Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m2 on days 1–5 and VP-16 50 mg/m2 on days 1–8; (2) TMZ 150 mg/m2 on days 1–5 and VP-16 50 mg/m2 on days 1–8; (3) TMZ 150 mg/m2 on days 1–5 and VP-16 50 mg/m2 on days 1–10; (4) TMZ 150 mg/m2 on days 1–5 and VP-16 50 mg/m2 on days 1–12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m2 for 5 days and VP-16 50 mg/m2 for 10 days every 28 days.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Finlay JL, Wisoff JH (1999) The impact of extent of resection in the management of malignant gliomas of childhood. Child’s Nerv Syst 15:786–788

    Article  CAS  Google Scholar 

  2. Finlay JL, Boyett JM, Yates AJ et al (1995) A randomized phase III trial in childhood high grade astrocytoma comparing vincristine, CCNU, and prednisone with the “eight-drugs-in-one-day” regimen: a report of the Children’s Cancer Group trial CCG-945. J Clin Oncol 13:112–123

    PubMed  CAS  Google Scholar 

  3. Lashford LS, Thiesse P, Jouvet A et al (2002) Temozolomide in malignant gliomas of childhood: a United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol 20:4684–4691

    Article  PubMed  CAS  Google Scholar 

  4. Finlay JL, Goldman S, Wong MC et al (1996) A pilot study of high dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent central nervous system tumors. J Clin Oncol 14:2495–2503

    PubMed  CAS  Google Scholar 

  5. Hodgson DC, Goumnerova LC, Loeffler JS et al (2001) Radiosurgery in the management of pediatric brain tumors. Int J Rad Oncol Biol Phys 50:929–935

    Article  CAS  Google Scholar 

  6. Fiorillo A, Maggi G, Greco N et al (2004) Second-line chemotherapy with the association of liposomal daunorubicin, carboplatin and etoposide in children with recurrent malignant brain tumors. J Neurooncol 66:179–185

    Article  PubMed  Google Scholar 

  7. Bouffet E, Mottolese C, Jouvet A et al (1997) Etoposide and thiotepa followed by ABMT (autologous bone marrow transplantation) in children and young adults with high-grade gliomas. Eur J Cancer 33(1):91–95

    Article  PubMed  CAS  Google Scholar 

  8. McCowage GB, Friedman HS, Moghrabi A et al (1998) Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas. Med Pediatr Oncol 30:75–80

    Article  PubMed  CAS  Google Scholar 

  9. Friedman HS, Krischer JP, Burger P et al (1992) Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study. J Clin Oncol 10:249–256

    PubMed  CAS  Google Scholar 

  10. Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7:241–248

    Article  PubMed  Google Scholar 

  11. Lilley ER, Rosenberg MC, Elion GB, Colvin OM, Bigner DD, Friedman HS (1990) Synergistic interactions between cyclophosphamide or melphalan and VP-16 in a human rhabdomyosarcoma xenograft. Cancer Res 50:284–287

    PubMed  CAS  Google Scholar 

  12. Patel VJ, Elion GB, Houghton PJ et al (2000) Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. Clin Cancer Res 6:4154–4157

    PubMed  CAS  Google Scholar 

  13. Ruggiero A, Rizzo D, Attinà G et al (2010) Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma. Eur J Cancer 46:2943–2949

    Article  PubMed  CAS  Google Scholar 

  14. Korones DN, Benita-Weiss M, Coyle TE et al (2003) Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma. Cancer 97:1963–1968

    Article  PubMed  CAS  Google Scholar 

  15. Korones DN, Smith A, Foreman N, Bouffet E (2006) Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas. Pediatr Blood Cancer 47:37–41

    Article  PubMed  Google Scholar 

  16. Marsoni S, Ungerleider RS, Hurson SB, Simon RM, Hammershaimb LD (1985) Tolerance to antineoplastic agents in children and adults. Cancer Treat Rep 69:1263–1269

    PubMed  CAS  Google Scholar 

  17. Smith M, Ho PT (1996) Pediatric drug development: a perspective from the cancer therapy evaluation program (CTEP) of the National Cancer Institute (NCI). Invest New Drugs 14:11–22

    Article  PubMed  CAS  Google Scholar 

  18. Le Tourneau C, Lee JJ, Siu LL (2009) Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101:708–720

    Article  PubMed  Google Scholar 

  19. Stupp R, Dietrich PY, Ostermann Kraljevic S et al (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375–1382

    Article  PubMed  CAS  Google Scholar 

  20. Available from URL: http://ctep.cancer.gov/forms/CTCAE.pdf

  21. Nicholson HS, Kretschmar CS, Krailo M et al (2007) Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children’s Oncology Group. Cancer 110:1542–1550

