression of the therapeutic gene in the interior of a cell. The simplest method is the direct introduction of therapeutic DNA into target cells by physical (i.e., electroporation) or chemical techniques (i.e., lipofection). This approach still remains limited in its application, as it is relatively inefficient, it can be used only with certain tissues and requires large amounts of DNA (Anwer, 2008).
The next difficulty for the foreign genetic material is that once within the cell, it must escape intracellular degradation to enter the nucleus to be expressed (Lechardeur and Lukacs, 2006). Therefore, gene delivery systems (vectors) were designed to protect the genetic material (Fig. 13). An ideal vector needs to meet three criteria: (1) it should protect the transgene (the transferred gene) against degradation by nucleases in the extracellular matrix; (2) it should bring the transgene across the plasma membrane and then into the nucleus of the target cells; and (3) it should have no harmful effects (Bergen et al., 2008).
Vectors for Gene Therapy:
Gene delivery can be accomplished using different vectors. Historically, viral vectors were the first used. Cell-based transfer and synthetic vectors have subsequently been developed and seem to be promising gene delivery methods (Germano and Binello, 2009).
(1) Viral Vectors:
Viruses used in brain tumor therapy can be divided into two categories:
A) Replication-incompetent viruses (viral vectors) that can not replicate and they act as mere vectors for gene transfer. In this case, the vector is derived from a virus from which all or most of the viral genes have been removed to minimize the virus-mediated toxicity. Two replication-incompetent viruses, retrovirus and adenovirus, were studied in clinical trials (Asadi-Moghaddam and Chiocca, 2009).
B) Replication-competent viruses (oncolytic viruses) that infect then replicate and lyse tumor cells with or without gene transfer and these viruses are used in the oncolytic virotherapy. In this case, selected viral genes are deleted or mutated so that viral targeting and/or replication can occur selectively in the tumor cells. Four replication-competent viruses; herpes simplex virus, replicating adenovirus, reovirus and Newcastle disease virus, were studied in clinical trials (Asadi-Moghaddam and Chiocca, 2009).
The most effective way to transfer DNA into somatic cells remains the use of viral vectors. Gene transfer using viral vectors has been carried out in numerous clinical trials. Retrovirus and adenovirus are the most studied vectors for brain tumors. Retroviruses were the first used vectors. Adenoviral vectors offer several theoretical advantages over retroviruses. These include increased efficiency and ability to transcribe genes without insertion in the host genome, thereby eliminating the risk of insertional mutagenesis (Germano and Binello, 2009).
(2) Cell-based Vectors:
Neural stem cells, neural progenitor cells, embryonic stem cells derived astrocytes, bone marrow-derived stem cells, mesenchymal stem cells, endothelial progenitor cells, and fibroblasts were used for gene transfer (Germano and Binello, 2009).
(3) Synthetic Vectors:
Liposomes are the most studied nanoparticles for gene delivery. Liposomes are spherical vesicles with a membrane composed of a phospholipid and cholesterol bilayer, and can deliver and release DNA and drugs (Benítez et al., 2008). Liposomes become an attractive alternative to viral vectors. Their main advantage includes safety and lack of immunogenicity but they have low efficiency. Liposomal vectors have been used to deliver therapeutic genes in rodents and in clinical trials for brain tumors (Germano and Binello, 2009).
[pic]
Fig. 13. Mechanism of vector-mediated gene therapy: a vector binds to the cell membrane then enters the cell. The gene then travels to the nucleus, where it becomes active. In the nucleus, the gene becomes transcribed into mRNA then mRNA becomes protein, and the desired effect occurs. In this case, the desired effect was to cause apoptosis of tumor cells by introduction of an apoptotic gene (Asadi-Moghaddam and Chiocca, 2009).
Approaches of Gene Therapy:
Five gene therapy approaches are currently being explored: (1) Suicide gene therapy (pro-drug activating gene therapy or chemotherapy-sensitizing gene therapy); (2) Tumor suppressor gene therapy; (3) Immunogene therapy (genetic immune modulation); (4) Anti-angiogenic gene therapy; and (5) Oncolytic virotherapy.
(1) Suicide gene therapy:
It is the most commonly used technique in clinical trials for brain tumors. It involves transducing tumor cells with a gene encoding an enzyme that can metabolize a nontoxic pro-drug to its toxic form (Asadi-Moghaddam and Chiocca, 2009).
Herpes simplex virus type-1 thymidine kinase/ ganciclovir: in this approach, the tumor cells are transduced to express herpes simplex virus thymidine kinase using retroviral or adenoviral vector and treated with the antiviral agent ganciclovir. Herpes simplex virus thymidine kinase is an enzyme that metabolizes nontoxic drugs such as ganciclovir, acyclovir, or valacyclovir, into a cytotoxic metabolite. The ganciclovir metabolite is incorporated into DNA, causing DNA elongation to terminate and subsequently cause cell death (Chen et al., 1994). Preclinical experiments demonstrated marked tumor elimination, despite gene transfer into only a small fraction of tumor cells. This was due to the cytotoxic effect of the transduced cells on the adjacent non-transduced cells which is called the bystander effect. Furthermore, the tumor cells treated with this approach displayed enhanced sensitivity to radiation in culture and in vivo (Asadi-Moghaddam and Chiocca, 2009).
Cytosine deaminase/5-Fluorocytosine: in this approach, the tumor cells are transduced to express cytosine deaminase and treated with the antifungal agent 5-Fluorocytosine. 5-Fluorocytosine is a pro-drug converted into cytotoxic active agent 5-fluorouracil by cytosine deaminase. 5-Fluorocytosine is nontoxic to human cells because of the lack of cytosine deaminase. The toxic effects of 5-fluorouracil are mediated by its intracellular metabolites, which cause DNA strand breakage leading to cell death (Aghi et al., 1998). Two preclinical studies for glioblastoma using an adenoviral vector carrying the cytosine deaminase gene demonstrated promising results (Asadi-Moghaddam and Chiocca, 2009).
Cytochrome P450/cyclophosphamide: as in previous approaches, cyclophosphamide is a pro-drug that is activated by liver-specific enzymes of the cytochrome P450 family. The active form of cyclophosphamide (phosphoramide mustard) is an alkylating agent that generates DNA cross links and consecutive DNA strand breaks. The efficacy of cyclophosphamide in treating brain tumors has been limited by the fact that its active metabolites are poorly transported across the blood-brain barrier (Wei et al., 1994).
Replacement of parts of the herpes simplex virus type-1 genome with the cytochrome P450 gene has led to the design of a herpes simplex virus type-1 vector that can kill tumor cells through three modes: 1) using viral oncolysis, 2) making the infected cell sensitive to cyclophosphamide, and 3) making the infected cell sensitive to ganciclovir. Animal studies of glioma cell lines showed tumor regression when the animals were treated with this modification (Asadi-Moghaddam and Chiocca, 2009).
