Abstract
Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review.
Introduction
Gliomas are the most common primary tumors of the brain and are classified on the basis of two histological criteria, the resemblance of tumor cells to normal glial cells and the relative degree of malignancy. Astrocytomas, for example, are comprised of tumor cells that resemble astrocytes while oligodendroglial tumors contain neoplastic cells that resemble oligodendrocytes. Malignancy is graded using a progressive 4 tier scale in which grades I and II are assigned to low grade or benign tumors and grades III and IV are assigned to high grade or malignant tumors.
Grade I astrocytomas are generally benign and frequently curable with complete surgical removal. Grade II astrocytomas also demonstrate slow growth and a high degree of cellular differentiation, but frequently infiltrate surrounding brain tissues. The median overall survival (OS) time after surgical diagnosis ranges from 6–8 years and is reflective of the time required for tumors to transform into higher grade lesions. Grade III astrocytomas, also known as anaplastic astrocytomas (AA), are diffusely infiltrating lesions with focal or dispersed regions of anaplasia and marked proliferative potential. The median OS time ranges from 2–3 years and is also generally determined by the amount of time required for the progression of tumors to grade IV. Grade IV astrocytomas, also known as glioblastoma multiforme or glioblastomas (GBM), are the most common and malignant glioma subtype. GBMs typically contain cellular polymorphism, nuclear atypia, brisk mitotic activity, neovascular proliferation, and areas of frank necrosis. Additionally, the aggressive invasion and diffuse infiltration of tumor cells into the surrounding brain tissue negate any possibility for a complete surgical tumor removal.
Over the past 30 years, significant changes in the standard treatment of malignant gliomas have been limited. Prior to the 1980’s, the median OS of patients with malignant gliomas was 6 months. In 1980, a prospective randomized trial was reported in which 467 patients with malignant gliomas were randomized to one of four treatment groups: semustine (MeCCNU), radiotherapy (XRT), carmustine (BCNU) plus XRT, or semustine plus XRT. Toxicities included acceptable skin reactions secondary to XRT and thrombocytopenia due to chemotherapy. Patients who received XRT alone or in combination with a nitrosourea (carmustine or semustine) had significantly improved OS compared to patients treated with semustine alone. The median OS of the carmustine plus XRT group (51 weeks) was greater than that of the semustine plus XRT (42 weeks) and XRT alone (36 weeks) groups, but the differences were not statistically significant.
Resource: http://www.ncbi.nlm.nih.gov/
Resource: http://www.nutritionforest.com/
Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review.
Introduction
Gliomas are the most common primary tumors of the brain and are classified on the basis of two histological criteria, the resemblance of tumor cells to normal glial cells and the relative degree of malignancy. Astrocytomas, for example, are comprised of tumor cells that resemble astrocytes while oligodendroglial tumors contain neoplastic cells that resemble oligodendrocytes. Malignancy is graded using a progressive 4 tier scale in which grades I and II are assigned to low grade or benign tumors and grades III and IV are assigned to high grade or malignant tumors.
Grade I astrocytomas are generally benign and frequently curable with complete surgical removal. Grade II astrocytomas also demonstrate slow growth and a high degree of cellular differentiation, but frequently infiltrate surrounding brain tissues. The median overall survival (OS) time after surgical diagnosis ranges from 6–8 years and is reflective of the time required for tumors to transform into higher grade lesions. Grade III astrocytomas, also known as anaplastic astrocytomas (AA), are diffusely infiltrating lesions with focal or dispersed regions of anaplasia and marked proliferative potential. The median OS time ranges from 2–3 years and is also generally determined by the amount of time required for the progression of tumors to grade IV. Grade IV astrocytomas, also known as glioblastoma multiforme or glioblastomas (GBM), are the most common and malignant glioma subtype. GBMs typically contain cellular polymorphism, nuclear atypia, brisk mitotic activity, neovascular proliferation, and areas of frank necrosis. Additionally, the aggressive invasion and diffuse infiltration of tumor cells into the surrounding brain tissue negate any possibility for a complete surgical tumor removal.
Over the past 30 years, significant changes in the standard treatment of malignant gliomas have been limited. Prior to the 1980’s, the median OS of patients with malignant gliomas was 6 months. In 1980, a prospective randomized trial was reported in which 467 patients with malignant gliomas were randomized to one of four treatment groups: semustine (MeCCNU), radiotherapy (XRT), carmustine (BCNU) plus XRT, or semustine plus XRT. Toxicities included acceptable skin reactions secondary to XRT and thrombocytopenia due to chemotherapy. Patients who received XRT alone or in combination with a nitrosourea (carmustine or semustine) had significantly improved OS compared to patients treated with semustine alone. The median OS of the carmustine plus XRT group (51 weeks) was greater than that of the semustine plus XRT (42 weeks) and XRT alone (36 weeks) groups, but the differences were not statistically significant.
Resource: http://www.ncbi.nlm.nih.gov/
Resource: http://www.nutritionforest.com/
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