Advertisement

Journal of Neuro-Oncology

, Volume 82, Issue 1, pp 95–101 | Cite as

Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme

  • Christopher D. Turner
  • Susan Chi
  • Karen J. Marcus
  • Tobey MacDonald
  • Roger J. Packer
  • Tina Young Poussaint
  • Sridhar Vajapeyam
  • Nicole Ullrich
  • Liliana C. Goumnerova
  • R. Michael Scott
  • Caitlin Briody
  • Christine Chordas
  • Mary Ann Zimmerman
  • Mark W. Kieran
Clinical–Patient Studies

Abstract

A phase II study was conducted to assess the efficacy of administering daily thalidomide concomitantly with radiation and continuing for up to 1 year following radiation in children with brain stem gliomas (BSG) or glioblastoma multiforme (GBM). Secondary objectives were to obtain preliminary evidence of biologic activity of thalidomide and to evaluate toxicities from chronic administration of thalidomide in this population.

Thirteen patients (2–14 years old) with newly diagnosed BSG (12 patients) or GBM (one patient) were enrolled between July 1999 and June 2000. All patients received focal radiotherapy to a total dose of 5,580 cGy. Thalidomide was administered once daily beginning on the first day of radiation and continued for 12 months or until the patient came off study. The starting dose was 12 mg/kg (rounded down to the nearest 50 mg) and was increased by 20% weekly, if tolerated, to 24 mg/kg or 1,000 mg (whichever was lower). Advanced imaging techniques and urine and serum analysis for anti-angiogenic markers were performed in some patients in an attempt to correlate changes with clinical effect of therapy.

No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression. The median duration of therapy was 5 months (range 2–11 months). Nine patients came off study for progressive disease (PD), three patients due to toxicity and one patient withdrew consent. Several patients on this study required more extended courses of high dose steroids than would have been otherwise expected for this population due to significant peritumoral edema and necrosis. No consistent pattern emerged from the biologic correlative studies from 11 patients. However, advanced imaging with techniques such as MR spectroscopy, MR perfusion and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were helpful in distinguishing growing tumor from treatment effect and necrosis in some patients.

The median time to progression (TTP) was 5 months (range 2–11 months) and the median time to death (TTD) was 9 months (range 5–17 months). In this small patient sample adding thalidomide to radiation did not improve TTP or TTD from historical controls, however, toxicity appeared to be increased.

Keywords

Thalidomide Radiation therapy Children Brain stem glioma Glioblastoma multiforme Advanced MR techniques Biologic correlative studies 

Abbreviations

DFCHCC

Dana-Farber/Children’s Hospital Cancer Center

CNMC

Children’s National Medical Center

GBM

Glioblastoma multiforme

BSG

Brain stem glioma

LDH

Lactate dehydrogenase

PD

Progressive disease

SD

Stable disease

PR

Partial response

CR

Complete response

bFGF

Basic fibroblastic growth factor

PDGF

Platelet derived growth factor

VEGF

Vascular endothelial growth factor

S.T.E.P.S.®

System for Thalidomide Education and Prescribing Safety

FDG PET

18-Fluorodeoxyglucose positron emission tomography

TTP

Time to progression

TTD

Time to death

Notes

Acknowledgements

A preliminary report of data from this study was presented in part at the Tenth International Symposium for Pediatric Neuro-Oncology in June 2002. Support for this study was provided through the Stop & Shop Family Pediatric Brain Tumor Program. Costs of data management were supported by Celgene Pharmaceuticals Corporation.