(2) Tumor suppressor gene therapy:
This includes transfer of tumor suppressor genes and cell-cycle modulators. The p53 tumor suppressor protein regulates cell-cycle progression and apoptosis in response to many external insults (e.g., DNA damage and oncogenic mutations) (Vousden K and Lane, 2007).
Mutations in the p53 gene resulting in loss of its function are common in astrocytomas, and are associated with tumor progression from low-grade astrocytoma to glioblastoma (Louis et al., 2001). Accordingly, the p53 gene became an attractive candidate for gene transfer in an attempt to restore cell cycle regulation in p53-mutated cells and induce apoptosis, even in tumors with intact functional genes, by causing enhanced expression of the gene product (Roth, 2006).
Another commonly affected cell-cycle pathway in gliomas is the retinoblastoma protein/cyclin-dependent kinases/cyclin-dependent kinase inhibitors circuit. Preliminary studies restoring the genomic region of these defects in glioblastoma cell lines demonstrated tumor growth arrest or apoptosis. Another candidate for a gene therapy approach is the epidermal growth factor receptor gene, which shows frequent amplification in primary glioblastomas (Asadi-Moghaddam and Chiocca, 2009).
Transfer of several pro-apoptotic genes, such as factor-related apoptosis-inducing ligand has shown promising pre-clinical results in vitro and in vivo studies. Transfer of caspase-8 was showed to augment apoptosis in vitro on human malignant glioma cells (Germano and Binello, 2009).
(3) Immunogene therapy:
Gene therapy approaches aiming at genetic immune modulation enhance the immune response against tumors by expressing cytokines and lymphokines. The frequently used cytokines to achieve genetic immune modulation are interleukin-2, interleukin-4, interleukin-12, interferon β, interferon γ, and granulocyte-macrophage colony stimulating factor. Several studies have been performed by infecting tumor cells ex vivo (outside the patient) with cytokine genes. Another model introduces immune modulating genes into the tumor so infection occurs in situ. Several phase I trials are currently underway using this strategy. However, for interleukin-2 and interferon γ severe CNS toxicity has been reported when these cytokines were secreted by tumor cells intracranially (Asadi-Moghaddam and Chiocca, 2009).
In a recent clinical trial in humans with recurrent gliomas, an adenoviral vector was employed to deliver the gene for human interferon β and this resulted in increased apoptosis in tumors (Chiocca et al., 2008). Gene therapy can also be used to generate tumor vaccines by inducing tumor antigen presentation by antigen presenting cells (Asadi-Moghaddam and Chiocca, 2009).
(4) Anti-angiogenic gene therapy:
Neovascularization is a feature of malignant gliomas and is dependent on several potent angiogenic factors secreted by tumor cells. Vascular endothelial growth factor is an important overexpressed angiogenic factor in gliomas. It has been shown that in vivo transfer of an adenoviral vector carrying gene for vascular endothelial growth factor in an antisense form inhibits glioma growth. Antisense form means single strands of DNA or RNA that can bind to a complementary RNA sequence preventing protein synthesis (i.e. preventing vascular endothelial growth factor synthesis) (Asadi-Moghaddam and Chiocca, 2009).
Other strategies are directed at the vascular endothelial growth factor receptors. A mutant vascular endothelial growth factor receptor was transferred into xenografted glioma using retroviral vector. Histological analysis revealed reduced vascular density, decreased tumor cell proliferation and increased apoptosis and necrosis (Benítez et al., 2008).
(5) Oncolytic Virotherapy:
Oncolytic viruses are engineered to selectively replicate in cancer cells killing these cells without affecting healthy cells. The virus replicates in the cancer cell then thousands of new viruses are released and infect neighboring cancer cells (Fig. 14). The cycle continues until tumor cells are completely eradicated (Benítez et al., 2008).
These viruses are capable of selectively lysing tumor or dividing cells, making their use potentially safe in the brain where most cells are not-dividing (Germano and Binello, 2009).
Oncolytic Adenovirus:
Oncolytic adenoviruses are engineered or naturally occurring strains of virus that replicate better in tumor cells versus normal cells (Asadi-Moghaddam and Chiocca, 2009).
[pic]
Fig. 14. General mechanism of oncolytic virus selectivity (Asadi-Moghaddam and Chiocca, 2009).
Herpes Simplex Virus Type-1:
Herpes simplex virus type-1 as an oncolytic virus offers several advantages: 1) the ability to incorporate large load of foreign DNA; 2) the ability to infect human cells with high efficiency; 3) the sensitivity to the anti-herpetic agents, such as ganciclovir providing a safety mechanism by which virus replication can be eliminated when needed; and 4) herpes simplex virus type-1 never integrates into the host genome so the risk of insertional mutagenesis is absent. The disadvantage of herpes simplex virus type-1 is that its genetic manipulation is more difficult than that of adenoviruses due to the large size of the viral genome (Asadi-Moghaddam and Chiocca, 2009).
Newcastle Disease Virus (NDV):
A phase I/II trial of intravenous infusion of an oncolytic Newcastle disease virus in glioblastoma patients reported that good tolerance to the virus was observed, but only one patient achieved a complete response (Freeman et al., 2006).
Reovirus:
Reovirus can replicate to very high levels in an infected cell, and thus it could provide a good therapeutic effect because the large number of virus could infect a large number of neighboring tumor cells. One of the issues that limit use of this virus relates to its small size which makes genetic manipulation difficult (Asadi-Moghaddam and Chiocca, 2009).
Gene Therapy Trials:
Six viruses; two replication-incompetent (retrovirus and adenovirus) and four replication-competent (adenovirus, herpes simplex virus type-1, Newcastle disease virus and reovirus) have been studied in clinical brain tumor trials in which the results have been published. Measles virus has been studied in glioma patients in a trial that is still ongoing and whose results have yet to be published (Asadi-Moghaddam and Chiocca, 2009).
Retrovirus and adenovirus have been genetically modified to express herpes simplex virus thymidine kinase with concurrent ganciclovir administration. The first study using gene therapy in glioma patients used stereotactic intratumoral inoculation of a retroviral vector carrying herpes simplex virus thymidine kinase gene in 15 patients with recurrent malignant brain tumor. Although this study showed some promising results in terms of antitumor efficacy, it was not a controlled or randomized protocol (Ram et al., 1997).
Two subsequent phase I and II studies in patients with recurrent glioblastoma were performed using a herpes simplex virus thymidine kinase followed by ganciclovir administration. The first study involved 12 patients and no treatment-related adverse effects were noted. The overall median survival was 6.8 months, with three patients surviving > 12 months and one patient was recurrence-free 2.8 years after treatment (Klatzmann et al., 1998).
A comparable international, multicenter study used herpes simplex virus thymidine kinase with concurrent ganciclovir administration in 48 patients with recurrent gliomas. The median survival time was 8.6 months, with a 12-month survival rate of 27%. Tumor recurrence was absent on MRI in seven patients for at least 6 months and in two patients for 12 months, and one patient remained recurrence-free at 24 months (Shand et al., 1999).
