By Ray M. Chu, MD

Approximately 40,000 new brain tumors are diagnosed each year in the United States, and 23% of these are glioblastoma multiforme (GBMs) (9200) (Central Brain Tumor Registry of the United States 2004-5). GBMs (Grade IV), anaplastic astrocytomas and anaplastic oligodendrogliomas (Grade III) are considered malignant brain tumors and are far more common in adults than low-grade tumors. As yet, there is no established cure for these high-grade tumors.

Surgical technology has continually advanced. In the past, neurosurgeons armed with little more than a pneumoencephalogram and a scalpel resected brain tumors; modern operating rooms today have operating microscopes, ultrasonic aspirators, ultrasound navigation, frameless stereotactic navigation and even intraoperative MRI. Despite all the modern advances available today, malignant brain tumors continue to defeat our efforts. For many years, the average survival for a patient with a glioblastoma (GBM) has remained 12-14 months (McClendon 2003), and survival rates to five years have remained less than five percent.

Malignant brain tumors have a tendency to invade the brain even to sites distant from the original tumor mass, although unlike metastatic tumors, high-grade brain tumors do not tend to invade non-neural sites in the body. Despite aggressive therapy and intensive research, 13,100 deaths were attributed to primary malignant brain tumors in 2002 (American Cancer Society 2002). Development of effective therapies for malignant tumors will require a long-term, aggressive effort.

Although the central nervous system is relatively immunoprivileged, the immune system does perform some surveillance of the brain in cases of infection or tumor. Unfortunately, natural immune surveillance does not always recognize the heterogeneous, ever-changing population of malignant brain tumor cells and is not potent enough to defeat a tumor, even if it is detected. Experimental strategies to boost the immune response include generation of potent antigen-presenting cells (dendritic cells) and exposure of them to tumor lysate antigens, tumor RNA or apoptotic tumor cells, or fusion with glioma cells (Parajuli 2004). In patients with recurrent GBM, subcutaneous vaccination with tumor lysate-pulsed dendritic cells produced an increase in median survival to 133 weeks in 14 patients and elicited antigen-specific CD8+ T cells (Yu 2004). Dendritic cell vaccination with tumor lysate also may produce better clinical responsiveness to chemotherapy (Wheeler 2004).

One problem with attempts to treat malignant glioma is its diffuse nature. The entirety of an enhancing mass can be resected, and yet tumor can recur from either microscopic cells that cannot be seen during surgery or from tumor cells that have invaded the normal surrounding brain. Few treatments have been developed that can track infiltrating glioma cells without harming normal brain.

In rats that have been implanted with experimental tumor cell lines, neural stem cells can later be inserted that demonstrate an ability to track tumor cells and continue to express a stable, inserted gene product, such as a chemotherapy prodrug (Aboody 2000). This finding opens a new pathway for following invading tumor cells more effectively and delivering a toxin to a tumor or a stimulant to the immune system. Stem cells have also been isolated from human brain tumors, opening new possibilities that may lead to novel and far more effective treatments than those currently available (Yuan 2004). An experimental protocol using stem cells to treat malignant brain tumors is being designed at Cedars-Sinai Medical Center currently.

As new chemotherapeutic agents are created and tested, a comprehensive review of novel chemotherapy drugs would be an article unto itself. However, optimizing treatment via alternate methods of chemotherapy delivery warrants discussion.

At least one of the many problems facing neurosurgeons and neuro-oncologists in the quest to defeat brain tumors is the blood-brain barrier (BBB). Cerebrovascular endothelial cells have tight junctions that limit transport of hydrophilic substances across them (Neuwelt 2004). The BBB limits the access of antibiotic medications, chemotherapy and even white blood cells to the brain. Many hydrophobic substances (e.g., inhalational anesthetics) directly cross cell membranes, and there are specialized transport systems for certain simple sugars, such as glucose, amino acids and proteins, such as insulin and transferrin. There are also energy-dependent pumps that can transport molecules, mainly out of the brain.

Although few instances of therapeutic manipulation of the BBB exist, one example is the rational drug design of Sinemet for Parkinson's disease. L-DOPA crosses the BBB through a neutral amino acid transporter and is converted by CNS DOPA decarboxylase into dopamine, while carbidopa cannot cross the barrier and inhibits peripheral DOPA decarboxylase to limit the systemic side effects of L-DOPA (Lang 1998). Sinemet radically changed the treatment of Parkinson's, which largely consisted of stereotactic ablative surgery in the past, although Sinemet alone is not usually a durable therapy over long periods of time.