References

  1. 1.
    Jennings MT, Sposto R, Boyett JM et al (2002) Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children’s Cancer Group. J Clin Oncol 20:3431–3437PubMedCrossRefGoogle Scholar
  2. 2.
    Freeman CR, Kepner J, Kun LE et al (2000) A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys 47:561–564PubMedCrossRefGoogle Scholar
  3. 3.
    Marcus KJ, Dutton SC, Barnes P et al (2003) A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma. Int J Radiat Oncol Biol Phys 55:1182–1185PubMedCrossRefGoogle Scholar
  4. 4.
    Benesch M, Lackner H, Moser A et al (2001) Outcome and long-term side effects after synchronous radiochemotherapy for childhood brain stem gliomas. Pediatr Neurosurg 35:173–180PubMedCrossRefGoogle Scholar
  5. 5.
    Walker DA, Punt JA, Sokal M (1999) Clinical management of brain stem glioma. Arch Dis Child 80:558–564PubMedCrossRefGoogle Scholar
  6. 6.
    Freeman CR, Perilongo G (1999) Chemotherapy for brain stem gliomas. Childs Nerv Syst 15:545–553PubMedCrossRefGoogle Scholar
  7. 7.
    Fine HA, Figg WD, Jaeckle K et al (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18:708–715PubMedGoogle Scholar
  8. 8.
    Fanelli M, Sarmiento R, Gattuso D et al (2003) Thalidomide: a new anticancer drug? Expert Opin Investig Drugs 12:1211–1225PubMedCrossRefGoogle Scholar
  9. 9.
    Fine HA, Wen PY, Maher EA et al (2003) Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol 21:2299–2304PubMedCrossRefGoogle Scholar
  10. 10.
    Crane E, List A (2005) Immunomodulatory drugs. Cancer Invest 23:625–634PubMedCrossRefGoogle Scholar
  11. 11.
    Teo SK (2005) Properties of thalidomide and its analogues: implications for anticancer therapy. Aaps J 7:E14–E19PubMedCrossRefGoogle Scholar
  12. 12.
    Mitsiades N, Mitsiades CS, Poulaki V et al (2002) Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99:4525–4530PubMedCrossRefGoogle Scholar
  13. 13.
    Fleming FJ, Vytopil M, Chaitow J et al (2005) Thalidomide neuropathy in childhood. Neuromuscul Disord 15:172–176PubMedCrossRefGoogle Scholar
  14. 14.
    Short SC, Traish D, Dowe A et al (2001) Thalidomide as an anti-angiogenic agent in relapsed gliomas. J Neurooncol 51:41–45PubMedCrossRefGoogle Scholar
  15. 15.
    Cha S (2006) Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging in pediatric patients. Neuroimag Clin N Am 16:137–147, ixGoogle Scholar
  16. 16.
    Freeman CR, Farmer JP (1998) Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40:265–271PubMedCrossRefGoogle Scholar
  17. 17.
    Carrie C, Negrier S, Gomez F et al (2004) Diffuse medulla oblongata and pontine gliomas in childhood. A review of 37 cases. Bull Cancer 91:E167–E183PubMedGoogle Scholar
  18. 18.
    Farmer JP, Montes JL, Freeman CR et al (2001) Brainstem Gliomas. A 10-year institutional review. Pediatr Neurosurg 34:206–214PubMedCrossRefGoogle Scholar
  19. 19.
    Kaplan AM, Albright AL, Zimmerman RA et al (1996) Brainstem gliomas in children. A Children’s Cancer Group review of 119 cases. Pediatr Neurosurg 24:185–192PubMedCrossRefGoogle Scholar
  20. 20.
    Packer RJ, Boyett JM, Zimmerman RA et al (1993) Hyperfractionated radiation therapy (72 Gy) for children with brain stem gliomas. A Childrens Cancer Group Phase I/II Trial. Cancer 72:1414–1421PubMedCrossRefGoogle Scholar
  21. 21.
    Reddy AT, Mapstone TB (2000) Brain stem tumors. In: Bernstein M, Berger MS (eds) Neuro-oncology: the essentials. Thieme Medical Publishers, Inc., New York, pp 352–362Google Scholar
  22. 22.
    Baumann F, Bjeljac M, Kollias SS et al (2004) Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J Neurooncol 67:191–200PubMedCrossRefGoogle Scholar
  23. 23.
    Chang SM, Lamborn KR, Malec M et al (2004) Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 60:353–357PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Christopher D. Turner
    • 1
  • Susan Chi
    • 1
  • Karen J. Marcus
    • 2
  • Tobey MacDonald
    • 3
  • Roger J. Packer
    • 3
  • Tina Young Poussaint
    • 4
  • Sridhar Vajapeyam
    • 4
  • Nicole Ullrich
    • 5
  • Liliana C. Goumnerova
    • 6
  • R. Michael Scott
    • 6
  • Caitlin Briody
    • 1
  • Christine Chordas
    • 1
  • Mary Ann Zimmerman
    • 1
  • Mark W. Kieran
    • 1
  1. 1.Department of Pediatric OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of MedicineDivision of Radiation Oncology, Children’s Hospital BostonBostonUSA
  3. 3.Departments of Neurology and Hematology/OncologyChildren’s National Medical CenterWashingtonUSA
  4. 4.Department of RadiologyChildren’s Hospital BostonBostonUSA
  5. 5.Department of NeurologyChildren’s Hospital BostonBostonUSA
  6. 6.Department of NeurosurgeryChildren’s Hospital BostonBostonUSA

Personalised recommendations