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In the United States, 11,900 children and adolescents under the age of 20 were diagnosed with cancer in 2001 and about 2,200 died of the disease. The diagnosis of invasive brain and nervous system cancers accounts for 17 percent of all pediatric cancers, second only to acute lymphocytic leukemia. About half of the diagnosed cases of brain tumors are malignant.
Although there are fifty neuroepithelial pediatric tumor classifications, medulloblastoma, a tumor arising in the lower portion of the brain that can spread to other regions of the brain and spinal cord, is the most common type of malignant childhood central nervous system cancer. Astrocytomas, a malignancy of cells (astrocytes) located throughout the brain, and brain stem gliomas, tumors that grow in the central region of the brain which can involve the spinal cord, are other types of pediatric brain tumors.
Although the annual mortality rate of pediatric cancer has decreased over the past two decades, the proportion of deaths from tumors of the central nervous system in the same population has increased from 18 percent to 30 percent. These figures clearly highlight the lack of positive outcomes in children with central nervous system malignancies compared to other pediatric tumors.
The cause of childhood brain tumors is largely unknown. While radiation exposure is a recognized risk factor for brain tumors, the role of other environmental toxins is unclear in children. “Less than 5 percent of pediatric brain tumors are associated with a known genetic disease, such as neurofibromatosis, a common genetic condition associated with benign tumor growths on nerve tissue,” said Katherine Warren, M.D., pediatric neuro-oncologist at the National Cancer Institute. “Although only 1 percent of childhood brain tumors are detected at birth or in the first few months of life, a significant number are diagnosed before age five, suggesting a developmental defect. As a matter of fact, defects in developmental growth signaling pathways have recently been identified in embryonal tumors.”
Historically, a diagnosis of brain cancer is provided by a pathologist, who views tissue samples under a microscope. Upon visual inspection of brain cells (histology), pathologists can then classify the tumor type. The limitations of this practice are that many brain tumors have a similar histology when they are actually very different tumors with greatly different prognoses and responses to therapies. “There are some children diagnosed with medulloblastoma who respond well to therapy while others do not,”
Warren explained. “And you can’t tell the difference by looking under the microscope.” In this new era of genomic analysis, tumor classification is moving toward the use of molecular signatures to more precisely classify and grade tumor tissues. In pediatric oncology, a major issue is the treatment of developing brain tissue where the potential for neurotoxicity is considerable. “If we could divide kids into different groups based on their prognosis, then those who don’t need aggressive therapy could be identified and treated less aggressively,” said Warren.
In addition to confusing tumor classifications, in the past, pediatric tumors were considered to be similar to tumors in adults. However, recent studies have revealed that pediatric brain tumors are very different biologically than their adult counterparts.
“What’s been happening recently is that we are realizing that pediatric tumors are different from adult tumors in many ways. Recent genetic and molecular testing on some pediatric tumors have revealed significant differences,” Warren said. “One example is a tumor called fibrillary astrocytoma, a tumor that occurs both in children and adults. Biologically they behave very differently even though they look the same under the microscope. This disease in children rarely will become a high-grade tumor during childhood years, but in adults it can turn into higher grade tumors and nobody knows why.” These observations are further supported by recent studies of molecular markers. Mutations in specific genes that cause disease in adults may not be the cause of disease in children. Future studies should provide fertile opportunities for drug target discoveries and related molecularly targeted therapies.
The use of surgery in treatment of pediatric brain tumors is well-established, but more effective treatments are needed. Imaging technologies have been used to non-invasively assess tumor status and treatment in children, thus eliminating the need to obtain repeated biopsies of the same tumor. The gains achieved in improved surgical resection of brain tumors also can be attributed to improved imaging technologies. Surgeons are now better able to locate a tumor and assess the margins, removing less of the normal brain tissue. This is a significant improvement because there is a direct correlation between the extent of tumor resection and survival in some types of brain tumors in pediatric patients.
Improved imaging technologies have also spurred advances in radiation therapy techniques. “For kids we are trying to tone down the radiation — to just deliver it to the tumor itself using a method called conformal radiation. We follow the outline of the tumor and give a small margin around it. The theory behind this is that normal brain tissue is less likely to be exposed to radiation,” Warren said. “All of these advances are possible due to imaging. Everything is tying together. We are doing molecular analyses to see which patients need more intensive therapy and then through the advances in imaging use conformational radiation to treat the tumor.”
In addition to providing information about the size and location of a tumor, imaging techniques are also providing data to evaluate the biochemical profile of the tumor,as well. Studies have shown that changes in the ratio of certain biochemical components of a tumor can aid an oncologist in determining if a tumor is actively growing. These results would support the choice of aggressive or less stringent treatment regiments.
Blood flow to tumors and tissues in the brain is also being examined through imaging. Evaluation of changes in the amount of blood flowing to tissues in the brain is essential to assess the effectiveness of anti-angiogenic drugs. These drugs do not target the tumor directly, but attack the cells lining the blood vessels that support tumor growth. The tumor size may not shrink, but a decrease in the number of blood vessels surrounding the tumor is a significant advance.
