Journal of Neuro-Oncology

, Volume 86, Issue 2, pp 175–181 | Cite as

Pegylated-liposomal doxorubicin and oral topotecan in eight children with relapsed high-grade malignant brain tumors

  • Sabine Wagner
  • Ove Peters
  • Christin Fels
  • Gisela Janssen
  • Anne-Kathrin Liebeskind
  • Axel Sauerbrey
  • Meinolf Suttorp
  • Peter Hau
  • Johannes E. A. Wolff
Clinical-Patient Studies


Background: The combination of topoisomerase I and II chemotherapeutic agents has shown promising preclinical synergistic effects in the treatment of high-grade malignant brain tumors such as high-grade gliomas and choroid plexus carcinomas. To confirm the effectiveness of this treatment combination and determine its possible toxicity, we conducted a retrospective review of the charts of children who received the therapy. Methods: Patients with relapsed malignant brain tumors who were given an individualized treatment of pegylated (PEG)-liposomal doxorubicin and topotecan were included in our study. PEG-liposomal doxorubicin was given intravenously at a dosage of 30–40 mg/m2 over 4 h once every 4 weeks. Additionally, an intravenous formulation of topotecan was given orally twice daily and was increased on an individual basis from a starting dosage of 0.3 mg/m2 per application to a total daily dosage of 0.6 mg/m2. Results: Eight patients were included. The main toxicity (NCI-CTC) after three cycles of the combination therapy was grade IV hematotoxicity (n = 3); grade III hematotoxicity (n = 2), grade III stomatitis (n = 1), grade III infection (n = 2), grade III diarrhea (n = 1); and grade II dermatitis (n = 1). In four patients, stable disease was achieved for 9, 23, more than 24, and more than 48 weeks, respectively. Conclusion: The schedule of PEG-liposomal doxorubicin with 30–40 mg/m2 every 4 weeks in combination with oral topotecan resulted in tumor response, but the toxicity was high. An individualized increasing dose of PEG-liposomal doxorubicin 10–20 mg/m2 every two weeks is now recommended.


Liposomal doxorubicin Oral topotecan Children Brain tumors 



Supported by Deutsche Kinderkrebsstiftung.