A similar phase I study was performed in 12 children (aged 2 to 15 years) with recurrent malignant supratentorial tumors. This study also used the previous approach. Disease progression occurred at a median time of 3 months after treatment, and the longest time until progression was 24 months with no adverse effects were noted (Packer et al., 2000).
A large controlled phase III trial seemed necessary for confirmation of the efficacy of the retroviral herpes simplex virus thymidine kinase with ganciclovir administration approach. This study used an adjuvant gene therapy protocol to the standard therapy of maximum surgical resection and irradiation for newly diagnosed glioblastoma. After 4 years of follow-up of 248 patients, survival analysis showed no advantage of gene therapy in terms of tumor progression and overall survival (Rainov, 2000).
A phase I/II trial evaluated an adenoviral vector expressing the herpes simplex virus thymidine kinase with ganciclovir administration gene in patients with primary or recurrent high-grade gliomas. This study was performed in a controlled randomized fashion on 36 patients (i.e., 17 in the treatment arm and 19 in the control group). The treatment group underwent surgical resection and adenoviral injection, followed by intravenous ganciclovir on postoperative day 5 for 14 days. The control group underwent resection only. The median survival in the gene therapy group was significantly longer than the control group (62 vs. 37 weeks) (Immonen et al., 2004).
An adenoviral vector delivering a wild-type copy of the p53 transgene was also evaluated in humans with recurrent gliomas. The vector was initially introduced by an implanted catheter placed in the middle of the tumor bed, followed by resection of the tumor to allow for studies related to p53 gene delivery and distribution. Again, while the treatment was well tolerated, the distribution of p53 gene into tumor was relatively low (Lang et al., 2003).
One recent trial evaluated an adenoviral vector in 11 patients with recurrent high-grade glioma introduced by stereotactic injection, followed by surgical resection and an additional injection of the vector into the tumor bed. The vector was well-tolerated in all patients. One patient experienced confusion after the postoperative injection, which was believed to be caused by local brain toxicity. Tumor resection after the viral treatment showed a biologic effect from the transferred gene (Chiocca et al., 2008).
A phase I trial evaluated the safety of an oncolytic herpes simplex virus type-1 in 9 patients with recurrent glioblastoma. Direct intratumoral injection was performed with no adverse clinical symptoms or induction of encephalitis, nor reactivation of latent herpes simplex virus, thus appearing as if tumor progression was controlled with some efficacy (Rampling et al., 2000).
Another clinical trial using a different herpes simplex virus type-1 mutant included 21 patients with recurrent glioma with similar results as they relate to safety (Markert et al., 2000).
Strategies to decrease the immune response prior to administration of virus have also provided strong pre-clinical data. The therapeutic effects of the oncolytic herpes simplex virus can be enhanced by co-administration of cyclophosphamide, which decreases production of gamma-interferon and results in additional spreading of the virus (Fulci et al., 2006).
A large phase III trial in Europe using herpes simplex virus type-1 is being conducted (Asadi-Moghaddam and Chiocca, 2009).
Enhancing Gene Therapy:
Currently, two delivery methods to enhance gene transfer have provided promising laboratory results: (1) convection-enhanced delivery and (2) ultrasound. The use of convection-enhanced delivery to homogenously cover larger areas of the brain has been described in laboratory studies and clinical trials for drug delivery. In convection-enhanced delivery, programmable pumps and specifically designed catheters are used. The hypothesis that ultrasound can be used to enhance efficacy of chemotherapeutics and intracellular gene delivery in glioma cells in vitro was recently tested in gliosarcoma model. The findings suggest that ultrasound may be useful to increase the efficacy of chemotherapy and gene therapy (Germano and Binello, 2009).
Finally, the problem of delivering genetic vectors into brain tumors and the efficient in situ gene transfer remains one of the most significant difficulties in gene therapy. The completed brain tumor gene therapy trials have offered some promising results. However, the results of most clinical studies have not lived up to the expectations created by experimental data. Although gene delivery to human patients seems to be safe, these studies have not yet translated into benefits in the clinic. At present, gene therapy is being studied in trials for brain tumors, and so far it is not available outside of a clinical trial (Asadi-Moghaddam and Chiocca, 2009).
Discussion
Discussion
It is thought that maximal surgical resection of gliomas, the commonest primary brain tumor, significantly improves survival but there is no good evidence from randomized trials that resection offers any survival advantage (Metcalfe and Grant, 2001).
Collected data on symptoms before and after surgical resection of brain tumors report that 32% had an improvement in their symptoms, 58–76% were not different, and 9–26% had a worsening. Neurosurgery can improve some symptoms, but it can also create new ones, it can be associated with local or systemic complications (Hart and Grant, 2007).
Despite advances in radiotherapy and chemotherapy along with surgical resection, the prognosis of patients with malignant brain tumors is poor. Therefore, the development of new treatment modalities is extremely important. Most brain tumor patients usually undergo multimodality treatments after histological diagnosis (Yamanaka and Itoh, 2007).
There are many controversies surrounding current non-surgical therapies. Drug delivery across the blood-brain barrier is one of the vital problems, so the dilemma now is what is the most efficient way to deliver drugs to the brain (Sawyers, 2006)? Also, it is difficult for the drugs to reach the intraparenchymal regions in the brain beyond the resection cavity. This becomes a burden with micrometastases and infiltrative satellites that are commonly seen in glioma. Therefore, researchers developed convection-enhanced delivery as a novel way to deliver drugs across blood-brain barrier as well as over a large volume of tissue. This method has become especially relevant in brain tumors as it bypasses blood-brain barrier and reduces systemic toxicities (Mercer et al., 2009).
There are several non-surgical treatment modalities for brain tumors starting with radiation therapy and chemotherapy that represent the backbone of the non-surgical treatment, till immunotherapy and antiangiogenic therapy that showed promising clinical results, and finally gene and viral therapies that hold promise in the near future. Also, we can not forget the endocrinal therapy that showed great success in the field of management of pituitary adenomas.
Radiation therapy plays a primary role in the management of most malignant and many benign brain tumors. It is used frequently postoperatively as (Stieber and Mehta, 2007):
(a) Adjunctive therapy: to 1) decrease local failure, 2) delay tumor progression, and 3) prolong survival (as in malignant gliomas).
(b) Curative treatment for diseases such as primitive neuroectodermal tumors and germ cell tumors.
(c) Therapy that stops further tumor growth as in schwannoma, meningioma, pituitary tumors, and craniopharyngioma.
Survival benefit for postoperative whole brain radiation therapy for glioma was demonstrated in studies going back three decades ago. Median survival increased from 17 weeks in patients treated with conventional measures to 37.5 weeks in patients treated with postoperative whole brain radiation therapy (Norden and Wen, 2006).
Subsequent advances in radiotherapy techniques have used advanced imaging of the tumor and focused on radiotherapy techniques that maximize treatment to the tumor while minimizing radiation to normal brain tissue. Focal radiotherapy, termed involved field radiotherapy has replaced whole brain radiation therapy as the standard approach. Some types of involved field radiotherapy include 3 dimensional conformal radiotherapy and intensity modulated radiotherapy that provides particular advantages when the target is critically close to the radiation-sensitive structures, as the dose to these structures can be minimized without affecting the dose to the tumor that needs to be treated (Omay and Vogelbaum, 2009).