Warren noted, “Anti-angiogenic drugs will most likely be combined with other agents that target the tumor directly. Currently, these agents are being tested alone for safety. Safety is always a concern when adopting new therapies to the pediatric patient population. So we lag behind the adults. There has been an issue with getting drugs to pediatric patients faster, so NCI has proposed a combined adult and pediatric trial that is still under discussion.”
Animation/Video
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Text Transcript
Scene 1:A blood sample is taken from a patient.
Scene 2: Laboratory specimens are arrayed on a chip using a mechanical device.
Scene 3: The samples on the chip are inserted into a mass spectrometer. Mass spectrometry has increasingly become the method of choice for analyses of complex protein samples. Mass spectrometry is a technique that measures two properties: the mass-to-charge ratio of a mixture of ions in the gas phase under vacuum; and the number of ions present at each mass-to-charge value.
Scene 4: The mass spectra, or chart, shows a series of peaks, each representing the ion or charged protein fragment present in a given sample.
Scene 5: The height of a peak on a chart is related to the abundance of a protein fragment. The size of the peaks and the distance between them are a fingerprint of the sample and provide a clue to its identity.
Scene 6: Knowing the identity of a protein fragment will allow researchers to develop drugs that can better target a specific defect that is causing the cancer to grow or spread.
Scene 7: The newly developed targeted drug can be give to the patient, potentially prolonging their survival.
Audio Clips
- NCI’s Pediatric Neuro-oncologist Dr. Kathy Warren discusses childhood brain tumors( Audio – Length: 01:40 – 1.57MB )
Text Transcript
NCI’s Pediatric Neuro-oncologist Dr. Kathy Warren discusses childhood brain tumors
“Basically, 2,000 kids in the United States get diagnosed with brain tumors a year. There’s about 20,000 adults that get diagnosed. And so there’s a big difference in the numbers even though both are still considered rare tumors in the scheme of things when you look at breast and colon. The majority of the adult tumors are gliomas, malignant gliomas. There is no majority tumor really for pediatric brain tumors. About half of the tumors that are diagnosed are malignant.
“So we narrow down to about 1,000 malignant tumors. Twenty percent of those are what we call magio blastomas. Ten to fifteen percent are brain stem gliomas. Ten to fifteen percent are astrocytomas. So you have very small numbers of a number of different brain tumors. And that’s been the problem in trying to study these tumors. And that’s why they always get grouped and lumped together when you do a study. So you get a new drug. You get a new cytotoxic drug in the past that’s non-specific and hence a dividing cell. And you try to treat these children with that. And sometimes you get a hit and it may respond. And sometimes you don’t.
“But what’s been happening recently is, number one, realize that the pediatric tumors are different from the adult tumors in many ways. They’ve started doing genetic and molecular testing on some pediatric tumors and have found some significant differences. So one example is there’s a tumor called fibrilary astrocytoma which is a grade two tumors. And it occurs in children and it occurs in adults. But biologically they behave very differently even though they look the same under the microscope. The fibrilary astrocytomas in children rarely will become high grade tumors during childhood years.”
- Dr. Lee Helman, NCI, discusses differences in treating children vs. adults with cancer
( Audio – Length: 01:02 – 981kb )
Text Transcript
Dr. Lee Helman, NCI, discusses differences in treating children vs. adults with cancer
“You have a big tumor on your pelvis. One patient has localized disease and one of has then disease in their spine. They’re treated the same. One of them is cured and one of them goes on to die. That’s sort of the example of what we don’t understand about why patients that have metastasis do so much worse than patients–and they are a real–there’s actually a stunning example of a young woman who was pregnant and developed pain and was told it was due to her pregnancy. Delivered the kid, still had pain. Said ah, it’s residual sciatica. Finally after six months someone got an x-ray and she had this big tumor in her pelvis. She died because it had metastasized.
“The other example was an Army–twenty year old kid in the Army. Same thing and his tumor was even bigger. But he hadn’t spread. Now both patients responded to the therapy. The tumor went away. The patient who has metastatic disease it always comes back.”
- Dr. Alan Wayne, NCI, discusses the need for new therapies for childhood cancers
( Audio – Length: 00:30 – 482kb )
Text Transcript
Dr. Alan Wayne, NCI, discusses the need for new therapies for childhood cancers
“So the two main reasons we need new therapies are they need to be more effective for these patients with resistance and to overcome the fact that we’re not curing everybody. Two, we need drugs that are less toxic. That enters in the era of targeted therapy. To design based on a molecular understanding of the biology of the disease so that we can counteract those mechanisms and reverse those mechanisms hopefully systemically such that there should be improved efficacy with less toxicity.”
Photos/Stills
1. Children’s Inn at NIH
2. Interior: Children’s Inn at NIH
3. Pediatric Patient in the NIH Clinical Center Intensive Care Unit
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