Abstract
Purpose
The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ.
Patients and methods
Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m2 days 1–7 and 15–21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks.
Results
Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44 %) had gross total resection. O6-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9 % (95 % CI 9.3–40.0 %). The median PFS and overall survival (OS) were 4.2 months (95 % CI 3.6–5.4 months) and 7.3 months (95 % CI 5.8–8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19 %; 95 % CI 7.2–36.4) were long-term survivors, with a median PFS and OS (50 % events) of 9.5 months (95 % CI 7.9–23.6) and 15.4 (95 % CI 8.9–NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed.
Conclusions
This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.
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References
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66.
Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004;10(6):1871–4.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.
Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17(8):2572–8.
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–40.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740–5.
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy: temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.
Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE 2nd, Bailey L, et al. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer. 2012;118(5):1302–12.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722–9.
Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol. 2007;25(22):3357–61.
Wick W, Steinbach JP, Küker WM, Dichgans J, Bamberg M, Weller M. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology. 2004;62(11):2113–5.
Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999;59(4):793–7.
Herrmann BG, Frischauf AM. Isolation of genomic DNA. Methods Enzymol. 1987;152:180–3.
Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277–80.
Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer. 2008;112(10):2267–73.
Narayana A, Kelly P, Golfinos J, Parker E, Johnson G, Knopp E, et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg. 2009;110(1):173–80.
Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer. 2010;116(22):5297–305.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–9.
Jeremic B, Grujicic D, Antunovic V, Djuric L, Stojanovic M, Shibamoto Y. Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach. J Neurooncol. 1994;21(2):177–85.
Nitta T, Sato K. Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer. 1995;75(11):2727–31.
Quigley MR, Flores N, Maroon JC, Sargent B, Lang S, Elrifai A. Value of surgical intervention in the treatment of glioma. Stereotact Funct Neurosurg. 1995;65(1–4):171–5.
Verhoeff JJ, Lavini C, van Linde ME, Stalpers LJ, Majoie CB, Reijneveld JC, et al. Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol. 2010;21(8):1723–7.
Kong DS, Lee JI, Kim JH, Kim ST, Kim WS, Suh YL, et al. Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol. 2010;12(3):289–96.
Acknowledgments
Financial support for this research was provided by Roche Farma, S.A. Jesús González, MD (Pivotal CRO) provided advice for writing and submitting this paper.
Conflict of interest
Carmen Balañá has received honoraria from Roche, Merck Serono, and Novartis for lectures and advisory boards. Gaspar Reynés has received honoraria from Roche and Merck (previously Schering Plough) for lectures and advisory boards.
Ethical standards
The study was performed after approval by the Independent Ethics Committee of each site and in accordance with the Declaration of Helsinki, the Good Clinical Practices, and local ethical and legal requirements (Spanish laws). Before study entry, all patients provided written informed consent according to local ethical committee regulations.
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Sepúlveda, J.M., Belda-Iniesta, C., Gil-Gil, M. et al. A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma. Clin Transl Oncol 17, 743–750 (2015). https://doi.org/10.1007/s12094-015-1304-0
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DOI: https://doi.org/10.1007/s12094-015-1304-0