Radiotherapy has side effects that include local scalp irritation, hair loss, somnolence and fatigue in the short term. Late side effects include radiation leuco-encephalopathy (comprising of dementia, incontinence and gait disturbance). Its effectiveness, ease of administration and acceptable short-term side effects profile make it a standard treatment for the most of malignant brain tumors (Hart and Grant, 2007).
Because the majority of malignant gliomas recur in close proximity to the original tumor and multifocal or disseminated disease is uncommon, there is great interest in maximizing the radiation dose to the tumor bed without increasing radiation exposure to the surrounding brain tissue. Stereotactic radiosurgery offer this advantage. It can deliver a high accurate single dose of radiation (Omay and Vogelbaum, 2009).
Stereotactic radiosurgery with a Gamma Knife or CyperKnife is now being used as (A) primary management or (B) booster treatment with whole brain radiation therapy, in brain metastasis (Yamamoto, 2007). Controversy persists as to whether stereotactic radiosurgery should be combined with whole brain radiation therapy? Although some reports have supported combining stereotactic radiosurgery with whole brain radiation therapy to achieve optimal tumor control and survival periods (Chidel et al., 2000), others have questioned usefulness of whole brain radiation therapy (Sneed et al., 2002). Neither the survival rate nor the local tumor recurrence rate differs significantly between groups with vs without whole brain radiation therapy (Yamamoto, 2007).
Although the size limitation on treatable lesions (should be < 4 cm) is crucial in stereotactic radiosurgery, tumor control rates of 90% can be expected if 1-4 lesions are irradiated with a peripheral dose of 20 Gy or more. In such cases, true recurrence is extremely rare. Post-radiosurgical MRI reveals disappearance of the tumors and complete cure (Pollock and Brown, 2002).
Gamma Knife radiosurgery is superior to whole brain radiation therapy for several reasons: (1) a brief hospital stay, (2) Higher control rates and earlier symptom palliation, (3) All observable lesions on MRI can be treated, (4) Other treatments, such as surgery and chemotherapy, need not be interrupted, (5) Availability of an alternative treatment allows whole brain radiation therapy to be reserved for subsequent treatment attempts when it become absolutely necessary, (6) Radiosurgery can be repeated, even after whole brain radiation therapy which usually cannot be repeated, (7) Patients never lose all of their hair, (8) A very low incidence of dementia can be expected, (9) Radiosurgery can be used as postoperative irradiation instead of whole brain radiation therapy that has several disadvantages (Yamamoto, 2007).
Stereotactic radiosurgery may represent also an alternative or supplementary modality to conventional surgery in small-volume low-grade astrocytomas. There is also evidence for beneficial effect of stereotactic radiosurgery on the survival of patients with high-grade gliomas (Szeifert et al., 2007). Future studies are needed to identify patients most likely to respond to stereotactic radiosurgery (Biswas et al., 2009).
Multiple studies demonstrated the efficacy and safety of stereotactic radiosurgery in treatment of meningioma, with tumor control rates ranging from 60 to 100% depending on the proportion of atypical or malignant meningiomas (Lee et al., 2002). Given the benefit of radiosurgery, stereotactic radiosurgery is increasingly used to treat patients as a primary therapy based on imaging criteria only (Flickinger et al., 2003). Radiosurgery is considered as an effective management choice for patients with small to medium-sized symptomatic, newly diagnosed or recurrent meningiomas of the brain (Kondziolka et al., 2008).
Stereotactic radiosurgery is also safe and highly effective treatment for patients with pituitary adenomas. Radiosurgery provides control of tumor growth in nearly all cases and hormone normalization in the majority of secretory tumors (Mayberg and Vermeulen, 2007).
Although, stereotactic radiosurgery is not a risk-free treatment and some patients may develop complications. Complications of stereotactic radiosurgery that have been reported include acute coronary events, severe pain, headaches, facial pain, new motor deficits, symptomatic hydrocephalus and delayed seizures (Vachhrajani et al., 2008).
Chemotherapy has played primarily an adjuvant role because of efficacy limitations related to the non-specific nature of chemotherapeutic agents, drug delivery issues, and inherent tumor chemoresistance (Cairncross et al., 1998). There is now clear evidence that chemotherapy can improve survival. Debates have continued over whether this increase in survival is clinically significant. Further trials need to consider the quality of life as well as survival benefit (Hart and Grant, 2007).
The most commonly used drugs were nitrosoureas, either alone or in combination with other agents (Walker et al., 1980).
Temozolomide is now the preferred agent for concurrent and adjuvant chemotherapy in patients with gliomas (Batchelor and Supko, 2008). More recent evidence supports temozolomide effect as a radiosensitizer also (Van Nifterik et al., 2007). Temozolomide was associated with significant improvements in median survival, progression-free survival, overall survival, and two-year survival. This improvement in survival was achieved with no harmful effect on the quality of life of the patients (Batchelor and Supko, 2008).
Concomitant chemo-radiotherapy followed by single-agent adjuvant treatment with the temozolomide was associated with a significant improvement in median survival and also it was well tolerated in all patients (Stupp et al., 2005). It is the current standard of care for glioma patients. Concomitant chemo-radiotherapy as well as the early introduction of chemotherapy, appears to be the key to improving outcome (Stupp et al., 2007).
Efforts to maximize efficacy of chemotherapy by overcoming the blood-brain barrier limitations included: (1) intra-arterial delivery, (2) disruption of the blood-brain barrier and (3) implantation of the drug directly in the tumor bed. Dose intensification intended to increase drug gradients across the blood-brain barrier for improved penetration is often faced by added systemic toxicity (Ashby et al., 2001).
Trials of molecularly targeted drugs as monotherapy for gliomas were disappointing, with some potential benefit when used in combination with nitrosurea or temozolomide. Combinations of multitargeted therapies are currently the focus of clinical trials (Kreisl, 2009).
Two aspects are noteworthy in regard to chemotherapeutic molecular agents. Pretreatment molecular profiling of tumors will be increasingly needed to determine if the mechanism of a drug is appropriate to the genetic alterations found within individual tumors. In addition to traditional clinical endpoints, biological end-points (change in serum tumor markers, measures of target inhibition) seem to be appropriate, and in particular dosing schedules in phase I trials that focus on the determination of an optimal biological dose rather than the maximum tolerated dose must be explored. Finally, multitargeted agents are needed to target simultaneously multiple signaling pathways that concur at the same time or sequentially, as a compensatory activation, to tumor growth and resistance to treatments (Soffietti et al., 2007).
Better understanding of the molecular pathogenesis of brain tumors will allow development of specifically targeted therapies. Correlative molecular studies, now included in most ongoing trials, will enhance our understanding of this disease and allow for rapid further improvement in outcome (Stupp et al., 2007).
