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Childhood Astrocytomas Treatment (PDQ®)

Treatment of Childhood Low-Grade Astrocytomas

To determine and implement optimal 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 make surgery difficult; consequently, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1).[1] 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.[2,3]

Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas

Standard treatment options for newly diagnosed childhood low-grade astrocytomas include the following:

Observation

Observation is an option for patients with NF1 or nonprogressive masses.[4-7] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[8-10]

Surgery

Surgical resection is the primary treatment for childhood low-grade astrocytoma [1,4,5,11] and surgical feasibility is determined by tumor location.

  • Cerebellum: Complete or near-complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum.[11]
  • Optic nerve: For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection, while curative, generally results in blindness in the affected eye.
  • Midline structures (hypothalamus, thalamus, brain stem, and spinal cord): Low-grade astrocytomas that occur in midline structures can be aggressively resected, with resultant long-term disease control;[8,9,12]; [13][Level of evidence: 3iiiA] however, such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis.[8]; [14][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.[15][Level of evidence: 3iiiDiii]
  • Cerebrum: Circumscribed, grade I hemispheric tumors are often amenable to complete surgical resection.[16]
  • Diffuse: Diffuse astrocytomas may be less amenable to total resection, and this may contribute to the poorer outcome.

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.[17]; [18][Level of evidence: 3iiDiii]

Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a COG study that included 518 evaluable patients.[11] Overall outcome for the entire group was 78% progression-free survival (PFS) at 8 years and 96% overall survival (OS) at 8 years. The following factors were related to prognosis:[11]

  • 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%).
  • Histology: Approximately three-fourths of patients had pilocytic astrocytoma; PFS and OS were superior for these patients when compared with 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%.[11]

    The extent of resection necessary for cure is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[1,6,11]

  • Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis. In a retrospective review of a different series of pediatric patients, children younger than 1 year with low-grade glioma demonstrated an inferior PFS compared with children aged 1 year and older.[19]

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.[20,21][Level of evidence: 3iiiC]

Adjuvant therapy

Adjuvant therapy following complete resection of a low-grade glioma is generally not required unless there is a subsequent recurrence of disease. Treatment options for patients with incompletely resected tumor must be individualized and may include one or more of the following:

A shunt or other cerebrospinal fluid diversion procedure may be needed.

Observation

In selected patients in whom a portion of the tumor has been resected, the patient may 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.[11]

Radiation therapy

Radiation therapy is usually reserved until progressive disease is documented [16,22] and may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children.[23,24] For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy, intensity-modulated radiation therapy, or stereotactic radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with these modalities.[25]; [26][Level of evidence: 3iDiii] 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.[27-29]; [30][Level of evidence: 2A]; [31][Level of evidence: 2C]; [32][Level of evidence: 3iiiDi]; [33][Level of evidence: 3iiiDii]; [15,34][Level of evidence: 3iiiDiii]

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.[8,35-37]; [31][Level of evidence: 2C]

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.[38] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.

Second surgery

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.[8]

Chemotherapy

Given the side effects associated with radiation therapy, postoperative chemotherapy may be initially recommended.

Chemotherapy may result in objective tumor shrinkage and delay the need for radiation therapy in most patients.[23,24,39,40] Chemotherapy is also an option that may delay or avoid radiation therapy in adolescents with optic nerve pathway gliomas.[41][Level of evidence: 3iiDii] 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 tumor progression or symptomatic nonresectable, low-grade gliomas are the following:

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 [24,39,45]; [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,[24,39] 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.[24,39,45] Whether vision is improved with chemotherapy is unclear.[50,51][Level of evidence: 3iiiC]

Targeted therapy

For children with symptomatic subependymal giant cell astrocytomas (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]; [53][Level of evidence: 2C]; [54][Level of evidence: 3iiiC] A multicenter, phase III, placebo-controlled trial of 117 patients confirmed these earlier findings; 35% of the patients in the everolimus group had at least a 50% reduction in the size of the SEGA, versus no reduction in the placebo group.[55][Level of evidence: 1iDiv] Whether reduction in size of the mass is durable, obviating the need for future surgery, is unknown.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • PBTC-029 (NCT01089101) (Selumetinib in Treating Young Patients With Recurrent or Refractory Low-Grade Glioma): This is a clinical trial to determine the side effects and the best dose of the MEK inhibitor selumetinib in children with low-grade astrocytoma (phase I component). Based on activity observed in the phase I component (now completed), the study has been modified to include phase II expansion cohorts for patients with pilocytic astrocytoma and other low-grade astrocytomas with BRAF genomic alterations and for NF1 patients with recurrent low-grade astrocytomas.
Current Clinical Trials

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.

Treatment of Recurrent Childhood Low-Grade Astrocytomas

Childhood low-grade astrocytomas may recur many years after initial treatment.

An individual plan needs to be tailored based on the following:

  • Patient age.
  • Tumor location.
  • Prior treatment.

Recurrent disease is usually at the primary tumor site, although multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[56,57] Most children whose low-grade fibrillary astrocytomas recur will harbor low-grade lesions; however, transformation into a higher grade tumor is possible.[58] Surveillance imaging will frequently identify asymptomatic recurrences.[59]

At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the following:

  • Initial tumor type.
  • Length of time between initial treatment and the reappearance of the mass lesion.
  • Clinical picture.

Standard treatment options for recurrent childhood low-grade astrocytomas include the following:

Second surgery

Patients with low-grade astrocytomas who relapse after being treated with surgery alone should be considered for another surgical resection.[60]

Radiation therapy

The rationale for the use of radiation therapy is essentially the same when utilized as first-line therapy or at the time of recurrence (refer to the Radiation therapy subsection of the Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas section of this summary). If the child has never received radiation therapy, local radiation therapy may be a treatment option, although chemotherapy in lieu of radiation may be considered, depending on the child's age and the extent and location of the tumor.[61][Level of evidence: 3iA]; [62][Level of evidence: 3iiiDi]

For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[28,31]

Chemotherapy

If there is recurrence at an unresectable site that has been previously irradiated, chemotherapy should be considered.[63]

In patients previously treated with surgery and radiation therapy, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control.[24,64] Vinblastine alone, temozolomide alone, or temozolomide in combination with carboplatin and vincristine may be useful at the time of recurrence for children with low-grade gliomas.[24,47,64]

Antitumor activity has also been observed for bevacizumab given in combination with irinotecan, which, in some cases, also results in clinical or visual improvement.[65] In a phase II study of bevacizumab plus irinotecan for children with recurrent low-grade gliomas, sustained partial response was observed in only two patients (5.7%), but the 6-month PFS was 85.4% (standard error [SE] ± 5.96%) and the 2-year PFS was 47.8% (SE ± 9.27%).[66] A pilot study of 14 patients with recurrent low-grade gliomas also evaluated bevacizumab plus irinotecan and observed 12 patients (86%) with objective responses.[67][Level of evidence: 3iiDi]; [68][Level of evidence: 3iiiDiv] No patients progressed on therapy (median treatment duration, 12 months), but 13 of 14 progressed after stopping bevacizumab at a median of 5 months.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • ACNS1022 (NCT01553149) (Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma): This is a randomized phase II clinical trial comparing low-dose to high-dose lenalidomide to see how well each works in treating children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas or optic nerve pathway gliomas. This clinical trial is based on results of a phase I study that observed tumor responses and long-term stable clinical disease for lenalidomide across a range of dose levels for children with recurrent low-grade gliomas.[69]
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood 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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  • Updated: December 11, 2014