Advertisement

Journal of Neuro-Oncology

, Volume 77, Issue 2, pp 193–198 | Cite as

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children’s oncology group

  • Murali M. ChintagumpalaEmail author
  • Henry S. Friedman
  • Clinton F. Stewart
  • James Kepner
  • Roger E. McLendon
  • Paul L. Modrich
  • Charles McCluggage
  • Peter Burger
  • Emi Holmes
  • Stephen Thompson
  • James Rutka
  • Jeff Michalski
  • Shiao Woo
  • Susan M. Blaney
  • Larry E. Kun
  • and Marc E. Horowitz
  • A Pediatric Oncology Group Study
Clinical-patient studies

Summary

The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Keywords

AGT activity in high-grade glioma in children high-grade glioma in children mismatch repair proteins in high-grade glioma in children phase II window therapy in high-grade glioma in children procarbazine in high-grade glioma in children resistance mechanisms in high-grade glioma in children topotecan in high-grade glioma in children 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Cohen ME, Duffner PK, Tebbi CK: Brain tumors in children: Diagnosis and management. In: Cameron K. Tebbi (ed) Major Topics in Pediatric and Adolescent Oncology. G.K. Hall and Co., Boston, 1982Google Scholar
  2. 2.
    Sposto R, Ertel IJ, Jenkin RDT, et al The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: Results of a randomized trial J Neuro Oncol 7: 165–177, 1989CrossRefGoogle Scholar
  3. 3.
    Finlay JL, Boyett JM, Yates AL, et al Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen J Clin Oncol 13(1):112–123, 1995PubMedGoogle Scholar
  4. 4.
    Horowitz ME, Etcubanas E, Christensen ML, Houghton JA, George SL, Green AA, Houghton PJ: Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: A model for anticancer drug development J Clin Oncol 6(2):308–314, 1988PubMedGoogle Scholar
  5. 5.
    Smith MA, Anderson B, Phase II window studies: 10 years of experience and counting J Pediatric Hematol Oncol 23(6):334–337, 2001CrossRefGoogle Scholar
  6. 6.
    Green SB, Byar DP, Walker MD, et al Comparisons of carmustine, procarbazine, and high-dose methylprednisone as additions to surgery and radiotherapy for the treatment of malignant glioma Cancer Treat Rpts 67(2): 121–132, 1983Google Scholar
  7. 7.
    Newton HB, Junck L, Bromberg J, et al Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure Neurology 40:1743–1746, 1990PubMedGoogle Scholar
  8. 8.
    Kumar ARV, Renaudin J, Wilson CB, et al Procarbazine hydrochloride in the treatment of brain tumors Neurosurgery 40:365–371, 1974Google Scholar
  9. 9.
    Newton HB, Bromberg J, Junck L, et al Comparison between BCNU and procarbazine chemotherapy for treatment of gliomas J Neuro Oncol 15:257–263, 1993CrossRefGoogle Scholar
  10. 10.
    Levin VA, Silver P, Hannigan J, et al Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report Int J Radiat Oncol 18(2):321–324, 1990CrossRefGoogle Scholar
  11. 11.
    Friedman HS, Houghton PJ, Schold SC, et al Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts Can Chem Phar 32(2):171–174, 1994Google Scholar
  12. 12.
    Blaney SM, Balis FM, Cole DE, et al Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion Can Res 53:1032–1036, 1993Google Scholar
  13. 13.
    Pratt CB, Stewart C, Santana VM, et al Phase I study of topotecan for pediatric patients with malignant solid tumors J Clin Oncol 12(3):539–543, 1994PubMedGoogle Scholar
  14. 14.
    Schold SC Jr, Brent TP, von Hofe E, Friedman HS, Mitra S, Bigner DD, Swenberg JA, Kleihues P, O6-alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts J Neurosurg 70(4):573–577, 1989PubMedCrossRefGoogle Scholar
  15. 15.
