Malignant Tumors in Central Nervous System

Abstract

Glioblastoma, medulloblastoma, primary central nervous system lenfoma (PCNSL), germinoma and CNS lenfoma are malignant tumors in CNS. Medulloblastoma is the most common form of malignant tumor in children. In the treatment of those tumors the combination of radiotherapy and chemotherapy is used. Temozolamid (TMZ), Dacarbazine (DTIC), Rituximab, and Cisplatine are common useful agents. Due to its lipophilic and small structure TMZ can cross the blood brain barrier and it is concentrated well for about 30%. For this reason, TMZ was revealed as a useful and functional agent especially in glioblastoma, medulloblastoma and CNS melanoma. Although agents mentioned here has toxicity effects, they are proved to be useful in malignant tumor treatment.

Introduction

Glioblastoma is the most common type of malignant brain tumor in adults which is usually fatal. Patients diagnosed with glioblastoma cannot survive more than two years. Adjuvant radiotherapy combined with temozolomide in clinical setting proved to be beneficial to survive with a low level of toxicity (1). Glioblastoma has its roots in astrocytes which has an important role in blood brain barrier. Due to an unknown reason the astrocytes expose to structural malformation and they increase in number.

The treatment of glioblastoma should be divided into two such as for newly diagnosed and for recurrent glioblastoma. For newly diagnosed glioblastoma the treatment involves radiotherapy combined with temozolamid 75 mg per day for six weeks and adjuvant temozolamid 150-200 mg per day. This type of treatment is called ‘Stupp Protocol’ accepted worldwide by clinicans. However, there is no any treatment protocol for recurrent glioblastoma. Temodar is the trade name of TMZ in US whereas it is Temodal in Europe. Temozolomid is an oral alkylating agent. It is used in the treatment of recurrent glioma having antitumor activity. For 5 days of every 28 days its daily therapy is at a dose of 150-200 mg. For up to seven weeks at a dose of 75 mg per day it is functional and safe. This dose decreases the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) which is associated with longer survival for patients having nitrosourea based adjuvent therapy (2). The most important limitation of TMZ is the rapid degradation, insufficient level of applied TMZ to the tumor and systemic toxicity. TMZ is a small lipophilic molecule which is administered orally and acts as a prodrug. It is a monofunctional DNA alkylating agent of imidazotetrazine class (3). In the study of Liu et al.(2014), focused ultrasound (FUS) is revealed as a supporter for Temozolomide to concentrate locally within the brain. FUS opens the BBB so that therapeutic agent delivery becomes much more possible (4).

Medulloblastoma is the most common form of malignant brain tumor in children. 1-2% of adults suffer from medulloblastoma. In infants, medulloblastoma is the most common form of malignant brain tumor which peaks in children between 3 to 9 years of age. Treatment of medulloblastoma is being improved. Nondisseminated medulloblastoma provides a long term survival for about 80% where children could live for 5 more years after the diagnosis with many free of the disease. Disseminated medulloblastoma benefits from intensive therapy and leads to an increased survival rates. Chemotherapy administration during and after radiotherapy with drug support such as cisplatin, vincristine, N-(2-chloroethyl)-N′-cyclo-hexyl-N-nitrosurea (CCNU), cyclophosphamide and etoposide can inrease the survival rate for about 85% in children. Due to its rare emergence of medulloblastoma in adults, the therapy options are limited. Cisplatin may result in peripheral neuropathy more in adults than in children. Peripheral neuropathy is much more severe after the administration of vincristine (5). TMZ is widely used in the treatment of metastasic melanoma. Dacarbazine (DTIC) is the only approved agent by Food and Drug Administration. TMZ can be converted into the same active metabolite3-methyl-(triazen-1- yl) imidazole-4-carboxamide which is also effective against melanoma. TMZ is used orally (6). In the study of Tawbi et al. (2012), decitabine (DAC) is administered to melanoma patients. In terms of toxicity of DAC, patients demonstrated an increased level of hematologic toxicity. Neutropenia took place in patients for 7 days. Other nonhematologic toxic effects were fatigue and nausea. It was revealed that most type of tumors are immunogenic. T cells respond to cancer cells. IL-2 is one of the first agents which provides immune regulation by activating T cells.

Primary CNS lymphoma (PCNSL) is a rare type of extranodal non-Hodgin’s lymphoma in brain, leptomeninges, spinal cord, eyes and within the CNS. There are diffuse large B cell lymphomas. Congenital or acquired immunodeficiency are risk factors for PCNSL (7). Whole brain radiotherapy is not sufficient for treatment and it also has neurotoxicity effect for patients older than 60 of ages. Therefore, a combination of WBRT and chemotherapy is used to treat PCNSL. Primary treatment method should be methotrexat and ara-C combination. In case of no response to this treatment protocol, patients should be treated with 40-50 Gy total brain radiation. Although the mechanism of action of Rituximab is not fully understood, is is useful in treatment of B-cell malignancy. Rituximab is not effective in all PCNSL patients. As Rituximab cannot pass the blood brain barrier sufficiently, it should be used in clinical setting trials. When used as a single agent, Rituximab is administrated weekly for 4 weeks. When combied with chemotherapy, it is used for every 3-4 weeks. Pharmacokinetic of Rituximab is similar to human IgG. It is distributed in intravascular and extravascular areas and within lymph nodes which includes both malignant B cells but also stromal cells, benign lymphocytes, extracelular matrix, vasculature, extravascular fluid proteins and a mixture of cytokines and chemokines.

Germinoma is the less malignant form of germ cell tumor. Pure germ line tumors are called germinoma and arise before five years of age. Bleomycine, cisplatine, and etoposide are used for initial, recurrent and metastasic germinomas to eliminate. Clinical manifestation of germinomas are genetic abnormalities. Klinefelter’s syndrome and Lange’s syndrome involve germinomas (8). As the main drug treatment, cisplatin is used. However, it may result in ototoxicity, renal damage, peripheral neuropathy and sterility (9). Survival rate for germinomas are five years for 96%. In the study of Patel et al. (1992), in conjunction with radiation therapy, intravaneously administered cisplatin was revealed to provide a high complete remission rate in patients (10).

In the treatment of CNS melanoma, TMZ was revealed as effective and safe as Dacarbazine. Furthermore, patients administrated TMZ but not Dacarbazine have a lower level of melanoma relapse. TMZ is an oral alkylating agent and due to its small size and lipophilic structure it can cross the BBB. Within the CNS, TMZ has a concentration level about 30%. There are specific cellular mechanisms resisting to alkylating agents including defects in DNA mismatch repair, increased excision repair and increased enzymatic removal of alkyl groups. O6-alkylguanine transferase (AGT), also known as O6- methylguanine methyltransferase remove methyl groups from O6- methylguanine. Overexpression of AGT can eliminate the toxicity of MTIC. However, TMZ decrases the level of AGT and so the drug resistance. Low dose TMZ enables sustained depletion. The most common adverse effects of TMZ were reported to be nausea, headache, fatigue and constipation. The ease of administration makes TMZ an alternative to DTIC for metastasic melanoma patients (11).