Immunotherapy gives the promise of targeting the tumor cells for destruction with an excellent specificity and efficiency, while at the same time completely sparing the normal cells (Mitchell et al., 2008). Immunotherapeutic approaches include: 1) passive immunotherapy, 2) active immunotherapy (tumor vaccines), and 3) adoptive immunotherapy (largely abandoned nowadays) (Omay and Vogelbaum, 2009).
Passive immunotherapy using the anti-vascular endothelial growth factor monoclonal antibodies bevacizumab (Avastins®) showed good results specially the combination of bevacizumab and chemotherapy that have shown promising response rates and evidence of prolongation of survival in recurrent glioblastoma patients (Vredenburgh et al., 2007).
Active immunotherapy or a successful vaccine for brain tumors has been a ‘holy grail’ in neuro-oncology (Ebben et al., 2009). Peptide-based vaccines represent a major focus of cancer vaccine research (Yamanaka and Itoh, 2007). Dendritic cell-based vaccines has also shown potential efficacy as a method of overcoming chemotherapy resistance (Liu et al., 2006). There are several promising vaccines under investigation in different phases including: (1) CDX-110, (2) DCVax, (3) Oncophage, (4) Poly-ICLC (Das et al., 2008).
Immunotherapy did not emerge as a single-modality treatment for brain tumors, but it may take its place as a very effective adjuvant therapy. Dendritic cell and peptide-based therapies appear promising as an approach to successfully induce antitumor immune response and prolong survival. They seem to be safe and without major side effects. Their efficacy should be studied in randomized controlled clinical trials (Yamanaka, 2009).
However, a number of limitations still exist on the clinical efficacy of immunotherapy with antibodies. The main unresolved problem stems from the question whether treatments administered systemically can achieve clinically significant levels at the site of intracranial tumors. Sufficient levels may not be achieved with the dosage and systemic route of administration. Clinical attempts to ‘open up’ the Blood-brain barrier to drug delivery have met with both failure and toxicity. Other problems that remain for systemic delivery are the high interstitial pressures in the tumor and surrounding tissue which prevent perfusion. In addition, the use of antibodies introduces a problem that is the antibodies themselves are antigenic. The development of human anti-human antibodies against the therapeutic antibodies is not infrequent event (Mitchell et al., 2008).
Currently, anti-angiogenic therapy is being increasingly adopted for treating glioblastoma (Argyriou et al., 2009). Because of vascular endothelial growth factor prominent role in glioma angiogenesis, its pathway was rapidly identified as an attractive therapeutic target (Chi et al., 2009).
Bevacizumab (Avastin®), as mentioned before, is an anti-vascular endothelial growth factor monoclonal antibodies but also has strong anti-angiogenic effect. Bevacizumab showed promising radiographic response proportions in recurrent glioblastoma and in recurrent anaplastic glioma. Responses were also associated with neurological improvement and reduction or discontinuation of corticosteroid requirements (Wagner et al., 2008). Additionally, several retrospective studies have reported similar findings with bevacizumab. Radiographic response proportions between 35% and 50% were observed with combination of bevacizumab and conventional chemotherapy (Guiu et al., 2008).
Cediranib which is a potent pan-vascular endothelial growth factor receptor inhibitor with modest activity against platelet derived growth factor receptor showed radiographic response in 56% of patients and there was a modest improvement in median overall survival. Furthermore, an antiedema effect was detected (Batchelor et al., 2008).
Other anti-angiogenic drugs include epidermal growth factor receptor inhibitors such as cetuximab, gefitinib and erlotinib. A phase I/II study investigating the efficacy and safety of cetuximab plus concomitant chemoradiotherapy is currently ongoing. Monotherapy with gefitinib is not superior in terms of efficacy over conventional chemotherapy. Overall, therapy with erlotinib or gefitinib is associated with modest therapeutic efficacy (Argyriou et al., 2009). The newer platelet derived growth factor receptor inhibitors, tandutinib and dasatanib, have potentially greater efficacy in malignant gliomas due to improved CNS penetration, and they are in clinical trials for recurrent gliomas (Chi et al., 2009).
A number of issues remain unresolved concerning the anti-angiogenic therapy, including: 1) toxicity profiles, 2) radiographic assessment, 3) biomarkers, and 4) resistance. A definite survival advantage has yet to be established but current evidence suggests that anti-angiogenic therapy has clinical benefits including steroid-sparing effect and increased progression-free survival (Chi et al., 2009).
Toxicity profiles of anti-angiogenic therapy include risks of hemorrhage and thrombosis that have been ongoing concerns with the use of anti-angiogenic drugs. Epistaxis is not infrequent. The intracranial hemorrhage risk appears to be low, and events are often asymptomatic (Norden et al., 2008). Common toxicities include fatigue and hypertension. Impaired wound healing is also observed (Lai et al., 2008). Other toxicities include proteinuria, skin toxicity, diarrhea and mucositis. Other rare but serious complications include myocardial infarction, stroke, posterior leukoencephalopathy, and thrombotic thrombocytopenic purpura (Chi et al., 2009).
Standard criteria of response to anti-angiogenic therapy, currently in use, are dependent on contrast-enhancement on CT or MRI (Macdonald et al., 1990). Obtaining accurate assessment of response is problematic in brain tumor patients (Sorensen et al., 2008).
Clinical data suggest that benefits gained from anti-angiogenic agents will be short-lived. One of the major problems is that almost all patients treated with anti-angiogenic therapy progress during treatment, as tumors finally acquire resistance (Quant et al., 2009).
Currently available treatments for brain tumors necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumors is promising as it can be delivered in situ and selectively targets the tumor cells while sparing the adjacent normal tissue (Germano and Binello, 2009). Five gene therapy approaches are currently being explored: (1) Suicide gene therapy; (2) Tumor suppressor gene therapy; (3) Immunogene therapy; (4) Anti-angiogenic gene therapy; and (5) Oncolytic virotherapy (Asadi-Moghaddam and Chiocca, 2009).
Suicide gene therapy is the most commonly used technique. Preclinical studies showed marked tumor elimination. Furthermore, the tumor cells treated with herpes simplex virus thymidine kinase with ganciclovir administration displayed enhanced sensitivity to radiation. A phase I/II trial evaluated this approach in glioma patients. The median survival in the gene therapy group was significantly longer than the control group (62 vs. 37 weeks) (Asadi-Moghaddam and Chiocca, 2009).
At present, gene therapy is being studied in trials for brain tumors, and so far it is not available outside of these clinical trials (Asadi-Moghaddam and Chiocca, 2009). Finally, gene therapy has not yet been an effective tool in the treatment of gliomas. It offers new ways to attack these tumors and when used together with surgery, chemotherapy and radiation therapy, it will be a valuable adjuvant therapy to improve survival and the quality of life of the patients (Benítez et al., 2008).
Problem of the delivery of genetic vectors into solid brain tumors and efficient in situ gene transfer remains one of the most significant hurdles in gene therapy. The efficiency of transduction could be improved. The currently used manual injection of vectors might be improved by the use of three-dimensional neuronavigation techniques and convection-enhanced delivery methods (Asadi-Moghaddam and Chiocca, 2009).
