Primary brain tumors—those that start in the brain rather than spread there from other parts of the body—are the most common “solid” tumors children get and are second only to leukemia in their overall incidence. They pose a major treatment challenge that has to be met by the coordinated efforts of a variety of health care professionals, including specialists in pediatric neurosurgery, radiation therapy, and oncology, as well as neuroradiologists and neuropathologists. Significant emotional stresses and problems may occur, requiring intervention by specialized health care professionals.
Every year, about 3,100 children in the United States are diagnosed as having brain or spinal cord tumors. Many tumors are controllable or curable with treatment, and over half of the children diagnosed with brain tumors will live more than five years. Every child’s therapy should be aggressively planned with the intent to cure if possible. This is true even in situations where the same tumor occurring in an adult would not likely be cured.
As is true of all pediatric cancers, but especially with brain tumors, most advances in treatment have been produced by clinical trials of new therapies. The National Cancer Institute (NCI) oversees a large cooperative group of almost all the children’s hospitals in the country—the Children’s Oncology Group (COG)—which develops new treatment protocols for children with brain tumors. These protocols generally represent the most advanced and promising methods of treatment.
Types Brain tumors are classified by the appearance of their cells under the microscope (histopathology) and their location in the brain. The types that occur in children are generally similar to those seen in adults, although there are a few types that are much more common in children.
There is a structure in the back part of the brain, a rooflike membrane called the tentorium. This is just above the cerebellum (the portion of the brain having to do with balance and coordination) and the brain stem. There are significant differences in the types of tumors occurring above and below this membrane, as well as in the methods used to make a diagnosis and follow the results of therapy.
About half the brain tumors in children occur below the tentorium, most being in the cerebellum or the nearby cavity called the fourth ventricle. This area of the skull cavity is the posterior fossa. Tumors in this region include astrocytomas, medulloblastomas, ependymomas, and brain stem gliomas.
The area above the tentorium, which makes up most of the brain, is called the supratentorial region. Tumors in this area include astrocytomas, cerebral neuroblastomas (primitive neuroectodermal tumors [PNET]), ependymomas, craniopharyngiomas, meningiomas, germ cell tumors, optic nerve gliomas, pineal tumors, and choroid plexus tumors.
There may be many different names for these tumors, especially as newer classification systems are more descriptive or accurate.
How It Spreads Brain tumors rarely spread outside the central nervous system but can spread within the brain and the spinal cord.
What Causes It Unknown, although some genetic disorders have been associated with an increased risk.
Screening
There are no effective screening measures.
Common Signs and Symptoms
Brain tumors are often difficult to diagnose because their signs and symptoms may mimic those of other common childhood disorders. Symptoms related to the increased pressure in the brain as the tumor expands include irritability, failure to thrive, headache, nausea, vomiting (which may or may not accompany nausea), and seizures. Symptoms related to the tumor’s location and the pressure it puts on nearby structures include weakness or changes in sensation in various parts of the body, difficulties in coordination or balance, vision and speech problems, and seizures.
Diagnosis
Physical Examination
• Complete neurologic examination.
• Evaluation for optic tract glioma includes neuro-ophthalmological testing, including visual fields. Subtle changes in the tumor that may not be apparent with CT or MRI scanning can be measured in this way. Young children may have a test called visual-evoked response for diagnosis and follow-up.
Blood and Other Tests
• Bone marrow may be analyzed for tumors that spread outside the central nervous system (medulloblastomas).
• For tumors that may spread to the spinal cord or through the cerebrospinal fluid (medulloblastomas, ependymomas, intracranial germ cell tumors, pineal tumors, cerebral neuroblastomas, or primitive neuroectodermal tumors [PNET]), spinal fluid is examined for malignant cells.
• For intracranial germ cell tumors, tumor markers including alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are measured in the blood and cerebrospinal fluid. The same markers are also measured in pineal tumors to exclude the possibility of a malignant germ cell tumor.
Imaging
• Imaging has conventionally been done by CT scan for the brain and myelography for the spinal cord. Recently, MRI imaging with gadolinium enhancement has been shown to be extremely sensitive, useful, and simpler for both the brain and spinal cord.
• Images of the entire brain and spinal cord should be done for tumors that may spread to the spinal cord (medulloblastomas, ependymomas, intracranial germ cell tumors, pineal tumors, cerebral neuroblastomas, PNET).
• Bone scans and bone marrow examinations are sometimes done in medulloblastoma because this tumor may spread outside the central nervous system, especially to bone and bone marrow.