    Friedman HS, Johnson SP, Dong Q, et al Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft Cancer Res 57(14):2933–2936, 1997PubMedGoogle Scholar
  16. 16.
    Friedman HS, McLendon RE, Kerby T et al.: DNA mismatch repair and O-alkylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 16(12): 3851–3857Google Scholar
  17. 17.
    Pratt CB, Stewart CF, Santana VM, Bowman L, Furman W, Ochs J, Marina N, Kuttesch JF, Heideman R, Sandlund JT, Avery L, Meyer WH, Phase I study of topotecan for pediatric patients with malignant solid tumors J Clin Oncol 12:539, 1994PubMedGoogle Scholar
  18. 18.
    Zamboni WC, Stewart CF, Thompson J, Santana VM, Cheshire PJ, Richmond LB, Xiaolong Luo, Poquette C, Houghton JA, Houghton PJ, Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts JNCI 90:505, 1998PubMedCrossRefGoogle Scholar
  19. 19.
    D’Argenio DZ, Schumitzky A: ADAPT II User’s Guide, 1st edn. Biomedical Simulations Resource, USC, Los Angeles, 1990Google Scholar
  20. 20.
    Gibaldi M, Perrier D: Pharmacokinetics, 2nd edn. New York, 1982Google Scholar
  21. 21.
    McLendon RE, Cleveland L, Pegram C, et al Immunohistochemical detection of the DNA repair enzyme O6-methylguanine-DNA methyltransferase in formalin-fixed paraffin-embedded astrocytomas Lab Invest 78:643–644, 1998PubMedGoogle Scholar
  22. 22.
    Harris LC, Potter PM, Remack JS, et al A comparison of human O6-methylguanine-DNA methyltransferase promoter activity in Mer+ and Mer cells Cancer Res 52:6404–6406, 1992PubMedGoogle Scholar
  23. 23.
    Harris LC, von Wronski MA, Venable CC, et al Changes in O6-methylguanine-DNA methyltransferase expression during immortalization of cloned human fibroblasts Carcinogenesis 17:219–224, 1996PubMedCrossRefGoogle Scholar
  24. 24.
    Stewart: Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor (PNET) J Clin Oncol 22(16):3357–65, 2004PubMedCrossRefGoogle Scholar
  25. 25.
    von Wronski MA, Brent TP, Effect of 5-azacytidine on expression of the human DNA repair enzyme O6-methylguanine-DNA methyltransferase Carcinogenesis 15:577–582, 1994CrossRefGoogle Scholar
  26. 26.
    Chang MN, Therneau TM, Wieand HS, Cha SS, Designs for group sequential phase II clinical trials Biometrics 43:865–875, 1987PubMedCrossRefGoogle Scholar
  27. 27.
    Chang MN, O’Brien PC, Confidence intervals following group sequential tests Controlled Clin Trials 7:18–26, 1986PubMedCrossRefGoogle Scholar
  28. 28.
    Friedman HS, Kokkinakis DM, Pluda J, Friedman AH, Cokgor I, Haglund MM, Ashley DM, Rich J, Dolan ME, Pegg AE, Moschel RC, McLendon RE, Kerby T, Herndon JE, Bigner DD, Schold Jr SC, Phase I trial of O6-Benzylguanine for patients undergoing surgery for malignant glioma J Clin Oncol 16:3570–3575, 1998PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Murali M. Chintagumpala
    • 1
    • 8
    Email author
  • Henry S. Friedman
    • 2
  • Clinton F. Stewart
    • 3
  • James Kepner
    • 4
  • Roger E. McLendon
    • 2
  • Paul L. Modrich
    • 2
  • Charles McCluggage
    • 1
  • Peter Burger
    • 5
  • Emi Holmes
    • 4
  • Stephen Thompson
    • 3
  • James Rutka
    • 6
  • Jeff Michalski
    • 7
  • Shiao Woo
    • 1
  • Susan M. Blaney
    • 1
  • Larry E. Kun
    • 3
  • and Marc E. Horowitz
    • 1
  • A Pediatric Oncology Group Study
  1. 1.Baylor College of MedicineHoustonUSA
  2. 2.Duke University Medical CenterDurhamUSA
  3. 3.St Jude Children’s Research HospitalMemphisUSA
  4. 4.Children’s Oncology Group Operations CenterArcadiaUSA
  5. 5.The Johns Hopkins HospitalBaltimoreUSA
  6. 6.Toronto Sick Children’s HospitalTorontoUSA
  7. 7.Washington University Medical SchoolSt. LouisUSA
  8. 8.Baylor College of MedicineHoustonUSA

Personalised recommendations