Treatment of Childhood Low-Grade Astrocytomas

Surgery
Observation
Radiation Therapy
Chemotherapy
Treatment Options Under Clinical Evaluation
        Current Clinical Trials

To determine and implement optimum management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.

In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in the diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.[1] Because the location of these tumors makes a surgical approach difficult, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1).[2] When associated with NF1, tumors may be of multifocal origin.

For children with low-grade optic pathway astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function.[3,4] Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the visual pathway.[1,2,5,6]; [7][Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[5,8] Observation is an option for patients with NF1 or nonprogressive masses.[1,5,9,10] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[11-13]

Surgical resection is the primary treatment for childhood low-grade astrocytoma [1,2,5,14] and surgical feasibility is determined by tumor location. For example, complete or near complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum. Similarly, circumscribed, grade I hemispheric tumors are often amenable to complete surgical resection.[14-16] For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection or local radiation therapy may result in prolonged progression-free survival (PFS).[17]

Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a Children’s Oncology Group study that included 518 evaluable patients.[14] Overall outcome for the entire group was 78% PFS at 8 years and 96% overall survival (OS) at 8 years. The following factors were related to prognosis:[14]

• Histology: Approximately three-fourths of patients had pilocytic astrocytoma, and PFS and OS for these patients was superior to that of children with nonpilocytic tumors.
• Extent of resection: Patients with gross total resection had 8-year PFS exceeding 90% and OS of 99%. By comparison, approximately one-half of patients with any degree of residual tumor (as assessed by operative report and by postoperative imaging) showed disease progression by 8 years, although OS exceeded 90%.
• Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis.
• Tumor location: Cerebellar and cerebral tumors showed higher PFS at 8 years compared with patients with midline and chiasmatic tumors (84% ± 1.9% versus 51% ± 5.9%).

Diffuse astrocytomas may be less amenable to total resection, and this may account for the poorer outcome. The extent of resection necessary for cure, as noted above, is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[2,9,14] The long-term functional outcome of cerebellar pilocytic astrocytomas is relatively favorable. Full-scale mean IQs of patients with low-grade gliomas treated with surgery alone are close to the normative population. However, long-term medical, psychological, and educational deficits may be present in these patients.[18,19][Level of evidence: 3iiiC]

Low-grade astrocytomas that occur in midline structures (e.g., hypothalamus, thalamus, brain stem, and spinal cord) can also be aggressively resected, with resultant long-term disease control;[11,12,20]; [21][Level of evidence: 3iiiA] however, such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis.[11]; [22][Level of evidence: 3iC] Because of the infiltrative nature of some deep-seated lesions, extensive surgical resection may not be appropriate and biopsy only should be considered.[23][Level of evidence: 3iiiDiii] Treatment options for patients with incompletely resected tumor must be individualized and may include observation, a second resection, chemotherapy, and/or radiation. A shunt or other cerebrospinal fluid diversion procedure may be needed.

Following resection, immediate (within 48 hours of resection per Children’s Oncology Group [COG] criteria) postoperative magnetic resonance imaging is obtained. Surveillance scans are then obtained periodically for completely resected tumors, although the value following the initial 3- to 6-month postoperative period is uncertain.[24]; [25][Level of evidence: 3iiDiii] In selected patients in whom a portion of the tumor has been resected, the patient may also be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow. Approximately 50% of patients with less-than-gross total resection may have disease that remains progression-free at 5 to 8 years, supporting the observation strategy in selected patients.[14]

Radiation therapy is usually reserved until progressive disease is documented,[16,26] and its use may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children.[27,28] Radiation therapy results in long-term disease control for most children with chiasmatic and posterior pathway chiasmatic gliomas, but may also result in substantial intellectual and endocrinologic sequelae, cerebrovascular damage, and possibly an increased risk of secondary tumors.[11,17,29,30]; [31][Level of evidence: 2C] An alternative to immediate radiation therapy is subtotal surgical resection, but it is unclear how many patients will have stable disease and for how long.[11] Radiation therapy and alkylating agents are used as a last resort for patients with NF1, given the theoretically heightened risk of inducing neurologic toxic effects and second malignancy in this population.[32] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.

For children with low-grade glioma for whom radiation therapy is indicated, conformal radiation therapy or stereotactic radiosurgery approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality. Care must be taken in separating radiation-induced imaging changes from disease progression during the first year after radiation, especially in patients with pilocytic astrocytomas.[33-35]; [36][Level of evidence: 2A]; [31][Level of evidence: 2C]; [37][Level of evidence: 3iiiDi]; [38][Level of evidence: 3iiiDii]; [23,39][Level of evidence: 3iiiDiii]

Given the side effects associated with radiation therapy, chemotherapy may be particularly appropriate for patients with NF1 and for younger children.

Chemotherapy may result in objective tumor shrinkage and will delay the need for radiation therapy in most patients.[27,28,40,41] Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.[42]

The most widely used regimens to treat progression or symptomatic nonresectable, low-grade gliomas are carboplatin with or without vincristine [27,28,43] or a combination of thioguanine, procarbazine, lomustine, and vincristine (TPCV).[41]; [44][Level of evidence: 1iiA] The COG reported the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year event-free survival rate was 39% ± 4% for the CV regimen and 52% ± 5% for the TPCV regimen.[44] Other chemotherapy approaches have been employed to treat children with progressive low-grade astrocytomas, including multiagent platinum-based regimens [28,40,45]; [46][Level of evidence: 2Diii] and temozolomide.[47,48]

Reported 5-year PFS rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas,[28,40] but most patients ultimately require further treatment. This is particularly true for children who initially present with hypothalamic/chiasmatic gliomas that have neuraxis dissemination.[49][Level of evidence: 3iiiDiii]

Among children receiving chemotherapy for optic pathway gliomas, those without NF1 have higher rates of disease progression than those with NF1, and infants have higher rates of disease progression than do children older than 1 year.[28,40,45] Whether vision is improved with chemotherapy is unclear.[50,51][Level of evidence: 3iiiC]

Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mTOR complex 1. These children are at risk for the development of subependymal giant cell astrocytomas (SEGA), in addition to cortical tubers and subependymal nodules. For children with symptomatic SEGAs, agents that inhibit mTOR (e.g., everolimus and sirolimus) have been shown in small series to cause significant reductions in the size of these tumors, often eliminating the need for surgery.[52][Level of evidence: 2C]; [53][Level of evidence: 3iiiC] Whether reduction in size of the mass is durable, obviating the need for future surgery, is currently unknown.

Early-phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities. Information about ongoing clinical trials is available from the NCI Web site.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood low-grade untreated astrocytoma or other tumor of glial origin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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