Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-27T08:30:21.051Z Has data issue: false hasContentIssue false
  • English
  • Français

New Directions in Pediatric Neuro-Oncology Practice: Impact of the Children's Cancer Group Study 9933, a Phase II Study of High-Dose Chemotherapy Before Radiation in Children with Newly Diagnosed High-Grade Astrocytoma

Published online by Cambridge University Press:  21 July 2006

Tobey J. MacDonald
Tobey J. MacDonald
Affiliation:
Hematology-Oncology, Children's National Medical Center, NW, Washington, DC, USA; Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Extract

ABSTRACT

Background: Despite the use of surgery, radiotherapy (RT) and standard chemotherapy, childhood high-grade astrocytoma (HGA) continues to carry a dismal prognosis. In an attempt to identify effective drug combinations and an alternative treatment strategy, the Children's Cancer Group (CCG) conducted a nationwide clinical trial that prospectively evaluated 102 children with HGA and post-operative residual disease for efficacy and toxicity of four courses of high-dose chemotherapy (HDCT) before RT. Design and methods: Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A); ifosfamide/etoposide (Regimen B); or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients received local RT followed by lomustine and vincristine. Results: Of 76 evaluable patients (median age 11.95 years, range 3–20 years), 30 patients relapsed during HDCT and 11 others did not complete HDCT due to toxicity. Non-hematologic serious toxicities were common (29%) and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24 ± 5% at 5 years and did not differ between groups. The 5-year, event-free survival (EFS) for all patients was 8 ± 3% and 14 ± 7% for Regimen A (p = 0.07). Patients who responded to HDCT had a nominally higher survival rate (p = 0.03 for trend). Interpretation: HDCT prior to RT provides no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor, and adversely effects ability to complete RT. Strong consideration should be given to investigating alternative strategies and novel biologic agents for this disease.