To date, significant success with BBB manipulation to treat brain tumors has yet to be made. The most successful example of BBB manipulation via osmotic agent is in cases of primary CNS lymphoma (Kraemer 2001). A dose-dependent association with survival was demonstrated when intra-arterial methotrexate was delivered in conjunction with osmotic disruption of the BBB with mannitol. For malignant primary brain tumors, a significant benefit to time to progression or survival has yet to be demonstrated.

Another approach involves manipulation of the blood-brain tumor barrier (BTB), rather than the BBB. RMP-7 is a bradykinin analogue that has a longer serum half-life than bradykinin and acts on bradykinin B2 receptors at the BTB, altering drug delivery to the tumor itself instead of to the entire brain (Black KL 1997, Liu 2001). Initial experience with intra-arterial RMP-7 in patients with recurrent malignant glioma demonstrated significantly increased permeability in areas of tumor without altering that of normal brain, leading to tumor volume reduction and durable responses (Black KL 1997, Cloughesy 1999). The optimal combination of chemotherapeutic agent(s) and RMP-7 has yet to be determined.

The BBB can also be mechanically bypassed via intrathecal or intraparenchymal insertion of chemotherapeutic agents, but ultimately, distribution of the drug is limited by diffusion. One method to alter the distribution is convection-enhanced delivery (CED), in which catheters are placed in the parenchyma and a drug can be delivered via an infusion pump to increase distribution in greater concentrations and at greater distances than simple diffusion (Kunwar S 2003). A targeted toxin, such as a part of a Pseudomonas exotoxin, can be linked to a brain tumor-specific target, such as the IL-13 receptor, which is overexpressed in human malignant gliomas but has little to no expression in normal human brain. This protocol is still experimental, and the toxin is not yet FSA-approved. Targeted toxins in general are potent in nanomolar concentrations and with CED have great therapeutic promise.

Further understanding of the BTB and the molecular characteristics of brain tumors themselves will change the way gliomas are treated in the future. Optimizing control of the BTB in combination with chemotherapy and/or bypassing the barrier entirely with convection-enhanced delivery of targeted toxins may lead to enhanced survival and delayed time to progression of tumor. Ongoing research in conjunction with the National Cancer Institute includes tumor analysis with cDNA microarrays and other molecular analysis to better determine which factors can predict prognosis and response to therapy, allowing targeted use of different therapies for particular patients.

Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97(23):12846-51, 2000.

Black KL, Cloughesy T, Huang SC, Gobin YP, Zhou Y, Grous J, Nelson G, Farahani K, Hoh CK, Phelps M. Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas. J Neurosurg 86:603-9, 1997.

Cancer Facts & Figures 2002. American Cancer Society, Inc. Surveillance Research, Atlanta, GA, 2002.

Central Brain Tumor Registry of the United States (CBTRUS) 2004-5. Primary Brain Tumors in the United States Statistical Report 1997-2001.

Cloughesy T, Black KL, Gobin YP, Farahani K, Nelson G, Villablanca P, Kabbinavar F, Vinuela F, Wortel C. Intra-arterial Cereport (RMP-7) and carboplatin: a dose escalation study for recurrent malignant gliomas. Neurosurg 44(2):270-8, 1999.

Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA: Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival. Neurosurgery 48(5): 1033¿1041, 2001.

Kunwar S. Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies.
Acta Neurochir Suppl. 88:105-11, 2003.

Lang AE, Lozano AM: Parkinson's disease: First of two parts. N Engl J Med 339: 1044-1053, 1998.

Liu Y, Hashizume K, Chen Z. Correlation between bradykinin-induced blood-tumor barrier permeability and B2 receptor expression in experimental brain tumors. Neurol Res 23:379-87, 2001.

McLendon RE, Halperin EC: Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 98:1745-8, 2003.

Neuwelt E. Mechanisms of disease: the blood-brain barrier. Neurosurgery 54(1):131-42, 2004.

Parajuli P, Mathupala S, Sloan AE. Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurg 55:1194-1204, 2004.

Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 10:5316-26, 2004.

Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumorlysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973-9, 2004.

Yuan X, Curtin J, Xiong Y, Like G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392-400, 2004.