High-Grade Gliomas

Kenneth J. Cohen, M.D., Director, Pediatric Neuro-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Kaleb Yohay, M.D., Pediatric Neurology, Johns Hopkins University School of Medicine

Normal brain is made up of several cell types including neurons, the main functional cell of the brain, and glia, which play a supportive role to the neurons. Glia are further subdivided into different types, each type with a different function, including oligodendrocytes which cover the axons of neurons with sheathes of myelin, and astrocytes which serve many functions including taking up excess neurotransmitters and creating the blood-brain barrier. Gliomas are tumors of glial cells, particularly astrocytes and oligodendrocytes. About 2/3 of all childhood brain tumors are gliomas.


Gliomas, like other tumors, occur when the mechanisms that keep cell growth in check, go awry, resulting in uncontrolled growth and destruction of surrounding normal tissue. Gliomas occur in the brain, which is particularly problematic because so many essential areas exist in a relatively small and enclosed space. A small amount of abnormal cellular growth can cause significant symptoms depending on the location of that growth in the brain.

Astrocytomas, or tumors presumably derived from astrocytes or their precursors, are the most common type of glioma. There are several types of astrocytomas including pilocytic astrocytoma, which is generally considered the most benign of this group, fibrillary astrocytoma, anaplastic astrocytoma and glioblastome multiforme, the most malignant of the gliomas. Oligodendrogliomas are much less common in pediatrics and are generally fairly slow growing.

The World Health Organization (WHO) has developed a grading system for astrocytomas. Grade I gliomas tend to be the least aggressive and Grade IV gliomas the most aggressive and malignant. The high-grade gliomas (HGGs) encompass the WHO Grade III gliomas (anaplastic astrocytoma, AA) and Grade IV gliomas (glioblastome multiforme, GBM).

As with most other forms of brain tumors, attempt for curative therapy in the high-grade gliomas begins with surgical resection. Ideally, the goal of surgery is to achieve a gross-total resection (GTR) meaning that the surgeon has removed all visible tumor and, when scans are obtained after the surgery, no apparent tumor remains. Newer techniques such as intraoperative MRI may allow the surgeon to obtain a more complete resection. One of the difficulties in achieving a GTR is that, particularly for GBM, microscopic tumor cells invisible on MRI or to the neurosurgeon may extend beyond apparent tumor boundaries. This is because these tumors are infiltrative, meaning they tend to weave in and out among normal brain structures. Some tumor cells may have already migrated to the other side of the brain, quite distant from the tumor seen on pre-operative scan and at surgery. In certain cases, surgical resection is not feasible and the surgeon may only obtain a biopsy to confirm the diagnosis. In contrast, there are some children with AA who appear to achieve a true GTR and have a meaningful chance of cure when followed with radiation therapy and/or chemotherapy.

Following surgery, patients are often treated with radiation therapy to the region of the brain where tumor was evident on scans and at surgery. Radiation therapy is routinely limited to areas where tumor was noted prior to surgery (the so-called tumor bed), as opposed to providing radiation therapy to the entire brain which has never proven beneficial in treating HGGs. There are a variety of ways to administer radiation therapy, but in general, conventional external beam radiation therapy is utilized. While radiation therapy has proven useful is achieving some measure of disease control, it, along with surgery, is rarely curative. This is particularly true for GBM.

The role of chemotherapy in the treatment of HGGs has been somewhat more controversial but is often utilized because of the high failure rate of surgery combined with radiation therapy in the treatment of the HGGs. There have been numerous studies looking at the role of chemotherapy in the treatment of HGGs and, on balance, chemotherapy has probably offered some benefit to certain patients. There are a large number of agents available, many of which are offered in the context of clinical trials. No standard of-care exists for chemotherapeutics in the treatment of HGG in children, meaning that no agents have so clearly shown benefit that they are broadly recognized as an obligate part of treatment. Adults with HHG are often treated with radiation therapy and temozolomide, but there is controversy in the pediatric neuro-oncology community about the utility of this approach.  Chemotherapy has been aggressively utilized in very young children in an effort to delay the use of radiation therapy until the children are a little older.  While this technique has proven somewhat effective for some forms of brain tumors, it has been less effective for children with HGGs.  One difficulty with chemotherapy has been how to make sure that drugs actually reach the area of the tumor.  This may prove difficult because of the blood brain barrier which tends to limit the movement of drugs from the rest of the body to the brain.  Many techniques have been developed to deal with this problem including the use of biodegradable wafers containing chemotherapeutic agents that are placed in the surgical bed at the time of resection, as well as agents that make the blood brain barrier more permeable or "leaky".

Other therapeutics are increasingly being studied. These include anti-angiogenesis agents (drugs that interfere with growth of blood vessels that feed the tumor), immunotoxins (a toxin is attached to an antibody that hones in on tumor cells), differentiating agents (which make the tumor behave in a less malignant way) and others. All of these approaches are highly experimental and are generally best administered under the guidance of a neuro-oncologist participating in clinical trials.

The next proposed national Children's Oncology Group (COG) trial for children with newly diagnosed HGG will be randomized to receive either temozolomide, arsenic trioxide or Vorinostat during radiotherapy.  Following the completion of this randomized portion of therapy, all patients will receive additional therapy with bevacizumab and irinotecan.


Despite improvements in surgical techniques, neuroimaging, radiation therapy and new chemotherapeutic agents, HGGs are notoriously difficult to cure. Cure can be seen in AA in a subset of patients who have had a complete surgical resection followed by irradiation + chemotherapy. Cure is extremely rare for GBM despite surgery, radiation therapy and chemotherapy. For these reasons, medical centers around the world are involved in basic science research trying to elucidate the basic mechanisms of brain tumor growth and in the development of novel therapies, as well as in clinical research to try to optimize the therapies that already exist and to test new therapies. It is only through research that better treatments and eventually a cure will be found for these tumors.

This article was written for the Childhood Brain Tumor Foundation, Germantown, MD, www.childhoodbraintumor.org. Revised by author, 2010.

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