Thalidomide as an Anti-angiogenic Agent in Relapsed Gliomas
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Background. Thalidomide (α-phthalimidoglutarimide), a synthetic sedative drug, has anti-angiogenic properties due to inhibition of growth-factor mediated neovascularisation and has been shown to inhibit tumour growth in experimental solid tumour models.
Aim. To assess response of recurrent malignant gliomas to thalidomide.
Methods. Eighteen patients with recurrent gliomas were enrolled to an open, non-randomised phase II trial between October 1997 and December 1999. All patients had failed following treatment with radiotherapy and chemotherapy with PCV and/or temozolomide regimens. Eleven patients had high-grade gliomas de novo and 7 high-grade gliomas following transformation of low-grade gliomas. Thalidomide was prescribed at 100 mg/day p.o. continuously. Response was assessed at 4-weekly intervals. Disease progression was defined as neurological deterioration and/or radiological evidence of increased tumour size. Treatment was discontinued at the time of disease progression, or if toxicity occurred, or at patients' request.
Results. Thalidomide was prescribed for a median of 42 days (range 7–244). Treatment was discontinued due to toxicity (peripheral sensory neuropathy) in 1 patient. Six patients died before response could be fully assessed and are classified as non-responders. Of 12 who continued treatment for more than 4 weeks, 1 patient had clinical and radiological response (PR), 2 patients had stable disease for 2 and 4 months respectively and 9 patients had disease progression. The median survival from the start of thalidomide was 2.5 months.
Conclusion. The efficacy of thalidomide in terms of response in recurrent gliomas is low, with a partial response rate of only 6%. Future studies should investigate thalidomide in combination with other agents and at an earlier stage of disease. Methods to assess anti-angiogenic properties such as changes in tumour vasculature could be employed as initial surrogate end-points in the investigation of efficacy.
- Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27–31, 1995
- Folkman J, Watson K, Ingber D, Hanahan D: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339: 58–61, 1989
- Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3: 65–71, 1992
- Goto F, Goto K, Weindel K, Folkman J: Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels [see comments]. Lab Invest 69: 508–517, 1993
- Bloemendal HJ, Logtenberg T, Voest EE: New strategies in anti-vascular cancer therapy [see comments]. Eur J Clin Invest 29: 802–809, 1999
- Giavazzi R, Giulia T: Angiogenesis and angiogenesis inhibitors in cancer. Forum (Genova) 9: 261–272, 1999
- Carroll RS, Zhang J, Bello L, Melnick MB, Maruyama T, Mc LBP: KDR activation in astrocytic neoplasms. Cancer 86: 1335–1341, 1999
- Li VW, Folkerth RD, Watanabe H, Yu C, Rupnick M, Barnes P, Scott RM, Black PM, Sallan SE, Folkman J: Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344: 82–86, 1994
- Plate KH, Breier G, Farrell CL, Risau W: Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest 67: 529–534, 1992
- Jensen RL: Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg Neurol 49: 189–195; discussion 196, 1998
- D'Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 91: 4082–4085, 1994
- Minchinton AI, Fryer KH, Wendt KR, Clow KA, Hayes MM: The effect of thalidomide on experimental tumors and metastases. Anticancer Drugs 7: 339–343, 1996
- Verheul HM, Panigrahy D, Yuan J, D'Amato RJ: Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. British J Cancer 79: 114–118, 1999
- Bauer KS, Dixon SC, Figg WD: Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 55: 1827–1834, 1998
- Carlesimo M, Giustini S, Rossi A, Bonaccorsi P, Calvieri S: Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 32: 866–869, 1995
- Crawford CL: Use of thalidomide in leprosy. Adverse Drug React Toxicol Rev 13: 177–192, 1994
- Tramontana JM, Utaipat U, Molloy A, Akarasewi P, Burroughs M, Makonkawkeyoon S, Johnson B, Klausner JD, Rom W, Kaplan G: Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1: 384–397, 1995
- Macdonald DR, Cascino TL, Schold SC, Cairncross JG: Response criteria for phase II studies of supratentorial gliomas. J Clin Oncol 8: 1277–1280, 1990
- Avgeropoulos NG, Batchelor TT: New treatment strategies for malignant gliomas. Oncologist 4: 209–224, 1999
- Lund EL, Spang-Thomsen M, Skovgaard-Poulsen H, Kristjansen PE: Tumor angiogenesis – a newtherapeutic target in gliomas. Acta Neurol Scand 97: 52–62, 1998
- Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B: Antitumor activity of thalidomide in refractory multiple myeloma [see comments]. New England J Med 341: 1565–1571, 1999
- Auerbach R, Arensman R, Kubai L, Folkman J: Tumorinduced angiogenesis: lack of inhibition by irradiation. Int J Cancer 15: 241–245, 1975
- Fine HA, Figg W, Jaeckle K et al.: Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708–715, 2000
- Thalidomide as an Anti-angiogenic Agent in Relapsed Gliomas
Journal of Neuro-Oncology
Volume 51, Issue 1 , pp 41-45
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