Keywords

Children's Cancer GroupHigh-Dose ChemotherapyHigh-Grade Astrocytoma
Type
Review Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 2 , Issue 1 , March 2007 , pp. 109 - 122
Copyright
© 2007 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abrahamsen, T.G., Lange, B.J., Packer, R.J., et al. (1995). A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors. Journal of Pediatric Hematology Oncology, 17, 134–139.Google Scholar
Allen, J.C., & Helson, L. (1981). High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. Journal of Neurosurgery, 55, 749–756.Google Scholar
Bobola, M.S., Berger, M.S., Ellenbogen, R.G., et al. (2001). O6-Methylguanine-DNA methyltransferase in pediatric primary brain tumors: relation to patient and tumor characteristics. Clinical Cancer Research, 7, 613–619.Google Scholar
Bottom, K.S., Ashley, D.M., Friedman, H.S., et al. (2000). Evaluation of pre-radiotherapy cyclophosphamide in patients with newly diagnosed glioblastoma multiforme. Writing Committee for The Brain Tumor Center at Duke. Journal of Neurooncology, 46, 151–156.Google Scholar
Castello, M.A., Clerico, A., Deb, G., et al. (1990). High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. American Journal of Pediatric Hematology Oncology, 12, 297–300.CrossRefGoogle Scholar
Cox, D.R., & Oakes, D. (1984). Analysis of Survival Data. London: Chapman and Hall.
Dohrmann, G.J., Farwell, J.R., Flannery, J.T., et al. (1976). Glioblastoma multiforme in children. Journal of Neurosurgery, 44, 442–448.Google Scholar
Esteller, M., Garcia-Foncillas, J., Andion, E., et al. (2000). Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New England Journal of Medicine, 343, 1350–1354.CrossRefGoogle Scholar
Finlay, J.L., Boyett, J.M., Yates, A.J., et al. (1995). Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group. Journal of Clinical Oncology, 13, 112–123.CrossRefGoogle Scholar
Finlay, J.L., Geyer, J.R., Turski, P.A., et al. (1994). Pre-irradiation chemotherapy in children with high-grade astrocytoma: tumor response to two cycles of the ‘8-drugs-in-1-day’ regimen. A Childrens Cancer Group study, CCG-945. Journal of Neurooncology, 21, 255–265.CrossRefGoogle Scholar
Finlay, J.L., August, C., Packer, R., et al. (1990). High-dose multi-agent chemotherapy followed by bone marrow rescue for malignant astrocytomas of childhood and adolescence. Journal of Neurooncology, 9, 239–248.Google Scholar
Grovas, A.C., Boyett, J.M., Lindsley, K., et al. (1999). Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme: report from the Children's Cancer Group. Medical Pediatric Oncology, 33, 83–87.3.0.CO;2-G>CrossRefGoogle Scholar
Heideman, R.L., Douglass, E.C., Langston, J.A., et al. (1995). A phase II study of every other day high-dose ifosfamide in pediatric brain tumors: a Pediatric Oncology Group Study. Journal of Neurooncology, 25, 77–84.CrossRefGoogle Scholar
Heideman, R.L., Douglass, E.C., Krance, R.A., et al. (1993). High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas. Journal of Clinical Oncology, 11, 1458–1465.CrossRefGoogle Scholar
Hongeng, S., Brent, T.P., Sanford, R.A., et al. (1997). O6-Methylguanine-DNA methyltransferase protein levels in pediatric brain tumors. Clinical Cancer Research, 3, 2459–2463.Google Scholar
Jeremic, B., Shibamoto, Y., Grujicic, D., et al. (1999). Pre-irradiation carboplatin and etoposide and accelerated hyperfractionated radiation therapy in patients with high-grade astrocytomas: a phase II study. Radiotherapy Oncology, 51, 27–33.CrossRefGoogle Scholar
Kalifa, C., & Grill, J. (2005). The therapy of infantile malignant brain tumors: current status? Journal of Neurooncology, 75 (3), 279–285. (review).Google Scholar
Kedar, A., Maria, B.L., Graham-Pole, J., et al. (1994). High-dose chemotherapy with marrow reinfusion and hyperfractionated irradiation for children with high-risk brain tumors. Medical Pediatric Oncology, 23, 428–436.CrossRefGoogle Scholar
Kuhl, J., Muller, H.L., Berthold, F., et al. (1998). Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT'88/'89. Klinische Padiatrie, 210, 227–233.CrossRefGoogle Scholar
Leibel, S.A., Sheline, G.E., Wara, W.M., et al. (1975). The role of radiation therapy in the treatment of astrocytomas. Cancer, 35, 1551–1557.3.0.CO;2-V>CrossRefGoogle Scholar
Marchese, M.J., & Chang, C.H. (1990). Malignant astrocytic gliomas in children. Cancer, 65, 2771–2778.3.0.CO;2-J>CrossRefGoogle Scholar
McCowage, G.B., Friedman, H.S., Moghrabi, A., et al. (1998). Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas. Medical Pediatric Oncology, 30, 75–80.3.0.CO;2-X>CrossRefGoogle Scholar
Pollack, I.F., Hamilton, R.L., Sobol, R.W., et al. (2006). O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort. Journal of Clinical Oncology, 24 (21), 3431–3437.CrossRefGoogle Scholar
Rilliet, B., & Vernet, O. (2000). Gliomas in children: a review. Childs Nervous System, 16, 735–741.CrossRefGoogle Scholar
Sheline, G.E. (1990). Radiotherapy for high grade gliomas. International Journal of Radiation Oncology Biology Physics, 18, 793–803.CrossRefGoogle Scholar
Silber, J.R., Blank, A., Bobola, M.S., et al. (1999). O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clinical Cancer Research, 5, 807–814.Google Scholar
Sposto, R., Ertel, I.J., Jenkin, R.D., et al. (1989). The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. Journal of Neurooncology, 7, 165–177.Google Scholar
van den Hauwe, L., Parizel, P.M., Martin, J.J., et al. (1995). Postmortem MRI of the brain with neuropathological correlation. Neuroradiology, 37, 343–349.CrossRefGoogle Scholar
Vinolas, N., Gil, M., Verger, E., et al. (2002). Pre-irradiation semi-intensive chemotherapy with carboplatin and cyclophosphamide in malignant glioma: a phase II study. Anticancer Drugs, 13, 163–167.CrossRefGoogle Scholar
Wisoff, J.H., Boyett, J.M., Berger, M.S., et al. (1998). Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group Trial No. CCG-945. Journal of Neurosurgery, 89, 52–59.CrossRefGoogle Scholar
Yule, S.M., Foreman, N.K., Mitchell, C., et al. (1997). High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study. Journal of Clinical Oncology, 15, 3258–3265.CrossRefGoogle Scholar