Summer 2005

Pediatric Brain Tumor Research Reduces Damage from Therapy

New Therapies Can Improve Survival

A recent study funded by the National Cancer Institute revealed that two-thirds of children who survive cancer develop other chronic health problems resulting from the treatments that saved their lives.

The study comes at a time when therapies for pediatric cancer are increasingly successful, and biomedical research is getting well-deserved recognition for those successes. Thirty years ago, 58 percent of children with cancer could expect to be cured, whereas now 75 percent can be cured. As more children survive, however, more attention is being paid to the price of the cure. Children with brain tumors fare among the worst of all cancer patients after being cured, often suffering from diminished cognitive capability and delayed mental development.

As a member of the Pediatric Brain Tumor Consortium, UCSF Benioff Children's Hospital has long been one of the leaders in devising and testing potential therapeutic advances. A number of clinical trials now underway are testing new methods for attacking refractory pediatric brain tumors. The availability of the Gamma Knife, as well as the more recently developed CyberKnife, allows physicians to more precisely deliver radiotherapy. New therapies and those under development in a number of areas promise to not only improve survival for children with brain tumors, but also lessen brain injury and improve general outcomes.

Mapping the Site

One of the most important prerequisites for reducing damage during tumor resection is functional mapping of the brain. During mapping, surgeons use electrodes to stimulate various brain areas and then test patients, who are sedated but awake. A complete map of the area affected by the tumor makes it possible for surgeons to know where important brain circuits lie and to choose a surgical course that will leave these circuits intact.

Such brain mapping is a skill that takes years to master. "There are a lot of subtleties involved," says Mitchel Berger, M.D., chair of the Department of Neurological Surgery and a pioneer of functional brain mapping. "For instance, the brain isn't very reactive at some temperatures, so if you let the brain temperature fall too far, you don't get a response to stimulation and you miss the functional significance of that part of the brain.

"It's a very complicated procedure with a huge learning curve. It's one thing when you've done 10 or 20 procedures, and another thing when you've done 500 or 600."

Berger has been doing functional brain mapping for 18 years. He is nationally recognized for treating brain and spinal cord tumors in adults and children.

Imaging Technologies

The potential for neuroimaging in diagnosing and treating brain tumors is much broader. Neuroimaging can be useful at almost every step of the way.

Grading brain tumors is now done through biopsy of the tumor tissue, but current research suggests that imaging could provide a more complete and accurate picture of the tumor grade and other characteristics. Tumor grading done via biopsy is, after all, based on the visual characteristics of the tumor cells. Metabolic parameters measured by magnetic resonance spectroscopy (MRS) supply physiological information about the internal biochemistry of cells.

When biopsy is necessary, imaging can assist in guiding physicians to specific areas in the tumor.

With physiological information provided by MRS, it is also possible to spot where the tumor is growing fastest, where and how thoroughly it is invading healthy tissue, and areas of hypoxia or angiogenesis. These factors are important not only for understanding how the tumor is growing, but also for the right therapies.

When chemotherapy or radiotherapy has begun, functional MRS allows physicians to immediately look at how tumor metabolism is being affected. Currently, oncologists check the effectiveness of a therapy by watching whether or not the tumor shrinks, which may take many scans over weeks.

By making diagnosis and therapy much more targeted and effective, imaging can play a big role in lowering the brain damage currently associated with tumor treatments.

Genomics, Proteomics and Small Molecule Control

Metabolic imaging is only one way of finding out what's going on biologically within a tumor. Very-large-scale assays for gene activity and protein function are providing a more detailed picture of the mechanisms that cancer cells are using to grow and evade the body's defenses. Such assays bring within reach the dream of one day being able simply to analyze blood serum to detect cancer cells, know the type and grade of the tumor, and monitor how it is responding to treatment.

As researchers pick out the important genetic and molecular components of cancer cell growth, they also will find the key points in the biochemical chain where they can interfere with that process. The success of Gleevec in treating leukemia has demonstrated that small molecules aimed precisely at blocking signaling molecules can be extremely effective in attacking cancer.

The challenge for the future, researchers say, will be to find and attack multiple targets that control cell growth and division, and to combine small molecule therapy with radiation and chemotherapies. These strategies are already being explored, and multiple clinical trials using this biologically targeted therapy are open for children with brain tumors at UCSF.

Drug Delivery

The basic challenge of cancer treatment is to cut out or kill precisely those cells that have become cancerous, while limiting the collateral damage to healthy cells. Additionally, administration of antitumor agents systemically has only a limited capability to enter the brain, resulting in high systemic toxicity and minimal CNS delivery. Clinical trials at UCSF are aimed at convection-enhanced delivery (CED) of cancer drugs, a method that involves using a catheter to infuse drugs into the tumor using positive pressure. This deposits a high concentration of the drug in the tumor and a steep concentration gradient a short distance away. Current clinical trials using CED are prioritizing drugs that have the ability to target tumor cells and leave normal cells untouched.

The trick to curing cancer has always been delivering deadly force only to malignant cells without harming noncancerous cells. This trick, however, has just as long been elusive and difficult to perform. Physicians have mostly been forced to use techniques that also kill rapidly dividing blood, hair and intestinal cells, or healthy cells that simply lie too close to the tumor target. New science and technology hold the promise of creating "smart bombs" for attacking brain tumors and preserving children's bright futures.

For more information, contact the Pediatric Neurological Surgery Program at (415) 353-7500.

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