The disadvantages of gene therapy include low tumoricidal effect and a limited distribution of the transgenes (transferred genes) and/or the vectors to tumor cells, making treatment localized peripherally from the main tumor mass. In addition virus-derived vectors may have the potential to create damaging immunological reactions by immune-mediated toxicity, especially in the presence of circulating antibodies to the virus vectors or by triggering immune reactions to self or transgene antigens (Omay and Vogelbaum, 2009).
The medical approach to pituitary adenomas greatly improved since availability of dopamine agonists such as: bromocriptine, cabergoline and quinagolide, and availability of somatostatin analogues such as: lanreotide and octreotide (Colao et al., 2009).
Bromocriptine is successful in 80–90% of patients with microprolactinomas in normalizing serum prolactin level, restoring gonadal function and shrinking tumor mass. For macroprolactinomas, normalization of serum prolactin level and tumor mass shrinkage occur in about 70% of patients. Cabergoline also is widely used to treat prolactinomas. The tumor shrinking effect of cabergoline is very rapid and improvement of visual field defects can be detected even after the administration of the first tablet. Cabergoline is superior over bromocriptine and can be given to patients previously intolerant or resistant to bromocriptine (Colao et al., 2009).
For growth hormone secreting adenomas, dopamine agonists are primarily effective only in tumors that co-secrete prolactin or that exhibit immunostaining for prolactin (Melmed et al., 2002). Somatostatin analogues appear to be more effective. They showed reduction in tumor size in 45% of patients (Bevan, 2005). Combination treatment with dopamine agonists and somatostatin analogues could be beneficial to better suppress growth hormone level and also on tumor shrinkage. The effect of somatostatin analogues on tumor shrinkage is reversible as demonstrated by tumor re-growth after stopping somatostatin analogues (Colao et al., 2009).
For thyroid stimulating hormone secreting adenomas, treatment depends mainly on the administration of somatostatin analogues, as dopamine agonists failed to persistently block thyroid stimulating hormone secretion in almost all patients and caused tumor shrinkage only in tumors that co-secrete prolactin (Kienitz et al., 2007).
A potential disadvantage of medical therapy for pituitary adenomas in general is that it requires life-long daily or weekly treatment. Hence, issues about compliance and cost become important, especially for younger patients. Somatostatin analogues are costly, and long-term use of these drugs makes this a significant issue. Common but often transient side effects of somatostatin analogues include nausea, abdominal discomfort and diarrhea. Furthermore, somatostatin analogues inhibit the secretion of insulin and glucagon and cause cholelithiasis in up to 20% of patients (Patil et al., 2009).
Side effects of bromocriptine include nausea, dizziness (orthostatic hypotension), nasal stuffiness, difficulty concentrating, depression, psychosis, and peripheral vasospasm. These side effects can be minimized by a slow increase in medication dosage and initiation of therapy at night. A rare side effect of bromocriptine is delayed reversible visual loss. Side effects with cabergoline are similar, but appear to be less common and less severe than bromocriptine. A recent study has suggested that cabergoline administration may be associated with cardiac valve insufficiency in patients with Parkinson’s disease (Patil et al., 2009).
Corticosteroids are an established treatment for symptomatic relief from brain edema and usually indicated in any patient with brain tumor. Dexamethasone is used most commonly as it has little mineralocorticoid activity and, possibly, a lower risk for infection and cognitive impairment compared with other corticosteroids (Batchelor and De Angelis, 1996). Dexamethasone produces symptomatic improvement within 24 to 72 hours. The usual starting dose is a 10 mg load, followed by 16 mg per day in patients who have significant symptomatic edema (Drappatz et al., 2007). There is a lack of randomized controlled trials to prove their effectiveness. Care needs to be taken when withdrawing steroids. Side effects are common and can be significant (Hart and Grant, 2007).
The side effects of corticosteroids are the driving force to search for alternative therapies for cerebral edema. Corticotropin-releasing factor reduces peritumoral edema by a direct effect on blood vessels. Inhibitors of vascular endothelial growth factor or inhibitors of its receptors reduce the tumor-related edema and they are more effective and less toxic alternatives (Drappatz et al., 2007).
Although the progress in understanding of the biology of brain tumors has improved, survival rates are improving only marginally. The heterogeneity of genetic and biochemical alterations and the invasive nature of malignant brain tumors especially gliomas, make the future treatment strategies for these neoplasms are likely to consist of a combination of agents or strategies that will act synergistically at different levels to stop tumor growth. Surgery and radiotherapy have not lost their importance and a recent advance in the use of concurrent chemo-radiation has improved survival in a large fraction of patients. A variety of new treatment modalities are undergoing development and are studied in various clinical trials. These new treatment modalities hold promise for further survival gains and improvement in the quality of life of the patients in the near future. Trials in this area need to be larger and randomized, with greater attention to symptom profile and quality of life in their outcome analysis.
There is no magic bullet for malignant brain tumors in the foreseeable future, and clinical improvements will likely be because of the synergistic effects of a multitargeted attack. Although preclinical data are promising, clinical trials have been delayed by ethical concerns, and all of the treatment strategies are still searching for a significant survival benefit in phase II or III clinical trials. These strategies have their own distinct advantages and limitations.
Summary
Summary
Despite advances in surgery, radiation, and chemotherapy, the prognosis for patients with malignant brain tumors has not markedly improved. Moreover, the non-specific nature of the conventional therapies for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues. There is an urgent need for a search for new treatment modalities that precisely target the tumor cells while minimizing collateral damage to the neighboring brain tissue.
For more than 30 years, stereotactic radiosurgery has provided patients with brain tumors an alternative focal treatment to surgery. Initially, only benign tumors, such as meningioma and acoustic neuroma, were selected for treatment. In the last 15 years, radiosurgery as a therapeutic option was also considered for patients with brain metastases who had controlled systemic disease and/or a good prognosis. Also we can use radiosurgery to treat small tumor residua following surgery. Radiosurgery is a safe and effective therapy. It provides local tumor control and prolongs survival.
Chemotherapy may be of value in selected patients, increasing survival by 2–3 months, and the two regimes that have been most widely used in the past were lomustine, as a single agent, and procarbazine, lomustine and vincristine as a combination regimen, more recently temozolamide is being increasingly used. There is also evidence that giving temozolamide in combination with radiotherapy, and continuing the drug thereafter, improves the survival by about 6 months, when compared to radiation alone.
Concomitant chemo-radiotherapy followed by single-agent adjuvant treatment with the alkylating agent temozolamide is the current standard of care for the patients with gliomas. The concomitant chemo-radiotherapy, as well as the early introduction of chemotherapy, appears to be a key to the improving outcome.
Recent developments in chemotherapy of brain tumors include the combination of cytotoxic, cytostatic and targeted therapies. Multitargeted compounds that simultaneously affect multiple signaling pathways, such as those involving epidermal growth factor receptors, platelet derived growth factor receptors and vascular endothelial growth factor receptors, are needed and increasingly employed.
