Adjuvant Therapies for High-Grade Gliomas in Children

Medical

Chemotherapy has been a mainstay in the treatment of malignant pediatric brain tumors, including HGGs. The role of chemotherapy in these patients, however, is not clear. Many studies have been performed for both newly diagnosed and recurrent disease in children.

CCNU, vincristine and prednisone

• Improves survival rates compared to radiation alone: A randomized trial performed more than three decades ago demonstrated improved survival rates in children with GBM who received CCNU, vincristine, and prednisone chemotherapy after radiation therapy as compared to patients who received radiation therapy alone (17).  The numbers of children treated in this study were small, and it was unclear whether LGGs were included. The remarkable 60% survival rate after 3 years in children with GBMs reported in this early series has not been duplicated by other studies (18).
• Administration prior to radiation without benefit: Pre-radiation chemotherapy with a variety of different regimens has not shown improved survival rates (34). Overall survival rates in children, in almost all studies, remain better than those reported in adults.

Temozolomide

• Promising in adults, less so in children: Temozolomide has become a standard component of the postsurgical management of adults with HGGs. Initial results in children have not been as promising, with disappointing response rates of approximately 20% (19,20).
• MGMT and tumor susceptibility in adults: In adults, data have shown that the efficacy of chemotherapy is heavily influenced by the expression of the MGMT gene, as patients with lower levels of expression fared better. This was believed to be because of the ability of MGMT to overcome damage caused by temozolomide, essentially causing drug resistance.
• MGMT and children: In a recent study performed by the Children’s Oncology Group, 107 patients with malignant gliomas were treated with surgical resection followed by radiotherapy with concomitant temozolomide, followed by standard courses of temozolomide. The 3-year, event-free survival for children with anaplastic gliomas was 13% and with GBM was 7%. There was a borderline statistically poorer 2-year event-free survival in those patients with MGMT overexpression. Results were not better than those obtained with CCNU and vincristine chemotherapy (21).

High-dose chemotherapy

• Mixed results: High-dose chemotherapy followed by autologous bone marrow rescue or peripheral stem cell rescue has produced mixed results. Some studies suggest a potential benefit, while others do not, of this more aggressive approach (22).

Radiation

• Accepted treatment for older children and adolescents: Radiation therapy for pediatric HGGs has not been proven beneficial by randomized prospective trials. There is substantial evidence, nonetheless, that it is indeed beneficial (23,24).
• 55 Gy standard dose: The dose of standard conformal radiation is 55 Gy (25).  Stereotactic radiosurgery, primarily for small tumor volumes and limited disease, has been used by some to avoid the multiple fractionated treatments and radiation dose of conformal radiotherapy (24, 26). This may be helpful in avoiding injury to the developing temporal lobes, as well as compact and vulnerable structures such as the optic apparatus, brainstem, and cranial nerves.

Immunotherapy

• Induction or potentiation of immune system against tumor: Immunotherapy for HGG is an attempt to induce the body’s own immune system to attack tumor cells and kill them. Unlike many therapeutic agents that have difficulty crossing the blood-brain barrier, the body’s immune cells can permeate this barrier to reach their target (27). Thus they can carry therapeutic agents to the tumor.
• Increased survival rate of children with GBM suggests efficacy: It is felt that one explanation for the improved 2-year survival rate seen in children as opposed to adults (26% vs. 7%) might be the developing immune system of the child plays a role in treatment of HGGs and that this might be further exploited (28).