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Centers of ExcellenceCHILDHOOD BRAIN TUMORS

Tumors of the central nervous system (CNS) are the most common solid tumor of childhood. The incidence has increased from 2.4 cases per 100, 000 lives (1973-1982) to 3.3 cases per 100,000 lives in 1986. Radiation treatments for pediatric CNS tumors has lagged behind our treatment strategies for other childhood cancers. Thus CNS tumors are the second most common cause of cancer-related deaths in children less than 15 years of age.

One of the major limiting factors in treatment is the sensitivity of the young brain (normal tissue) to the effects of conventional external beam radiation (XRT). Although conventional radiotherapy is the most effective therapy available to date, late effects on normal brain may significantly affect the quality of life in long-term survivors.

The younger the child at the time of treatment, the size and location of the radiation field necessary to cover the tumor, radiation dose and number of treatments all play a role in cognitive, endocrine and neurologic sequellae (complications).

Another major concern of physicians and parents is the induction of secondary tumors in long-term (10+ years) survivors of CNS tumors. It appears that for the immediate future, XRT will continue to play a major role in the treatment of pediatric CNS tumors.

Radiosurgery (cobalt60 or linear accelerator), used for appropriately selected patients, can minimize side effects and maximize the benefits of XRT. The ability to precisely focus radiosurgery treatments and minimize surrounding normal brain radiation dose should diminish those consequences in follow-up research. In addition, the ability of radiosurgery to deliver higher doses of radiation to the primary tumor site should provide better long-term tumor control or possible cure.

The avoidance of secondary tumors to date never reported after radiosurgery in children and adolescents is another significant benefit of this technology.

The most common cause for spontaneous intracranial bleeding in children and adolescents is due to a vascular malformation such as an AVM. The use of radiosurgery (specifically cobalt60 Gamma Knife) in these non-tumor settings is particularly suited to children because of the minimization to mental and endocrine development to the normal surrounding young or immature brain.

The use of Gamma Knife radiosurgery has been used rarely, if ever, in children with functional disorders because they rarely are seen in this age range.

Pediatric Technical Issues

In adults, radiosurgery is not limited by the age factor. In children less than 24 months old, for whom radiosurgery may seem most attractive due to the higher sensitivity of normal brain tissue to ionizing radiation, we are limited by the lack of skull thickness. Placement of the stereotactic localization frame for treatment is limited to infants older than 20 months of age. Although on the surface it may seem feasible to place the stereotactic skeletal fixation frame on a younger child, the presence of a growing skull with open sutures (growth plates) would result in the skull deforming as the frame is placed for treatment, thereby losing an amount of precision which is likely to be unacceptable for radiosurgery treatment.

We have routinely been able to treat infants 20 months or older with the Gamma Knife radiosurgery instrument without compromising precision or penetration of a pin through the skull. In young children, the use of long placement pins are necessary because of their small head circumference, making placement of the frame more critical than in adolescents and adults. Because of the need to use long pins, special care must be used when moving the child for scanning and during interlocking the frame to the appropriate treatment helmet. "Gentle" is the key word to remember.

All infants and children as well as many adolescents prefer to have their treatment under anesthesia. Preoperative teaching is important so the procedure can go as planned. All children and their parents should be educated by treating staff prior to the date of radiosurgery.

Mild oral sedation, to calm the child, is given prior to intubation or intravenous (IV) line placement and the parents are allowed to remain with their child during the initial phase of anesthesia. Anesthesia is usually accomplished with a continuous IV drip of Propofal (Diprivan), which allows the child to awaken immediately at the end of the procedure with little or no lasting effects. In older children and adolescents, the option to have deep sedation for frame placement only with monitored anesthesia during scanning, planning and treatment is evaluated.

The decision to intubate is based on the ability of anesthesia to always have a secure airway. Once the treatment frame is placed, safe intubation is excluded. Therefore, if there is any question regarding the child's ability to tolerate the entire procedure, intubation is chosen rather than accepting the risk of aborting the procedure. Local anesthesia at the pin sites is only used in patients being sedated for frame placement and not in those patients having the procedure under general anesthesia.

Patients with vascular malformations do not tolerate the length of the entire treatment procedure, therefore all are intubated and remain sedated with the drug Propofal until the frame is removed. This strategy has been successful in more than 150 pediatric patients undergoing Gamma Knife radiosurgery.

Disease Development

Although radiosurgery can deliver high doses of radiation to small areas in the brain without significant exposure to surrounding normal brain, it is limited by dose volume (size) constraints.

In all large cooperative clinical group trials to date, the extent of surgical resection has a profound influence in response to treatment and survival. Therefore microsurgery (open skull surgery) plays a major role in the treatment of pediatric CNS tumors. In addition, aggressive surgical removal should make more tumors amenable to radiosurgery.

However, to date, there has been no prospective randomized trial to evaluate the efficacy of radiosurgery as the primary treatment for selected partially removed tumors, as an adjunct treatment to chemotherapy or as a boost to conventional external beam radiotherapy. It is reasonable to conclude XRT's curative potential is presently limited by the tolerance of surrounding normal structures and the ability of a particular tumor to spread from its primary site. To date, our inability to control a tumor at its original site of occurrence (local control) is the major obstacle we face in neuro-oncology.