Immunotherapy has emerged as a promising tool in the management of brain tumors. Many novel immunotherapeutic strategies are currently being investigated in human trials, and have already been found safe and efficacious in preliminary studies. Dendritic cell and peptide-based strategies are promising approaches. Their efficacy should be determined in large randomized controlled clinical trials.
An effective vaccine would be a potent addition to current therapeutic arsenal against brain cancers. Significant progress has been made that offers new hope and novel therapeutic opportunities. However, it is important to realize that much additional work lies ahead before an effective brain tumor vaccine is validated for clinical use.
Current evidence suggests that angiogenesis inhibitors have clinical utility for brain tumor patients. Clinical benefits have manifested primarily as steroid sparing effects and increased progression-free survival but a definite survival advantage has yet to be established with these drugs. Several issues and obstacles remain in the clinical development of effective anti-angiogenic agents for brain tumor patients.
Anti-angiogenic drugs such as bevacizumab, cediranib, vandentanib, aflibercept, and cilengitide are being evaluated in combination with standard therapy. Other trials are evaluating combinations of anti-angiogenic therapy with different cytotoxic agents or targeted agents in attempts to improve upon the efficacy gains already observed.
Tremendous progress has been made in the field of gene therapy over the past decade and clinical trials are beginning to show some clinical efficacy. As we learn more about the biology of brain tumors and identify efficacious genes to stop their growth, the clinical utility of gene delivery strategies will become increasingly evident.
Gene therapy offers new approaches to treat brain tumors specially gliomas. However, the results from clinical trials have not yet fulfilled the expectations generated from very successful basic experiments. Gene therapy offers new ways to attack these tumors and when used together with surgical, chemotherapeutic and radiation treatments will be a valuable adjuvant therapy to improve survival and the quality of life of patients.
The management of pituitary tumors poses a unique challenge that also requires a multimodality treatment approach. This includes neurosurgical tumor resection, medical therapy, radiotherapy and radiosurgery. Since the late 1990s, several new medical therapies have emerged. The efficacy of dopamine agonists in prolactin secreting adenomas and efficacy of somatostatin analogues in growth hormone and thyroid stimulating hormone secreting adenomas is well established. More recently, data are accumulating suggesting a potential therapeutic role of dopamine agonists also in patients with adrenocorticotrophic hormone secreting adenomas and non-functioning pituitary adenomas.
A major cause of death in glioblastoma patients (more than 60% of cases) is brain herniation due to cerebral edema, so corticosteroids are usually indicated in any patient with brain tumor with symptomatic peri-tumoral edema. The mechanism of action of corticosteroids is not well understood. Corticosteroids reduce the tumor-associated edema in patients with brain metastases or primary brain tumor as illustrated by CT studies. It produces symptomatic improvement within 24 to 72 hours.
The prognosis for patients with malignant brain tumors is poor. Conventional treatments such as surgery, radiation therapy, and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. The overall treatment of brain tumor patients remains a challenge. Although mortality remains a primary concern, morbidity and quality of life are important issues.
Recommendations
Recommendations
Brain tumors are a group of heterogeneous neoplasms that need multimodality treatments aiming at curing the patients or at least increasing survival and at the same time improving quality of life of those patients.
The available trials have provided results that have challenged previously held beliefs and breathed new air into treatment areas.
Based on the available data the following recommendations for further research are suggested:
1) More experimental studies to clear the vague points in the genetics and molecular pathogenesis of brain tumors.
2) More large randomized controlled double-blinded trials for the different treatment modalities to conclude specific treatment protocols.
3) More trials interesting in improving quality of life of the patients. Although survival is an important endpoint, quality of life is as important.
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Arabic Summary
الملخص العربي
يُطلق وصف أورام المخ على أي نمو شاذ بأي خلايا أو أنسجة تتواجد ضمن الجمجمة، سواء أكانت أوراما حميدة لا تحتوي على خلايا متسرطنة أو أوراما خبيثة تتكون من خلايا سرطانية أو أورام ناشئة بمواضع أخرى من الجسم وتنتشر لتصل إلى المخ وتسمى أوراماً ثانوية.
رغم التطور الملحوظ في العلاج الجراحي وكل من العلاج الإشعاعي والعلاج الكيماوي لأورام المخ فإن المآل المرضي لهؤلاء المرضي مازال غير جيد ، لذا فنحن في حاجة ماسة إلى وسائل علاجية جديدة حيث يحتاج هؤلاء المرضى إلى علاجات متعددة للسيطرة على هذه الأورام.
لقد كان يُعتقد أن إستئصال أكبر كم ممكن نسيج الورم يُحسن بشكل ملحوظ فترة بقاء هؤلاء المرضى على قيد الحياة ، ولكن لا يوجد أي دليل قوي يثبت ذلك من خلال الدراسات العشوائية ، كما أن الإستئصال الكامل لأورام المخ في حد ذاته هو عملية صعبة المنال سواء كان ذلك لطبيعة أورام المخ (خصوصا الأورام الدبقية) في توغلها داخل نسيج المخ أو لوجود الورم في مناطق قريبة من مراكز حيوية في المخ ، وبالتالي فإن الإستئصال الجراحي نجاحه محدود وقد يؤدي إلى مضاعفات عصبية أو عجز في بعض وظائف المخ.
العلاج الإشعاعي هو علاج باستخدام التطبيقات المختلفة للإشعاع المؤين لتدمير الخلايا السرطانية وتقليص الورم ، وقد لُوحظت قدرة العلاج الإشعاعي على إطالة فترة بقاء هؤلاء المرضى على قيد الحياة في خلال الثلاث عقود الماضية ، ويُستخدم العلاج الإشعاعي كعلاج مساعد بعد العلاج الجراحي وخصوصا في الأورام الدبقية أو كعلاج شفائي في حالات أورام الأديم الظَّاهِر العصبي وأورام الخلايا التناسلية أو كعلاج لمجرد إيقاف إزدياد حجم الورم والحفاظ على حجمه الحالي كما هو الحال في الأورام السحائية وأورام الغدة النخامية.
أما العلاج الإشعاعي الجراحي فهو يستخدم جرعة عالية من الإشعاع تطلق لمرة واحدة وبدقة عالية على نسيج الورم فقط وليس على كل المخ كما هو الحال في العلاج الإشعاعي العادي بغرض تدمير الورم نهائيا ، ومن أشهر وسائل هذا العلاج هو سكين جاما. وقد أُستُخدم هذا العلاج في باديء الأمر في علاج أورام المخ الحميدة مثل الأورام السحائية وكذلك أورام الغدة النخامية وكان بديلا جيداً للجراحة. أما الآن فيستخدم هذا العلاج ايضا في أورام المخ الثانوية محققا نجاح جيد في حالات مختارة ولكن هذا العلاج مازال نجاحه محدود في مجال الأورام الدبقية.