  1. 1.
    Parimoo D, Garcia A, Roman L et al (2000) Phase I trial of liposomal doxorubicin-Doxil(d) and topotecan (t) in advanced pelvic malignancies. Proc Am Soc Clin Oncol 19:1616Google Scholar
  2. 2.
    Pautier P, Germann N, Faivre S et al (2000) Phase I study of Caelyx (KLX- Stealth stabilized liposomal doxorubcin-Doxil) in combination with topotecan. Proc Am Soc Clin Oncol 19:910Google Scholar
  3. 3.
    Hamilton A, Hochster H, Rosenthal M et al (2000) Continuous infusion topotecan (TP-Cl) with doxil (Dx): a phase I study of dual topoisomerase inhibition. Proc Am Soc Clin Oncol 19:777Google Scholar
  4. 4.
    Voest EE, Verhaar MJ (2001) A phase II study of the combination Doxil and topotecan in platinum resistant ovarian cancer. Proc Am Soc Clin Oncol 20:2479Google Scholar
  5. 5.
    Geertsen PF, Stroyer I, Herrstedt J et al (2001) Phase I study of topotecan (T) and pegylated liposomal doxorubicin (Caelyx) in patients (pts) with progressive ovarian cancer within 12 months after first-line platinum-paclitaxel containing chemotherapy. Proc Am Soc Clin Oncol 20:2479Google Scholar
  6. 6.
    Blum RH, Carter SK (1974) Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med 80:249–259PubMedGoogle Scholar
  7. 7.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRefGoogle Scholar
  8. 8.
    De Graff WG, Myers LS Jr, Mitchell JB et al (2003) Protection against Adriamycin (R) cytotoxicity and inhibition of DNA topoisomerase II activity by 3,4-dihydroxybenzoic acid. Int J Oncol 23:159–163PubMedGoogle Scholar
  9. 9.
    Burden DA, Osheroff N (1998) Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1400:139–154PubMedGoogle Scholar
  10. 10.
    Bottero V, Busuttil V, Loubat A et al (2001) Activation of nuclear factor κB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells. Cancer Res 61:7785–7791PubMedGoogle Scholar
  11. 11.
    Wolff JE, Trilling T, Molenkamp G et al (1999) Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol 125:481–486PubMedCrossRefGoogle Scholar
  12. 12.
    Stan AC, Casares S, Radu D et al (1999) Doxorubicin-induced cell death in highly invasive human gliomas. Anticancer Res 19:941–950PubMedGoogle Scholar
  13. 13.
    Valdivieso M, Burgess MA, Ewer MS et al (1984) Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study. J Clin Oncol 2:207–214PubMedGoogle Scholar
  14. 14.
    Paridaens R (1998) Efficacy of paclitaxel or doxorubicin used as single agents in advanced breast cancer: a literature survey. Semin Oncol 25:3–6PubMedGoogle Scholar
  15. 15.
    Siegal T, Horowitz A, Gabizon A (1995) Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 83:1029–1037PubMedGoogle Scholar
  16. 16.
    Vaage J, Barbera-Guillem E, Abra R et al (1994) Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts. Cancer 73:1478–1784PubMedCrossRefGoogle Scholar
  17. 17.
    Gabizon A, Martin F (1997) Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 54:15–21PubMedCrossRefGoogle Scholar
  18. 18.
    Allen TM (1998) Liposomal drug formulations. Rationale for development and what we can expect for the future. Drugs 56:747–756PubMedCrossRefGoogle Scholar
  19. 19.
    Wagner S, Erdlenbruch B, Langler A et al (2004) Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for pediatric oncology and hematology. Cancer 100:1750–1757PubMedCrossRefGoogle Scholar
  20. 20.
    MacDonald D, Cairncross G, Stewart D et al (1996) National Clinical Institute of Canada Clinical Trials Group. Phase II study of topotecan in patients with recurrent malignant glioma. Ann Oncol 7:205–207PubMedGoogle Scholar
  21. 21.
    Blaney SM, Phillips PC, Packer RJ et al (1996) Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78:527–531PubMedCrossRefGoogle Scholar
  22. 22.
    Friedman HS, Kerby T, Fields S et al (1999) Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke. Cancer 85:1160–1116PubMedCrossRefGoogle Scholar
  23. 23.
    McCabe FL, Johnson RK (1994) Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan. Cancer Invest 12:308–313PubMedCrossRefGoogle Scholar
  24. 24.
    De Cesare M, Zunino F, Pace S et al (2000) Efficacy and toxicity profile of oral topotecan in a panel of human tumor xenografts. Eur J Cancer 36:1558–1564PubMedCrossRefGoogle Scholar
  25. 25.
    Pratesi G, De Cesare M, Zunino F (2000) Improvement of therapeutic index of low-dose topotecan delivered per os. Ann NY Acad Sci 922:330–333PubMedCrossRefGoogle Scholar
  26. 26.
    Saylors RL 3rd, Stine KC, Sullivan J et al (2001) Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19:3463–3469PubMedGoogle Scholar
  27. 27.
    Wolff JE, Molenkamp G, Westphal S, Pietsch T, Gnekow A, Kortmann RD, Kuehl J (2000) Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Cancer 89:2131–2137PubMedCrossRefGoogle Scholar
  28. 28.
    Fabel K, Dietrich J, Hau P et al (2001) Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer 92:1936–1942PubMedCrossRefGoogle Scholar
  29. 29.
    Hau P, Fabel K, Baumgart U et al (2004) Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 100:1199–1207PubMedCrossRefGoogle Scholar
  30. 30.
    Olson F, Mayhew E, Maslow D, Rutsum Y, Szoka F (1982) Characterization, toxicity and therapeutic efficacy of adriamycin encapsulated in liposomes. Eur J Cancer Clin Oncol 18:167–176PubMedCrossRefGoogle Scholar
  31. 31.
    Harris L, Batist G, Belt R et al (2002) TLC D-99 Study Group. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94:25–36PubMedCrossRefGoogle Scholar
  32. 32.
    Lyass O, Uziely B, Ben-Yosef R et al (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037–1047PubMedCrossRefGoogle Scholar
  33. 33.
    Marina NM, Cochrane D, Harney E et al (2002) Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study. Clin Cancer Res 8:413–418PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Sabine Wagner
    • 1
    • 2
  • Ove Peters
    • 1
    • 2
  • Christin Fels
    • 1
    • 2
  • Gisela Janssen
    • 3
  • Anne-Kathrin Liebeskind
    • 4
  • Axel Sauerbrey
    • 5
  • Meinolf Suttorp
    • 6
  • Peter Hau
    • 7
  • Johannes E. A. Wolff
    • 2
    • 8
  1. 1.Department of Pediatric OncologyKrankenhaus der Barmherzigen BrüderRegensburgGermany
  2. 2.University of RegensburgRegensburgGermany
  3. 3.Department of Pediatric OncologyUniversity of DüsseldorfDusseldorfGermany
  4. 4.Department of Pediatric OncologyHELIOS-Klinikum Berlin-BuchBerlinGermany
  5. 5.Department of Pediatric OncologyHelios KlinikumErfurtGermany
  6. 6.Department of Pediatric OncologyUniversity of DresdenDresdenGermany
  7. 7.Department of Neuro-OncologyUniversity of Regensburg, District Medical CenterRegensburgGermany
  8. 8.Department of Pediatrics, Unit 87The University of Texas M.D. Anderson Cancer CenterHoustonUSA

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