    Article  PubMed  CAS  Google Scholar 

  22. Chamberlain MC, Kormanik PA (1997) Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol 17:230–234

    Article  PubMed  CAS  Google Scholar 

  23. Ashley DM, Meier L, Kerby T et al (1996) Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 14:1922–1927

    PubMed  CAS  Google Scholar 

  24. Needle MN, Molloy PT, Geyer JR et al (1997) Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol 29:28–32

    Article  PubMed  CAS  Google Scholar 

  25. Ridola V, Barone G, Lazzareschi I, Ruggiero A, Rizzo D, Riccardi R (2011) Feasibility study of 21-day-on/7-day-off temozolomide in children with brain tumors. J Neurooncol 103:147–153

    Article  PubMed  CAS  Google Scholar 

  26. Ruggiero A, Cefalo G, Garré ML et al (2006) Phase II trial of temozolomide in children with recurrent high-grade glioma. J Neurooncol 77:89–94

    Article  PubMed  CAS  Google Scholar 

  27. Verschuur AC, Grill J, Lelouch-Tubiana A, Couanet D, Kalifa C, Vassal G (2004) Temozolomide in paediatric high-grade glioma: a key for combination therapy? Br J Cancer 91:425–429

    Article  PubMed  CAS  Google Scholar 

  28. Toffoli G, Corona G, Basso B, Boiocchi M (2004) Pharmacokinetic optimisation of treatment with oral etoposide. Clin Pharmacokinet 43:441–466

    Article  PubMed  CAS  Google Scholar 

  29. Relling MV, Mahmoud HH, Pui CH et al (1996) Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin Oncol 14:399–404

    PubMed  CAS  Google Scholar 

  30. Kiya K, Uozumi T, Ogasawara H et al (1992) Penetration of etoposide into human malignant brain tumors after intravenous and oral administration. Cancer Chemother Pharmacol 29:339–342

    Article  PubMed  CAS  Google Scholar 

  31. Slevin ML, Clark PI, Joel SP et al (1989) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:1333–1340

    PubMed  CAS  Google Scholar 

  32. Hande KR, Krozely MG, Greco FA, Hainsworth JD, Johnson DH (1993) Bioavailability of low-dose oral etoposide. J Clin Oncol 11:374–377

    PubMed  CAS  Google Scholar 

  33. de Jong RS, Mulder NH, Dijksterhuis D, de Vries EG (1995) Review of current clinical experience with prolonged (oral) etoposide in cancer treatment. Anticancer Res 15:2319–2330

    PubMed  Google Scholar 

  34. Chamberlain MC (1993) Recurrent brainstem gliomas treated with oral VP-16. J Neurooncol 15:133–139

    Article  PubMed  CAS  Google Scholar 

  35. Chamberlain MC, Grafe MR (1995) Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. J Clin Oncol 13:2072–2076

    PubMed  CAS  Google Scholar 

  36. Chamberlain MC (1997) Recurrent cerebellar gliomas: salvage therapy with oral etoposide. J Child Neurol 12:200–204

    Article  PubMed  CAS  Google Scholar 

  37. Chamberlain MC (1997) Recurrent supratentorial malignant gliomas in children. Long-term salvage therapy with oral etoposide. Arch Neurol 54:554–558

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Oncology Division, Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168, Rome, Italy

    Antonio Ruggiero, Daniela Rizzo, Giorgio Attinà, Ilaria Lazzareschi, Palma Maurizi, Vita Ridola, Stefano Mastrangelo & Riccardo Riccardi

  2. Pediatric Oncology Division, Pausilipon Children’s Hospital, Naples, Italy

    Roberta Migliorati

  3. Pediatric Oncology, University-Hospital of Parma, Parma, Italy

    Patrizia Bertolini

  4. Department of Bio-Images and Radiological Sciences, “A. Gemelli” Hospital, Catholic University, Rome, Italy

    Cesare Colosimo

Authors
  1. Antonio Ruggiero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giorgio Attinà
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilaria Lazzareschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Palma Maurizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vita Ridola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefano Mastrangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roberta Migliorati
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patrizia Bertolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cesare Colosimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Riccardo Riccardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniela Rizzo.

Additional information

Antonio Ruggiero and Daniela Rizzo contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruggiero, A., Rizzo, D., Attinà, G. et al. Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors. J Neurooncol 113, 513–518 (2013). https://doi.org/10.1007/s11060-013-1145-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-013-1145-z

Keywords

Search

Navigation