Abstract
We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m2, days 1–21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.
Similar content being viewed by others
References
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) 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 10(5):459–466
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745
Johnson DR, Leeper HE, Uhm JH (2013) Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis. Cancer 119(19):3489–3495
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15(9):943–953
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708
Herrlinger U, Schäfer N, Steinbach J, Weyerbrock A, Hau P, Goldbrunner R, Leutgeb B, Urbach H, Stummer W, Glas M (2014) The randomized, multicenter Glarius trial investigating bevacizumab/irinotecan vs standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients: final survival results and quality of life. Neuro Oncol 16:ii23–ii24
Balana C, Gallego O, Vieitez JM, De Las Penas R, Herrero A, Peralta S, Luque R, Gil M, Villa S, Etxaniz O, Carrato C, Sepulveda J, Grp Espanol I (2011) Phase II randomized study of preradiation treatment with temozolomide (TMZ) and bevacizumab (BEV) previous to TMZ plus radiation plus BEV versus the same treatment without BEV therapy in unresectable glioblastoma (GB): GENOM 009. J Clin Oncol 29 (15)
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972
Balana C, Carrato C, Ramirez JL, Cardona AF, Berdiel M, Sanchez JJ, Taron M, Hostalot C, Musulen E, Ariza A, Rosell R (2011) Tumour and serum MGMT promoter methylation and protein expression in glioblastoma patients. Clin Transl Oncol 13(9):677–685
Brada M, Ashley S, Dowe A, Gonsalves A, Huchet A, Pesce G, Reni M, Saran F, Wharram B, Wilkins M, Wilkins P (2005) Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide. Ann Oncol 16(6):942–949
Bauchet L, Mathieu-Daude H, Fabbro-Peray P, Rigau V, Fabbro M, Chinot O, Pallusseau L, Carnin C, Laine K, Schlama A, Thiebaut A, Patru MC, Bauchet F, Lionnet M, Wager M, Faillot T, Taillandier L, Figarella-Branger D, Capelle L, Loiseau H, Frappaz D, Campello C, Kerr C, Duffau H, Reme-Saumon M, Tretarre B, Daures JP, Henin D, Labrousse F, Menei P, Honnorat J (2010) Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004. Neuro Oncol 12(7):725–735
Chang SM, Parney IF, Huang W, Anderson FA Jr, Asher AL, Bernstein M, Lillehei KO, Brem H, Berger MS, Laws ER (2005) Patterns of care for adults with newly diagnosed malignant glioma. JAMA 293(5):557–564
Graus F, Bruna J, Pardo J, Escudero D, Vilas D, Barcelo I, Brell M, Pascual C, Crespo JA, Erro E, Garcia-Romero JC, Estela J, Martino J, Garcia-Castano A, Mata E, Lema M, Gelabert M, Fuentes R, Perez P, Manzano A, Aguas J, Belenguer A, Simon A, Henriquez I, Murcia M, Vivanco R, Rojas-Marcos I, Munoz-Carmona D, Navas I, de Andres P, Mas G, Gil M, Verger E (2013) Patterns of care and outcome for patients with glioblastoma diagnosed during 2008–2010 in Spain. Neuro Oncol 15(6):797–805
Wick W, Hermisson M, Kortmann RD, Kuker WM, Duffner F, Dichgans J, Bamberg M, Weller M (2002) Neoadjuvant gemcitabine/treosulfan chemotherapy for newly diagnosed glioblastoma: a phase II study. J Neurooncol 59(2):151–155
Balana C, Lopez-Pousa A, Berrocal A, Yaya-Tur R, Herrero A, Garcia JL, Martin-Broto J, Benavides M, Cerda-Nicolas M, Ballester R, Balart J, Capellades J (2004) Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM). J Neurooncol 70(3):359–369
Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM, Dufour H, Figarella-Branger D (2007) Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25(12):1470–1475
Grossman SA, O’Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R (2003) Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol 21(8):1485–1491
Chauffert B, Feuvret L, Bonnetain F, Taillandier L, Frappaz D, Taillia H, Schott R, Honnorat J, Fabbro M, Tennevet I, Ghiringhelli F, Guillamo JS, Durando X, Castera D, Frenay M, Campello C, Dalban C, Skrzypski J, Chinot O (2014) Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEFdagger. Ann Oncol 25(7):1442–1447
Hofland KF, Hansen S, Sorensen M, Engelholm S, Schultz HP, Muhic A, Grunnet K, Ask A, Costa JC, Kristiansen C, Thomsen C, Poulsen HS, Lassen U (2014) Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: a randomized phase II study. Acta Oncol 53(7):939–944
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247
Blumenthal DT, Won M, Mehta MP, Curran WJ, Souhami L, Michalski JM, Rogers CL, Corn BW (2009) Short delay in initiation of radiotherapy may not affect outcome of patients with glioblastoma: a secondary analysis from the radiation therapy oncology group database. J Clin Oncol 27(5):733–739
Lawrence YR, Blumenthal DT, Matceyevsky D, Kanner AA, Bokstein F, Corn BW (2011) Delayed initiation of radiotherapy for glioblastoma: how important is it to push to the front (or the back) of the line? J Neurooncol 105(1):1–7
Khasraw M, Holodny A, Goldlust SA, DeAngelis LM (2012) Intracranial hemorrhage in patients with cancer treated with bevacizumab: the Memorial Sloan-Kettering experience. Ann Oncol 23(2):458–463
Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P, Sanchez JJ, Rosell R (2003) O-6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 9(4):1461–1468
Galanis E, Wu W, Cloughesy T, Lamborn K, Mann B, Wen PY, Reardon DA, Wick W, Macdonald D, Armstrong TS, Weller M, Vogelbaum M, Colman H, Sargent DJ, van den Bent MJ, Gilbert M, Chang S (2012) Phase 2 trial design in neuro-oncology revisited: a report from the RANO group. Lancet Oncol 13(5):196–204
Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, di Tomaso E, Duda DG, Jain RK (2009) A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69(13):5296–5300
Prados M, Cloughesy T, Samant M, Fang L, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Das A, Friedman HS (2011) Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab. Neuro Oncol 13(1):143–151
Gallego Perez-Larraya J, Lahutte M, Petrirena G, Reyes-Botero G, Gonzalez-Aguilar A, Houillier C, Guillevin R, Sanson M, Hoang-Xuan K, Delattre JY (2012) Response assessment in recurrent glioblastoma treated with irinotecan-bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria. Neuro Oncol 14(5):667–673
Acknowledgments
The authors thank Anna del Prado (Marketing Farmacéutico & Investigación Clínica, SL) for her invaluable assistance throughout the study.
Funding
This study was funded by the Spanish Instituto Carlos III (FISS-ICIII: project EC08/00071). In addition, MSD provided neoadjuvant temozolomide and funds for MGMT assessment, and Roche-Spain provided funds for data management and the centralized review of response and progression.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Balana, C., De Las Penas, R., Sepúlveda, J.M. et al. Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial. J Neurooncol 127, 569–579 (2016). https://doi.org/10.1007/s11060-016-2065-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-016-2065-5