أما العلاج الكيماوي فقد لعب دور مساعد منذ البداية وذلك لنجاحه المحدود كعلاج وحيد لأورام المخ لصعوبة إجتيازه للحائل الدموي الدماغي ، وأحدث أنواعه هو عقار التيموزولميد واللذي حقق نجاحا لحد ما في علاج الأورام الدبقية وخصوصا عند إقترانه بالعلاج الإشعاعي حيث أدى إلى زيادة فترة بقاء المرضى على قيد الحياة مقارنة بالعلاج الإشعاعي منفرداً.
لذا يعتبر العلاج الإشعاعي والكيماوي هما العمود الفقري للعلاجات غير الجراحية لمعظم أورام المخ وخصوصا الأورام الدبقية وذلك عند إستخدامهما بشكل متزامن مع بِدء العلاج الكيماوي بشكل مبكر وإستكماله بعد الإنتهاء من العلاج الإشعاعي.
العلاج المناعي هو أحد وسائل العلاج التي ظهرت لمهاجمة أورام المخ والتي أوضحت نتائج مشجعة حيث يتميز بقدرته على مهاجمة خلايا الورم بخصوصية وفعالية عالية مع الحفاظ في نفس الوقت على خلايا المخ ، ويعتبر العلاج المناعي آمن وفعَّال حسب الدراسات التي أُجريت عليه. والعلاج المناعي قد يكون علاج مناعي نشِط أو علاج مناعي سلبي أو علاج مناعي يتبنى إستخدام خلايا مناعية معينة واللذي نادراً مايستخدم حالياً.
العلاج المناعي النشِط يستهدف إستثارة جهاز المناعة لدي المريض لإحداث إستجابة مناعية مضادة للورم وذلك عن طريق لقاحات معينة ، ويوجد بعض اللقاحات التي أظهرت نتائج واعدة في مجال علاج أورام المخ وتنتظر المزيد من الدراسة على أعداد كبيرة من المرضى ، أم العلاج المناعي السلبي فيتضمن إعطاء المريض أجسام مضادة معدَّة مسبقاً خارج جسم المريض وتستهدف هذه الأجسام المضادة خلايا الورم ، ومن أشهر أنواعه عقار البيڤاسيزيوماب واللذي أظهر نتائج مشجعه خصوصاً عند إقترانه بالعلاج الكيماوي. وبالرغم أن العلاج المناعي لم يُكتشف ولم يُستخدم ليكون علاج وحيد لأورام المخ إلا أنه سوف يأخذ مكانه كعلاج مساعد هام جداً وفعَّال.
حيث أن أورام المخ وخصوصاً الأورام الدبقية تتميز بوعائية دموية عالية فإن العلاج المضاد لتكوين الأوعية الدموية سيكون من العلاجات الفعَّالة والهامة واللذي بدأ يُستخدم بشكل كبير لعلاج أورام المخ ، وعقار البيڤاسيزيوماب السالف ذكره له تأثير مضاد لتكوين الأوعية الدموية وأيضا يقلل التضخم الناشيء حول معظم أورام المخ التي أظهرت إستجابة جيدة لهذا العقار ، لذا فالعلاج المضاد لتكوين الأوعية الدموية له قدرة عالية على إيقاف نمو الورم.
أما العلاج الچيني فيتم بإستخدام مادة چينية مثلRNA أو DNA وإدخالها داخل خلايا الورم لتحقيق هدف مُعين وهو تدمير خلايا الورم ويتم ذلك عن طريق إدخال چين إنتحاري أو چين مثبط للتورم أو چين يزيد الدفاعات المناعية للجسم أو چين يقلل من قدرة الورم على تكوين أوعية دموية جديدة ، وحتى الآن العلاج الچيني هو علاج تحت الدراسة ولم يتم تطبيقه على أعداد كبيرة من المرضى ولكنه أظهر نتائج مشجعة في هذه الدراسات الأولية ، ويعتبر العلاج الچيني أحد الأسلحة المتاحة لمهاجمة أورام المخ وسوف يكون وسيلة علاج فعَّالة وخصوصاً عند إستخدامه مع كل من العلاج الإشعاعي والعلاج الكيماوي.
أما بالنسبة للعلاج الهرموني فقد حقق نتائج باهرة في علاج أورام الغدة النخامية سواء في تقليل حجم الورم أو في السيطرة على الإفراز الهرموني وتوصيله الى معدلاته الطبيعية بالنسبة للأورام المفرزة للهرمونات ، وتوفر كل من محفزات الدوبامين ومشابهات السوماتوستاتين أدى الى طفرة في مجال علاج هذه الأورام.
ونظراً لأن أورام المخ دائماً ما تكون مصحوبة بتورم وتضخم في نسيج المخ المحيط بها مما يؤدي الى زيادة في الضغط داخل الجمجمة مُحدِثاً العديد من الأعراض ، لذا فإن دور الأدوية المثبطة للتورم هو دور حيوي وهام جداً حيث تُستعمل تقريبا في كل أورام المخ ، ومن أهم هذه الأدوية وأكثرها إستعمالا هي الكورتيكوستيرويدز وأهمها عقار الديكساميثازون وقد حققت هذه الأدوية نجاح رائع في تقليل التضخم المحيط بالورم وبالتالي تقليل الأعراض الناتجة عنه بشكل جيد وسريع ولكنها أيضا مصحوبة ببعض الآثار الجانبية مما إستلزم البحث عن بدائل لهذه الأدوية يكون لها آثار جانبية.
بالرغم من التقدم الملحوظ في فهم بيولوچيا أورام المخ إلا أن التقدم في إطالة فترة بقاء هؤلاء المرضى على قيد الحياة تقدم بسيط نوعاً ما ، لكن مازال العلاج الإشعاعي والعلاج الكيماوي وإستخدامهم بشكل متزامن له أهمية قصوى ، وظهور بعض العلاجات الجديدة التي أظهرت نتائج مشجعة يعطي الأمل لهؤلاء المرضى ويجعلنا نتوقع تقدم وشيك في مجال علاج أورام المخ.
الإتجاهات الحديثة في العلاج غير الجراحي لأورام المخ
رسالة توطئة للحصول على درجة الماﭽيستير في
الأمراض النفسية و العصبية
مقدمة من
الطبيب/ هشام محمد إبراهيم العدروسي
تحت إشراف
الأستاذ الدكتور/ محمـد يـاسـر متولـي
أستاذ الأمراض النفسية و العصبية
كلية الطب – جامعة عين شمس
الدكتور/ عمرو عبد المنعم محمد
مدرس الأمراض النفسية و العصبية
كلية الطب – جامعة عين شمس
جامعة عين شمس
كلية الطب
2010
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Downstream
Upstream
Stimulating host immune system
Peptide known to be associated with CNS cancers
Activated CTLs
Inoculated
patient
DCs
Tumor cells
Cell fusion
Stimulating host immune system
Activated CTLs
Inoculated patient
mRNA
Gene + Vector
Tumor cell
nucleus
Oncolytic Virus
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