Diffuse Intrinsic Pontine Gliomas

Conventional treatment for children with diffuse intrinsic pontine glioma (DIPG) is radiation therapy to involved areas. Such treatment will result in transient benefit for most patients, but over 90% of patients will die within 18 months of diagnosis. The conventional dose of radiation therapy ranges between 5,400 cGy and 6,000 cGy given locally to the primary tumor site in single daily fractions.

Hyperfractionated (twice daily) radiation therapy techniques have been used to deliver a higher dose, and studies using doses as high as 7,800 cGy have been completed. Evidence demonstrates that these increased radiation therapy doses do not improve the duration or rate of survival for patients with DIPG whether given alone,[1,2] or in combination with chemotherapy.[3] Studies evaluating the efficacy of various radiosensitizers as a means for enhancing the therapeutic effect of this modality are under study but to date have failed to show significant improvement in outcome.[2,3,4,5,6]

The utility of chemotherapy in the treatment of patients with newly diagnosed DIPG is unproven.[2,3,5,6,7,8,9,10] To date, neither adjuvant or neoadjuvant chemotherapy, nor immunotherapy when added to radiation therapy has been demonstrated to improve survival for children with DIPG. Similarly, studies utilizing high-dose therapy with stem cell rescue have been ineffective in extending survival.[11] Studies using new anti-cancer agents with alternative mechanisms of actions and brain stem radiation are ongoing.

Treatment options under clinical evaluation

• The Children’s Oncology Group recently completed a phase II study of low-dose temozolomide during irradiation followed by adjuvant temozolomide on a 5-day schedule (ACNS0126).[12] Results are pending. The current COG trial is a phase I/II study of topotecan and concomitant radiation therapy (ANCS0224).[13]
• The Pediatric Brain Tumor Consortium is coordinating multiple studies, including a phase II study (PBTC-014) [14] of an oral farnesyl protein transferase inhibitor (tipifarnib) administered during and after radiation therapy, which is closed and results are pending; a phase II study (PBTC-006) [15] of imatinib mesylate after radiation therapy; and a phase II study (PBTC-007) [16] of an anti-epidermal growth factor receptor (EGFr) agent (gefitinib) during and after radiation therapy.

Focal or Low-grade Brain Stem Gliomas

In general, maximal surgical resection should be attempted.[17] Patients with residual tumors may be candidates for additional therapy including radiation or adjuvant therapy including 3-dimensional conformal approaches. Information about ongoing clinical trials is available from the NCI Web site.

Patients with small tectal lesions and hydrocephalus but no other neurological deficits may be treated with cerebrospinal fluid diversion alone and have follow-up with sequential neuroradiographic studies unless there is evidence of progressive disease.[17]

Neurofibromatosis

Children with neurofibromatosis type I and brain stem gliomas may have a different prognosis than other patients who have intrinsic lesions. Patients with neurofibromatosis may present with a long history of symptoms or be identified on screening tests; a period of observation may be indicated before instituting any treatment.[18] Brain stem gliomas in these children may be indolent and may require no specific treatment for years.[19]

References:

1. Freeman CR, Krischer JP, Sanford RA, et al.: Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study. Int J Radiat Oncol Biol Phys 27 (2): 197-206, 1993.
2. Mandell LR, Kadota R, Freeman C, et al.: There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43 (5): 959-64, 1999.
3. Allen J, Siffert J, Donahue B, et al.: A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas. Cancer 86 (6): 1064-9, 1999.
4. Freeman CR, Kepner J, Kun LE, et al.: A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys 47 (3): 561-4, 2000.
5. Broniscer A, Leite CC, Lanchote VL, et al.: Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. Brainstem Glioma Cooperative Group. J Clin Oncol 18 (6): 1246-53, 2000.
6. Doz F, Neuenschwander S, Bouffet E, et al.: Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d'Oncologie Pédiatrique. Eur J Cancer 38 (6): 815-9, 2002.
7. Jenkin RD, Boesel C, Ertel I, et al.: Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group. J Neurosurg 66 (2): 227-33, 1987.
8. Blaney SM, Phillips PC, Packer RJ, et al.: Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78 (3): 527-31, 1996.
9. Jennings MT, Sposto R, Boyett JM, et al.: Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group. J Clin Oncol 20 (16): 3431-7, 2002.
10. Wolff JE, Westphal S, Mölenkamp G, et al.: Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer 87 (9): 945-9, 2002.
11. Bouffet E, Raquin M, Doz F, et al.: Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 88 (3): 685-92, 2000.
12. Cohen KJ, Children's Oncology Group: Phase II Pilot Study of Adjuvant Temozolomide Concurrently With Postoperative Radiotherapy and Then Alone As Maintenance Therapy in Children With Newly Diagnosed Anaplastic Astrocytoma, Glioblastoma Multiforme, Gliosarcoma, or Diffuse Intrinsic Pontine Glioma, COG-ACNS0126, Clinical trial, Completed.
13. Robertson PL, Children's Oncology Group: Phase I/II Study of Topotecan, Filgrastim (G-CSF), and Radiotherapy in Young Patients With Newly Diagnosed Malignant Intrinsic Pontine Brain Stem Glioma, COG-ACNS0224, Clinical trial, Closed.
14. Haas-Kogan DA, Pediatric Brain Tumor Consortium: Phase I/II Study of Tipifarnib and Radiotherapy in Pediatric Patients With Non-Disseminated Intrinsic Diffuse Brainstem Gliomas (Phase I Closed to Accrual as of 1/3/06), PBTC-014, Clinical trial, Closed.
15. Pollack I F, Pediatric Brain Tumor Consortium: Phase I/II Study of Imatinib Mesylate With or Without Radiotherapy in Children With Newly Diagnosed Poor Prognosis Brainstem Glioma or Recurrent High-Grade Intracranial Glioma (Phase I, strata I and IIA closed to accrual as of 5/10/04.), PBTC-006, Clinical trial, Closed.
16. Geyer JR, Pediatric Brain Tumor Consortium: Phase II Study of Gefitinib and Brain Irradiation in Children With Newly Diagnosed Brain Stem Tumors or Incompletely Resected Supratentorial Malignant Gliomas, PBTC-007, Clinical trial, Closed.
17. Vandertop WP, Hoffman HJ, Drake JM, et al.: Focal midbrain tumors in children. Neurosurgery 31 (2): 186-94, 1992.
18. Bilaniuk LT, Molloy PT, Zimmerman RA, et al.: Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39 (9): 642-53, 1997.
19. Molloy PT, Bilaniuk LT, Vaughan SN, et al.: Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45 (10): 1897-902, 1995.