Biopsy
• Tumors of the brain stem, the medulla, and the pons (brain stem glioma) may be biopsied. The procedure is risky. They cannot be removed surgically (radiation therapy is the standard treatment). Stereotactic needle biopsy techniques may enable biopsy to be done when it could have an effect on treatment—for example, if it is not certain that a mass in this area is malignant, if the tumor grows outward and protrudes into the ventricles, or if there is a need to remove part of the tumor because of pressure symptoms.
• Biopsy of optic tract glioma is not always possible because it is difficult to expose the area surgically.
Staging
There are no generally useful staging systems for most brain tumors, although some are classified according to grade. With brain stem glioma, for example, tumors in the higher region—the midbrain—are more likely to be lower grade and have a higher chance of long-term survival than tumors lower down in the pons and the medulla (40 percent versus less than 20 percent).
A variety of staging systems have been used for medulloblastoma. The Children’s Oncology Group has divided this tumor into low and high stages groups. Essentially, low stage implies smaller tumors without metastases, in which the tumor remaining after surgery is smaller than 1.5 cubic cm. High stage refers to larger tumors with evidence of metastatic spread or brain stem involvement, and tumors larger than 1.5 cubic cm remaining after surgery.
Treatment Overview
Treatment includes surgery, with or without radiation therapy, and for some tumors, chemotherapy. Radiation therapy of pediatric brain tumors is very complex and should be carried out in facilities with extensive experience.
Chemotherapy has recently shown some activity in children with brain tumors. Children with high-stage medulloblastoma are treated with maximal surgical resection followed by radiation therapy and chemotherapy to prevent relapse. There is great interest in using chemotherapy after surgery as the only therapy in children under age three, since radiation therapy to the brain in this age group may seriously impair brain development.
Clinical Trials All children with brain tumors should be considered for entry into clinical trials. This form of cancer is rare in children, and trials offer the advantage of the pooled experience of pediatric cancer centers around the country.
Pediatric clinical trials are designed in two ways. One method divides the children into two groups, with one receiving the best currently accepted standard treatment and the other receiving the new therapy that appears promising. The other method is to evaluate a single new treatment in all patients and then compare the results with those obtained with existing therapy, often in the same institution.
Treatment by Tumor Type
Medulloblastoma
Medulloblastoma is the most common malignant brain tumor of childhood, accounting for approximately 20 percent of all primary childhood central nervous system tumors. It arises in the cerebellum and may spread to adjacent tissues. It can also spread via the cerebrospinal fluid to the rest of the brain or to the spinal cord and very rarely to sites outside the nervous system. If it occurs elsewhere in the brain, it is called primitive neuroectodermal tumor (PNET).
Standard Treatment An attempt is made to surgically remove as much tumor as possible. Studies are done during and after the operation to define the risk of relapse, and treatment is given according to the best estimate of low-stage or high-stage disease.
For low-stage disease, standard therapy after surgery is a high dose of radiation to the tumor area and a lower dose to the entire brain and spine. Lowering the dosage of radiation to reduce problems with nervous system development reduces the chance for cure. Children under three should be entered in studies that use chemotherapy and probably delayed or modified radiation therapy.
Treatment of high-stage disease involves chemotherapy in addition to surgery and radiation therapy similar to that given in low-stage disease.
These patients should be considered for entry into clinical trials to establish the best combination and sequence of chemotherapy.
Five-Year Survival About 60 percent
Recurrent Cancer Medulloblastoma that recurs after radiotherapy should be considered for treatment with investigational protocols using new agents. Fewer than one-third of those patients respond, and long-term control of disease is unusual.
Cerebellar Astrocytoma
These are generally low-grade tumors occurring in the cerebellum. Spread is unusual.
Standard Treatment The primary treatment is surgical removal of the tumor, which is successful in removing the entire tumor in most cases. In contrast to most other brain tumors, some patients with microscopic and even larger residual tumor after surgery may survive a long time without any symptoms or tumor growth even without postoperative therapy. This may be significant because a second operation may produce neurological problems.
The use of radiation therapy for patients with astrocytoma depends on the anatomic location and extent of tumor and whether it is resectable or not. Radiation therapy is indicated for unresectable tumors (midbrain and thalamic lesions).
Ten-Year Survival About 80 percent
Recurrent Cancer Cerebellar astrocytoma that recurs is treated, if possible, with another surgery. If this is not possible, local radiation is used. If it recurs in an area where it can’t be removed and has already received maximum radiation, chemotherapy should be considered. Since there is little information available about the role of chemotherapy, Phase I and Phase II clinical studies should be considered.
Infratentorial Ependymoma
These tumors arise from the cells lining the fourth ventricle (a cavity within the brain), as well as those lining a cavity in the center of the spinal cord. They can occur anywhere in the brain or spinal cord, but 60 percent of them start in the part of the brain in the back of the skull, the posterior fossa. The prognosis depends on the grade and size of the tumor and the degree of spread. These tumors may spread via the spinal fluid pathways.
