Abstract
Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg to a maximum tolerated dose of 500 mg/d.
Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300 mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival.
Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.
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References
Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of twenty-five major cancers in 1990. Int J Cancer 80: 827–841, 1999
Pisani P, Parkin DM, Bray FI, Ferlay J: Estimates of the worldwide mortality from twenty-five major cancers in 1990. Int J Cancer 83: 18–29, 1999
Giles G: Epidemiology of brain cancer. Cancer Forum 22(2): 126–127, 1998
Grossman SA, Norris LK: Adjuvant and neoadjuvant treatment for primary brain tumors in adults. Semin Oncol 22(6): 530–539, 1995
Huncharek M, Muscat J: Treatment of recurrent high grade astrocytoma; results of a systematic review of 1415 patients. Anticancer Research 18: 1303–1312, 1998
Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82: 4–6, 1990
Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human glioma in vivo. Nature 359: 845–848, 1992
Takahashi J, Fukumoto M, Igorshi K, Oda Y, Kikuchi H, Hatanaka M: Correlation of bFGF expression levels with degree of malignancy and vascularity in human gliomas. J Neurosurg 76: 792–798, 1992
Kerbel RS: Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer agents. Bioessays 13(1): 31–36, 1991
Pluda JM: Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 24(2): 203–218, 1997
Quiltz R: Thalidomide in oncology: the peril and the promise. JMCC 6(5): 483–495, 1999
Kruse FE, Joussen AM, Rohrschneider K, Becker MD, Volcker HE: Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Opthalmol 236(6): 461–466, 1998
D'Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91: 4082–4085, 1994
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeldis J, Barlogie B, Siegel D, Crowley J: Antitumor activity of thalidomide in refractory multiple myeloma. NEJM 341(21): 1565–1571, 1999
Little RF, Wyvill KM, Pluda JM, Welles L, Marshall V, Figg WD, Newcomb FM, Tosato G, Feigal E, Steinberg SM, Whitby D, Goedert JJ, Yarchoan R: Activity of thalidomide in AIDS-related Kaposi's sarcoma.JCO 18(13): 2593–2602, 2000
Figg WD, Bergan R, Brawley, Tompkins A, Linehan M, Duray P, Bauer KS, Pluda J, Reed E: Randomized Phase II study of thalidomide in androgen-independent prostate cancer (AIPC). Proc Ann Meet Am Soc Clin Oncol 16: 333, 1997 (Abstract)
Eisen T, Boshoff C, Mak I, Sapunar F, Vaghan MM, Pyle L, Johnston SRD, Ahern R, Smith IE, Gore ME: Continuos low dose thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. BJC 82(4): 812–817, 2000
Marx GM, Levi JA, Bell DR, Boyle F, McCowatt S, Monk R, Wheeler H: A phase I/II trial of thalidomide as an antiangiogenic agent in the treatment of advanced cancer. Proc Ann Meet Am Soc Clin Oncol 18: A454, 1999 (Abstract)
Fine HA, Figg WD, Jaeckle K, Wen PY, Kyritsis AP, Loeffler JS, Levin VA, Black PM, Kaplan R, Pluda J, Yung WKA: Phase II study of the anti-angiogenic agent thalidomide with recurrent high-grade gliomas. JCO 18(4): 708–715, 2000
Tassler PL, Dellon Al: Correlation of measurements of pressure perception using the pressure-specified sensory device with electrodiagnostic testing. J Occup Med 37: 62–66, 1995
Hilkens PHE, van den Bent MJ: Chemotherapy induced peripheral neuropathy. J Periph Nerv Sys 2: 350–361, 1997
Yunh WKA. Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. JCO 17(9): 2762–2771, 1999
Beith J, Cook R, Robinson B, Levi J, Bell D, Wheeler H: Modulation of resistance to BCNU by depleting MGMT activity with procarbazine in patients with relapsed highgrade gliomas (Meeting abstract). Proc Ann Meet Am Soc Clin Oncol 16: A1375, 1997 (Abstract)
Hess CW, Hunziker T, Kupfer A, Ludin HP: Thalidomide induced peripheral neuropathy: a prospective clinical, neurophysiological and pharmacogenetic evaluation. Neurol 223: 83–89, 1986
Harland CC, Steventon GB, Marsden JR: Thalidomide-induced neuropathy and genetic differences in drug metabolism. Eur J Clin Pharmac 49(1-2): 1–6, 1995
Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE: Vascular endothelial growth factor (VEGF) is released from platelets during clotting: implications for measurement of circulating VEGF levels in clinical disease. Clinical Science 94(4): 395–404, 1998
Wynendaele W, Derua R, Hoylaerts MF, Pawinski A, Waelkens E, de Bruijn EA, Pariaens R, Merlevede W, van Oosterom AT: Vascular endothelial growth factor measured in platelet poor plasma allows optimal separation between cancer patients and volunteers: a key to study an angiogenic marker in vivo? Ann Onc 10(8): 965–971, 1999
Lee JK, Hong YJ, Han CJ, Hwang DY, Hong SI: Clinical usefulness of serum and plasma vascular endothelial growth factor in cancer patients: which is the optimal specimen? Int J Can 17: 149–152, 2000
Tynninen O, Aronen in patients HJ, Ruhala M, Paetau A, von Bpguslawski K, Salonen O, Jaaskelainen J, Paavonen T: MRI enhancement and microvascular density in gliomas: correlation with tumor cell proliferation. Invest Rad 34(6): 427, 1999
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Marx, G.M., Pavlakis, N., McCowatt, S. et al. Phase II study of Thalidomide in the treatment of recurrent glioblastoma multiforme. J Neurooncol 54, 31–38 (2001). https://doi.org/10.1023/A:1012554328801
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DOI: https://doi.org/10.1023/A:1012554328801