Treatment Options for Glioblastoma.
Following the seminal trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), concurrent temozolomide and radiotherapy has become the new standard of care for patients with newly diagnosed glioblastoma multiforme (GBM). Investigation of emerging therapies (which are now used as salvage therapy) such as small-molecule inhibitors (for example, epidermal growth factor receptor inhibitors) and convection-enhanced delivery (CED) of targeted toxins (for example, interleukin-13/pseudomonas exotoxin) is likely to build on the EORTC/NCIC treatment platform and will, it is hoped, improve survival rates in patients with GBM. The majority of adjuvant Phase I and II trials being conducted by the brain tumor consortia are based on the EORTC/NCIC treatment platform and have added a targeted therapy in an effort to find a promising synergistic treatment. Furthermore, researchers in the consortia are continuing to explore treatments for recurrent GBM, not otherwise eligible for local therapies, such as CED. The treatments under study include novel cytotoxic chemotherapy as well as small-molecule inhibitors; these are being assessed in a variety of Phase I or II trials.
According to World Health Organization estimates, there are 100 different types of brain tumor. Furthermore, the data obtained for the Surveillance, Epidemiology, and End Results Program yielded an estimate of 18,500 new cases of primary brain tumors in 2005. Of these, 50% were glial and 50% of all gliomas were GBMs. Glioblastomas multiforme are biologically aggressive tumors that present unique treatment challenges due to the following characteristics: 1) localization of tumors in the brain; 2) intrinsic resistance of these lesions to conventional therapy; 3) limited capacity of the brain to repair itself; 4) the spread of malignant cells into brain parenchyma; 5) the variably disrupted blood–brain barrier complicating drug delivery; 6) tumor capillary leakage, with resultant peritumoral edema and intracranial hypertension; 7) the limited response to therapy; and 8) the neurotoxicity of treatments directed at gliomas.
Based on early trials by BTSG and RTOG investigators, treatment of newly diagnosed GBMs has evolved to include maximum safe extent of resection (as enunciated in the National Comprehensive Cancer Network central nervous system guidelines), conventionally fractionated external- beam radiotherapy to the tumor (as defined by the RTOG), and the administration (or not) of alkylator chemotherapy (most often nitrosoureas such as BCNU). The value of near-total or complete resection for GBM continues to be debated, primarily because no prospective trial has been conducted to assess the extent of resection as a primary outcome measure. A single metaanalysis, multiple single-institution retrospective studies, and data from the BTSG all support the value of large-volume resection in adults with GBM; however, other opinions exist.
The value of adjuvant chemotherapy has been debated and remains controversial despite prior metaanalyses by Fine, et al., and more recently by Stewart. Their studies demonstrated modest improvement in 1- and 2-year survival rates (5–6 and 4–5%, respectively) with the inclusion of adjuvant chemotherapy. Last year, and during the conduct of the Glioma Outcomes Project (a project comprising 560 patients with newly diagnosed gliomas that preceded the EORTC/NCIC publication), in which 58 community and university centers were involved, the following pattern of care for adults with newly diagnosed gliomas was seen. All patients underwent surgery; 87% received radiotherapy; 88% received anticonvulsant therapy (the majority not in accordance with the American Academy of Neurology guidelines); 54% received chemotherapy; 29% used alternative medicines; and 15% enrolled in clinical trials.
The preliminary reports of Stupp and colleagues and the recently published randomized European and Canadian trial have substantially altered the algorithm for initial treatment of GBM. These studies clearly demonstrated a benefit for chemotherapy (that is, TMZ) in the initial treatment of patients with GBM by showing an improvement in median (14.6 compared with 12 months) and 2-year survival (27 compared with 10%) in patients receiving or not receiving TMZ. Consequently, this treatment regimen (TMZ given concurrently with radiotherapy, followed by six monthly cycles of TMZ) has become the new standard of care for patients with newly diagnosed GBM.
Following the seminal trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), concurrent temozolomide and radiotherapy has become the new standard of care for patients with newly diagnosed glioblastoma multiforme (GBM). Investigation of emerging therapies (which are now used as salvage therapy) such as small-molecule inhibitors (for example, epidermal growth factor receptor inhibitors) and convection-enhanced delivery (CED) of targeted toxins (for example, interleukin-13/pseudomonas exotoxin) is likely to build on the EORTC/NCIC treatment platform and will, it is hoped, improve survival rates in patients with GBM. The majority of adjuvant Phase I and II trials being conducted by the brain tumor consortia are based on the EORTC/NCIC treatment platform and have added a targeted therapy in an effort to find a promising synergistic treatment. Furthermore, researchers in the consortia are continuing to explore treatments for recurrent GBM, not otherwise eligible for local therapies, such as CED. The treatments under study include novel cytotoxic chemotherapy as well as small-molecule inhibitors; these are being assessed in a variety of Phase I or II trials.
According to World Health Organization estimates, there are 100 different types of brain tumor. Furthermore, the data obtained for the Surveillance, Epidemiology, and End Results Program yielded an estimate of 18,500 new cases of primary brain tumors in 2005. Of these, 50% were glial and 50% of all gliomas were GBMs. Glioblastomas multiforme are biologically aggressive tumors that present unique treatment challenges due to the following characteristics: 1) localization of tumors in the brain; 2) intrinsic resistance of these lesions to conventional therapy; 3) limited capacity of the brain to repair itself; 4) the spread of malignant cells into brain parenchyma; 5) the variably disrupted blood–brain barrier complicating drug delivery; 6) tumor capillary leakage, with resultant peritumoral edema and intracranial hypertension; 7) the limited response to therapy; and 8) the neurotoxicity of treatments directed at gliomas.
Based on early trials by BTSG and RTOG investigators, treatment of newly diagnosed GBMs has evolved to include maximum safe extent of resection (as enunciated in the National Comprehensive Cancer Network central nervous system guidelines), conventionally fractionated external- beam radiotherapy to the tumor (as defined by the RTOG), and the administration (or not) of alkylator chemotherapy (most often nitrosoureas such as BCNU). The value of near-total or complete resection for GBM continues to be debated, primarily because no prospective trial has been conducted to assess the extent of resection as a primary outcome measure. A single metaanalysis, multiple single-institution retrospective studies, and data from the BTSG all support the value of large-volume resection in adults with GBM; however, other opinions exist.
The value of adjuvant chemotherapy has been debated and remains controversial despite prior metaanalyses by Fine, et al., and more recently by Stewart. Their studies demonstrated modest improvement in 1- and 2-year survival rates (5–6 and 4–5%, respectively) with the inclusion of adjuvant chemotherapy. Last year, and during the conduct of the Glioma Outcomes Project (a project comprising 560 patients with newly diagnosed gliomas that preceded the EORTC/NCIC publication), in which 58 community and university centers were involved, the following pattern of care for adults with newly diagnosed gliomas was seen. All patients underwent surgery; 87% received radiotherapy; 88% received anticonvulsant therapy (the majority not in accordance with the American Academy of Neurology guidelines); 54% received chemotherapy; 29% used alternative medicines; and 15% enrolled in clinical trials.
The preliminary reports of Stupp and colleagues and the recently published randomized European and Canadian trial have substantially altered the algorithm for initial treatment of GBM. These studies clearly demonstrated a benefit for chemotherapy (that is, TMZ) in the initial treatment of patients with GBM by showing an improvement in median (14.6 compared with 12 months) and 2-year survival (27 compared with 10%) in patients receiving or not receiving TMZ. Consequently, this treatment regimen (TMZ given concurrently with radiotherapy, followed by six monthly cycles of TMZ) has become the new standard of care for patients with newly diagnosed GBM.
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