Standard Treatment Surgical excision followed by high-dose radiation to the back part of the brain is the usual treatment. The tumor can be completely removed surgically in about 30 percent of cases. Radiotherapy to the entire brain and spinal cord is controversial, being used most commonly in high-grade tumors.
There is no clear benefit for adjuvant chemotherapy, although consideration should be given to using chemotherapy to delay or modify radiation therapy in very young children.
Five-Year Survival 25 to 60 percent
Recurrent Cancer This tumor is seldom controlled permanently if it recurs after surgery and radiotherapy. About one-third of patients respond to cisplatin, so Phase I and II clinical trials should be considered.
Brain Stem Glioma
Tumors arising in the brain stem are often astrocytomas, tumors of neuron-support cells. These are also referred to as brain stem gliomas. They may be low, intermediate, or high grade. The majority of these tumors growing in the brain stem cannot be removed surgically.
Standard Treatment The usual treatment is high-dose radiation therapy (over 5,500 cGy). Higher doses may be possible using twice-daily (hyperfractionated) treatment.
The role of chemotherapy is not well defined. Occasionally, patients may be candidates for surgical removal. Children younger than three may be given chemotherapy to delay or modify radiation therapy to reduce the risk of neurologic impairment.
Two-Year Survival Varies with site and grade of tumor
Investigational Chemotherapy before the standard radiotherapy treatment
Recurrent Cancer There is no standard therapy for recurrent brain stem glioma. These children cannot have surgery and have already received maximum radiation therapy, and there are no standard chemotherapy drugs that have significant results. They should be entered in a Phase I or Phase II clinical drug trial.
Cerebral Astrocytoma
Low Grade
These tumors may sometimes be completely removed surgically, in which case they have a favorable prognosis. These tumors spread by extension to the adjacent brain and sometimes occur in multiple sites.
Standard Treatment The treatment for low-grade supratentorial astrocytoma is surgery. If the tumor cannot be completely removed, radiotherapy is given after the operation. In some centers, radiotherapy is withheld until progression of disease is shown. The role of chemotherapy is not defined, but initial results are promising.
Five-Year Survival 50 to 80 percent
Recurrent Cancer Patients may benefit from chemotherapy if tumors recur after maximum surgery and radiation therapy. No standard agents have a high degree of response, although cyclophosphamide (Cytoxan), cisplatin (Platinol), and the nitrosoureas may be useful. Carboplatin (Paraplatin) has shown promise. Consideration should be given to clinical trials.
Cerebral Astrocytoma
High Grade
Sometimes called anaplastic astrocytoma or glioblastoma multiforme, these tumors often grow rapidly and involve portions of the brain that cause major neurological problems.
Standard Treatment Treatment includes surgery, radiation therapy, and chemotherapy. Radiation is given after as complete a surgical resection as possible to an area that encompasses the entire tumor and sometimes the whole brain.
A Children’s Cancer Group (CCG) study with radiation therapy and three chemotherapy agents (vincristine [Oncovin]+ lomustine [CeeNU] + prednisone) produced a 46 percent survival of five years compared with 18 percent for children treated with radiation therapy alone. Again, children under the age of three may receive chemotherapy to delay or modify radiotherapy. A number of clinical trials are evaluating the role of newer chemotherapeutic agents.
Two-Year Survival Less than 25 percent. The prognosis may be better if the tumor can be totally removed. Younger patients and those with lower-grade tumors may do better.
Recurrent Cancer Chemotherapy is given if relapse occurs after radiation therapy. Since no standard agents have a high degree of activity, entry in a clinical trial should be considered.
Supratentorial Ependymoma
These ependymomas arise outside the posterior fossa (back of the skull), usually within and adjacent to the ventricles.
Standard Treatment Surgery followed by radiation therapy is the usual treatment. In low-grade tumors, the primary tumor area is given radiation. With high-grade tumors, the entire brain and spinal cord are treated.
Adjuvant chemotherapy is under evaluation. Consideration should be given to its use in very young children to delay or modify radiation therapy.
Two-Year Survival About 40 percent
Investigational Various radiotherapy trials, with and without chemotherapy
Recurrent Cancer This tumor is seldom controlled if it recurs after surgery and radiation therapy, although one-third of patients respond to cisplatin. Phase I and II clinical studies should be considered.
Craniopharyngioma
These benign tumors arise in the central portion of the brain and produce problems primarily because of their location. Since they are benign, metastasis is unknown.
