Journal of Neuro-Oncology

, Volume 67, Issue 1–2, pp 191–200 | Cite as

Combined Thalidomide and Temozolomide Treatment in Patients with Glioblastoma Multiforme

  • Fabian Baumann
  • Miroslava Bjeljac
  • Spyros S. Kollias
  • Brigitta G. Baumert
  • Sebastian Brandner
  • Valentin Rousson
  • Yasuhiro Yonekawa
  • René L. Bernays


Objectives: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study.

Patients and methods: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system.

Results: Median survival was 103 weeks (95% CI, 65–141 weeks) for TT-patients and 63 weeks (95% CI, 49–77 weeks) for T-patients (p <  0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20–52 weeks) and 17 weeks (95% CI, 13–21 weeks) for the T-group (p <  0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities.

Conclusions: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.

antiangiogenic therapy brain chemotherapy glioblastoma multiforme survival temozolomide thalidomide treatment 


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  1. 1.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95: 190–198, 2001PubMedGoogle Scholar
  2. 2.
    Nieder C, Grosu AL, Molls M: A comparison of treatment results for recurrent malignant gliomas. Cancer Treat Rev 26: 397–409, 2000PubMedGoogle Scholar
  3. 3.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17: 2572, 1999PubMedGoogle Scholar
  4. 4.
    Surawics TS, Davis F, Freels S, Laws ER Jr, Menck HR: Brain tumor survival: results from the National Cancer Data Base. J Neuro-Oncol 40: 151–160, 1998Google Scholar
  5. 5.
    Prados MD, Levin V: Biology and treatment of malignant glioma. Semin Oncol 27: 1–10, 2000PubMedGoogle Scholar
  6. 6.
    Stewart LA: Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359: 1011–1018, 2002PubMedGoogle Scholar
  7. 7.
    Forsting M, Albert FK, Kunze S, Adams HP, Zenner D, Sartor K: Extirpation of glioblastomas. MR and CT follow-up of residual tumor and regrowth patterns. Am J Neuroradiol 14: 77–87, 1993PubMedGoogle Scholar
  8. 8.
    Shrieve DC, Alexander E III, Black PM, Wen PY, Fine HA, Kooy HM, Loeffler JS: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90: 72–77, 1999PubMedGoogle Scholar
  9. 9.
    Schiffer D, Chio A, Giordana MT, Mauro A, Migheli A, Vigliani MC: The vascular response to tumor infiltration in malignant gliomas. Morphometric and reconstruction study. Acta Neuropathol (Berl) 77: 369–378, 1989Google Scholar
  10. 10.
    Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848, 1992CrossRefPubMedGoogle Scholar
  11. 11.
    D'Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91: 4082–4085, 1994PubMedGoogle Scholar
  12. 12.
    Fine HA, Figg WD, Jaeckle K, Kyritsis AP, Loeffler JS, Levin VA, Black PM, Kaplan R, Pluda JM, Yung WK: Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708–715, 2000PubMedGoogle Scholar
  13. 13.
    Marx GM, Pavlakis N, McCowatt S, Boyle FM, Levi JA, Bell DR, Cook R, Biggs M, Little N, Wheeler HR: Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme. J Neuro-Oncol 54: 31–38, 2001CrossRefGoogle Scholar
  14. 14.
    Short SC, Traish D, Dowe A, Hines F, Gore M, Brada M: Thalidomide as an anti-angiogenic agent in relapsed gliomas. J Neuro-Oncol 51: 41–45, 2001CrossRefGoogle Scholar
  15. 15.
    Newlands ES, O'Reilly SM, Glaser MG, Bower M, Evans H, Brock C, Brampton MH, Colquhoun I, Lewis P, Rice-Edwards JM, Illingworth RD, Richards PG: The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer 32A: 2236–2241, 1996PubMedGoogle Scholar
  16. 16.
    Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83: 588–593, 2000CrossRefPubMedGoogle Scholar
  17. 17.
    Stupp R, Dietrich PY, Ostermann KS, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S: 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, 2002CrossRefPubMedGoogle Scholar
  18. 18.
    Marx J: Angiogenesis.Aboost for tumor starvation. Science 301: 452–454, 2003PubMedGoogle Scholar
  19. 19.
    Adlard JW: Thalidomide in the treatment of cancer. Anticancer Drugs 11: 787–791, 2000PubMedGoogle Scholar
  20. 20.
    Singhal S, Mehta J: Thalidomide in cancer: potential uses and limitations. BioDrugs 15: 163–172, 2001CrossRefPubMedGoogle Scholar
  21. 21.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8: 1277–1280, 1990PubMedGoogle Scholar
  22. 22.
    Kleihues P, Burger PC, Collins VP, Newcomb EW, Ohgaki H, Cavanee WK: Pathology and Genetics: Tumours of the Nervous System. IARC Press (International Agency for Research on Cancer), Lyon, France 2000, pp 29–39Google Scholar
  23. 23.
    Wesseling P, Ruiter DJ, Burger PC: Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neuro-Oncol 32: 253–265, 1997CrossRefGoogle Scholar
  24. 24.
    Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey LE: A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Neuro-Oncology 4: 39–43, 2002CrossRefPubMedGoogle Scholar
  25. 25.
    Moller DR, Wysocka M, Greenlee BM, Ma X, Wahl L, Flockhart DA, Trinchieri G, Karp CL: Inhibition of IL-12 production by thalidomide. J Immunol 159: 5157–5161, 1997PubMedGoogle Scholar
  26. 26.
    Flageul B, Wallach D, Cavelier-Balloy B, Bachelez H, Carsuzaa F, Dubertret L: Thalidomide and thrombosis. Ann Dermatol Venereol 127: 171–174, 2000PubMedGoogle Scholar
  27. 27.
    Brandes AA, Scelzi E, Salmistraro G, Ermani M, Carollo C, Berti F, Zampieri P, Baiocchi C, Fiorentino MV: Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer 33: 1592–1596, 1997CrossRefPubMedGoogle Scholar
  28. 28.
    Marras LC, Geerts WH, Perry JR: The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer 89: 640–646, 2000CrossRefPubMedGoogle Scholar
  29. 29.
    Chisholm RA, Stenning S, Hawkins TD: The accuracy of volumetric measurement of high-grade gliomas. Clin Radiol 40: 17–21, 1989PubMedGoogle Scholar
  30. 30.
    Xue D, Albright RE Jr: Preoperative anaplastic glioma tumor volume effects on patient survival. J Surg Oncol 72: 199–205, 1999CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Fabian Baumann
    • 1
  • Miroslava Bjeljac
    • 1
  • Spyros S. Kollias
    • 2
  • Brigitta G. Baumert
    • 3
  • Sebastian Brandner
    • 4
  • Valentin Rousson
    • 5
  • Yasuhiro Yonekawa
    • 1
  • René L. Bernays
    • 1
  1. 1.Department of NeurosurgeryUniversity of ZurichZurichSwitzerland
  2. 2.Institute of NeuroradiologyUniversity of ZurichZurichSwitzerland
  3. 3.Department of Radiation OncologyUniversity of ZurichZurichSwitzerland
  4. 4.Department of Neuropathology, University Hospital ZurichUniversity of ZurichZurichSwitzerland
  5. 5.Department of BiostatisticsUniversity of ZurichZurichSwitzerland

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