Within the radiosurgery industry, there are several types of technology available. Each technology brings with it advantages and limitations in treatment. Each child should be first be evaluated for radiosurgery treatment with the cobalt60 Gamma Knife technology. This particular technology is capable of targeting the radiation dose to the brain with the highest degree of precision at this time. If treatment is deemed to not be appropriate with the Gamma Knife, it is then recommended that treatment with linear accelerator equipment be evaluated. The following is an attempt to outline the present as well as the potential uses we see for radiosurgery with young children.

Low Grade Tumors

Total surgical resection of a low-grade tumor should be the goal of microsurgery. However, tumors in certain locations within the brain make this goal unobtainable. Many tumors presenting in the basal ganglia or brain stem are not resectable without significant neurologic deficient. Small focal low-grade astrocytic tumors of the brain stem or basal ganglia that either are deemed unacceptable operative risks or which have a residual tumor nodule after microsurgery are excellent candidates for radiosurgery if the remaining tumor volume is less than 3cm in size.

The area where radiosurgery is not generally applicable in young children is the region of the optic nerves and optic chiasm. Astrocytic tumors grow directly within these critical structures and cannot be excluded from the treatment volume during radiosurgery treatment. However, other intra- and parasellar tumors are amenable to radiosurgery if there is 2 mm or greater distance between the region to be treated and the optic pathways. Many focally residual or recurrent craniopharyngiomas (benign tumors near the pituitary stalk), particularly intrasellar recurrences or recurrences within the cavernous sinus, are treatable with radiosurgery with minimal risks.

For patients who have not received prior conventional external beam radiation, the dose to the optic chiasm should remain below 9 g-y. If prior XRT has been given, the dose planning becomes critical and each case must be evaluated individually. Knowing the prior radiation doses and fields treated are critical information to the radiosurgery team as the feasibility of treatment is accessed and a safe radiosurgery treatment plan is developed.

With pituitary tumors, similar results as seen in adults are expected in children. Those tumors that are not cured by surgery or medical management are treatable with radiosurgery. The dose limiting structure is still the optic pathways.

Children with neurofibromatosis (NF) type I but especially type II are excellent candidates for radiosurgery. NF type II is associated with bilateral acoustic neuromas and intracranial meningiomas, often multiple sites. The chance for deafness in bilateral acoustic neuromas is very high. Radiosurgery with Gamma Knife in these cases has achieved 90 percent or greater tumor control rates. More importantly, hearing preservation in children with useful hearing is twice as likely with Gamma Knife radiosurgery than microsurgery. In addition, facial nerve preservation is better.

Meningiomas tend to occur along the skull base and as in adults, the cavernous sinus is a frequent site. Surgical resection is likely to impart significant cranial nerve defects, but complete removal of the tumor is unusual. Even with the most careful microsurgical technique, complications " such as cranial nerve deficit or vascular flow injury " are significant. External beam XRT, even with advanced planning programs, is likely to deliver a significant dose to the temporal lobes with possible delayed recent memory deficits or progressive carotid artery occlusion (blockage) such as moya moya syndrome, developing three to 10 months after radiation therapy. (Moya moya is a rare disorder in which the main blood vessels leading to the brain are blocked or severely constricted.)

Radiosurgery results in a tumor control rate of 95 percent with no mortality and complications in 3 to 5 percent of cases. In order to have these positive results with radiosurgery, it is important to identify appropriate candidates before surgical intervention has taken place and particularly prior to the use of any external beam radiation therapy.

Young patients with NFII should be evaluated for Gamma Knife radiosurgery as a primary treatment whenever they are initially diagnosed or when a new tumor develops.

Similarly, other patients with hereditary neurocutaneous disorders (of the skin, nerves or central nervous system) should be evaluated for radiosurgery. Patients with tuberous sclerosis (TS) develop giant cell astrocytomas within the ventricular system. The pathology of these tumors is rarely in question and a biopsy is not beneficial. With radiosurgery being highly effective for this vascular benign tumor, no invasive surgery may be required. Patients with von Hippel-Lindau disorder are prone to develop multiple highly vascular tumors called hemangioblastomas.

These tumors are well circumscribed and usually round. Careful radiosurgery planning can control the majority of these tumors without microsurgery or the need for external beam XRT or embolization procedures.

High Grade Tumors

High grade astrocytomas, while infrequent in children, represent a daunting challenge and may necessitate multiple types of treatments. Standard fractionated XRT (received over time) prolongs survival. Surgical resection to decrease the tumor volume is a critical factor in determining the success of XRT. In children, chemotherapy has also been shown to be of benefit. The use of high dose XRT by implanting high activity I125 (radioactive iodine) seeds into the residual or recurrent tumor had shown improved survival but the risk of radiation necrosis requiring reoperation to remove scar tissue has been as high as 40 percent and often carried significant permanent complications. The technique requires stereotaxic placement of the I125 seeds and five days in the hospital. Patients must be confined to their room because of radiation exposure to other patients.