Standard Treatment Surgery is the treatment of choice and produces a high rate of control in most patients. For recurrent unresectable tumors, radiotherapy is recommended. There is no reported role for chemotherapy.
Ten-Year Survival About 80 percent
Intracranial Germ Cell Tumor
Germ cell brain tumors—there are a number of subtypes—usually arise in the central portion of the brain. Under the microscope, they resemble more common germ cell tumors of the testis and ovary. The prognosis relates to the cell type and is especially favorable in patients with germinoma.
Standard Treatment The role of surgery is usually a biopsy to establish the diagnosis, since the location of these tumors usually prevents complete removal. Germinoma may be treated with radiation therapy to the brain and spinal cord, with high doses to the tumor and somewhat lower doses to the rest of the nerve tissue. There is emerging evidence that local radiation therapy plus chemotherapy produces equivalent cure rates.
Advanced or disseminated germinomas, as well as the various germ cell tumors other than germinomas, are usually treated with radiation to the brain and spinal cord. There are several views about the dosage and areas that should be treated.
Nongerminoma germ cell tumors may respond to a variety of chemotherapeutic agents, including bleomycin, cisplatin, etoposide, cyclophosphamide, and vincristine. The role of adjuvant chemotherapy, in addition to radiation, is not yet determined for these tumors that arise within the brain, although chemotherapy is extremely effective in these tumors elsewhere in the body.
Survival Variable
Recurrent Cancer Intracerebral germ cell tumors may be responsive to the same type of chemotherapy combinations used against germ cell tumors in other locations—PVB (cisplatin + vinblastine + bleomycin) and VAC (vincristine + dactinomycin + cyclophosphamide).
If the tumor recurs after treatment with these programs, Phase I and II clinical studies should be used to try to find agents that may be useful in treating this tumor, which is often responsive to chemotherapy.
Pineal Region Tumors
Three principal groups of tumors—germ cell tumors, pineal parenchymal tumors, and astrocytomas—account for tumors in this region. The pineal parenchymal tumor resembles medulloblastoma, but it develops in the region of the pineal gland in the center of the brain. The prognosis depends upon the size of the tumor and its degree of spread.
Standard Treatment The usual treatment is radiation therapy. There is some controversy about the possibility of surgical removal, although biopsy is recommended whenever possible to establish a diagnosis. A high dose of radiation is given to the tumor, with a lower dose to the brain and spinal cord.
Studies are exploring the role of chemotherapy for poorly differentiated pineal tumors, although well-differentiated tumors may be treated with simple local radiation therapy. Young children may be given chemotherapy to delay or modify the radiation treatments.
Two-Year Survival Less than 50 percent
Optic Tract Glioma
These tumors grow along the optic tracts of the brain that carry visual impulses. They are low-grade and slow-growing astrocytomas that produce visual symptoms.
Standard Treatment Radiation therapy is the usual treatment for optic tract gliomas that are growing. Some tumors that do not appear to be growing and have no symptoms may be carefully observed without treatment as long as they are stable.
Chemotherapy has not been used as an adjuvant to radiation therapy as part of standard treatment, but the previous considerations about the risks of radiation in children under the age of three apply. The use of vincristine and other drugs of relatively low toxicity has enabled radiation therapy to be delayed in more than 80 percent of children and is being further evaluated.
Five-Year Survival Over 75 percent
Cerebral Neuroblastoma (Supratentorial Primitive Neuroectodermal Tumor, or PNET)
There are a variety of names for these tumors. They are poorly differentiated tumors, which microscopically may have features of various primitive tumors of other cell types. Prognosis depends upon the extent of disease.
Standard Treatment The usual treatment is high-dose radiation therapy. Many radiation oncologists also radiate the entire brain and spinal cord because of this tumor’s tendency to spread to the rest of the central nervous system through the cerebrospinal fluid. Chemotherapy has been used in several clinical trials, especially in younger children. It appears to produce good control and has particular value in younger children to delay or avoid the use of radiation therapy and its consequences. Carboplatin may be a particularly useful drug.
Two-Year Survival 30 to 50 percent
Treatment Follow-Up
• Repeated clinical evaluation, emphasizing initial neurologic signs and symptoms.
• Repeated CT or MRI scanning.
• Repeated studies of any other abnormal tests, such as cerebrospinal fluid and visual fields.
• Since radiotherapy can affect growth hormone production and brain development, careful endocrine and neurologic follow-up is very important.
The Most Important Questions You Can Ask
• What type of brain tumor does my child have?
• How does it usually behave?
• What is the chance of cure?
• What is the standard treatment and how successful is it?
• Should radiotherapy be used? When?
• Should chemotherapy be used? When?
• If the treatment is not completely effective or my child relapses later, what else can be done?
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