With Gamma Knife radiosurgery treatment, the boost of radiation to the local tumor area, assuming an appropriate size, may allow the young patient to forego the procedure of radioactive implants. Emerging research is suggesting that the incidence of reoperation and/or symptomatic radiation necrosis appears much less with radiosurgery than with iodine seed implantation. This is one step in a multiple disciplined approach to treating these tumors in children.

In children, primitive neuroectodermal tumors such as medulloblastoma, ependoymoblastoma and pineoblastoma are more common than malignant gliomas. Although they have a propensity to disseminate within the spinal fluid spaces, the main site of treatment failure is at the primary tumor site. Protocols using radiosurgery boosts to the primary site are under evaluation but no prospective trials are underway at this time. For the present, radiosurgery has been saved for treating local recurrences or by single institutions in selected patients. Clearly, radiosurgery as the primary treatment with these tumors is not an option. But it has promise as an adjunct to surgery, external beam XRT and chemotherapy in these patients.

One area in which Gamma Knife radiosurgery has shown promising results is in focally recurrent ependymomas (arising from the ventricles or spinal cord), where local recurrence of the tumor is the usual reason for failure. Survival is improved with radiosurgery where surgical resection has left 10 percent or less of the tumor mass. Experience suggests focal residuals may be more effectively treated with less permanent complication with radiosurgery rather than fractionated external beam XRT. Even more encouraging has been the experience this treatment has with a small number of children with multiple recurrences after XRT and chemotherapy, who were then treated with radiosurgery with positive results.

The use of microsurgery usually results in leaving some residual tumor attached to the brain stem. Best results have been shown when this residual tumor was treated with radiosurgery or radiosurgery is utilized when the recurrence has been diagnosed. For example, one young patient with prior open skull surgery followed by external beam XRT and chemotherapy over a three-year period had two recurrences. This patient now remains disease-free for more than five years after Gamma Knife radiosurgery. The ability to deliver a high local dose of radiation close to the brain stem, especially to irregular targets, can only be done using the preciseness of Gamma Knife technology.

Arteriovenous Malformations

Gamma Knife radiosurgery either alone or in combination with interventional microradiology (embolization) techniques is very attractive in children with complex deep seated or brain stem AVMs. Given their long period of risk for recurrent hemorrhage, 25 to 50 percent chance of size increase and tendency toward seizures, observing these lesions and taking no treatment action is not very attractive.

Most studies suggest the risk of rebleed in children with AVMs is significantly greater than adults. Additionally, brain stem AVMs carry a high morbidity (complication rate) and mortality (death rate) in children. The goal is to reduce the size and flow of blood within the AVM when possible. Neuro-interventional techniques to occlude aneurysm within the middle of the AVM hopefully will reduce the risk of rebleeding, allowing enough time for radiosurgery to occlude the AVM.

Radiosurgery success is inversely related to the size and flow rate of AVMs. The usual time to resolution and occlusion in adults is two to three years for AVMs approximately 3 cm in size. For reasons as yet unclear, children have a shorter time to obliteration of the AVM after radiosurgery treatment than adults. It is not unusual to see a child's AVM disappear in less than one year and even six months past radiosurgery. For lesions 3 cm or less, the rate of complete occlusion approaches 80 percent with a less than 1 percent treatment mortality and less than 3 percent treatment morbidity. For larger AVMs less than 5 cm, we have used embolization or multiple treatments of Gamma Knife radiosurgery spaced one to three years apart until complete obliteration has been confirmed by angiography.

There has never been a secondary tumor reported following radiosurgery for an AVM in a child, with the follow up in reported following radiosurgery for an AVM in a child, with the follow up in Europe being more than 20 years.

Where appropriate with AVMs, radiosurgery is easy on the child, cost effective and allows a rapid return to all activities with minimal risk.

Summary

Gamma Knife radiosurgery is playing a larger role than ever in children with specific neurosurgical disorders and tumors. It is likely its use will expand in the treatment of both low-grade and malignant intracranial tumors. Its use as an adjunct treatment to surgery and external beam radiation has become more defined in recent years. In some instances, it may replace surgery and/or standard fractionated (over time) radiation therapy. It will remain the gold standard for treating many AVMs.

Future uses of radiosurgery in functional disorders such as epilepsy, obsessive/ compulsive disorder and the rare movement disorder in childhood will probably be explored in the near future, as they are now being explored in adults.

Treatments for diagnosis previously not considered in the past may be suitable in the future for radiosurgery. These include ocular tumors such as retinoblastoma, childhood nasal pharyngeal and skull base tumors, giant cell tumors, etc. Future uses for radiosurgery with young children may include combination treatments with intracranial immuno-therapy, regular and radiosensitizing chemotherapy and new fractionation schemes in conjunction with external beam radiotherapy.

The future for radiosurgery remains exciting, especially in children where limiting radiation to normal tissue is a critical issue. Patients and families are better informed than ever before in the history of medicine. The Internet and support groups provide information allowing families to seek out the treatment centers with the most experience in treating childhood tumors. Gamma Knife radiosurgery will be demanded as part of the armentarium in treating children and providing hope for cure.

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