Subscribe to RSS
Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future directionFinancial support and sponsorship Nil.
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ) (oral alkylating agent) is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations.
12 July 2021 (online)
© 2015. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
- 1 Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002;61:215-25.
- 2 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;352:987-96.
- 3 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;10:459-66.
- 4 Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 2008;26:4189-99.
- 5 Julka PK, Sharma DN, Mallick S, Gandhi AK, Joshi N, Rath GK. Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide: A mono-institutional experience of 215 patients. J Cancer Res Ther 2013;9:381-6.
- 6 Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial. J Clin Oncol 2013;31:4085-91.
- 7 Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 2012;13:707-15.
- 8 Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916-26.
- 9 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;370:699-708.
- 10 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;370:709-22.
- 11 Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first line radiotherapy and temozolomide: Retrospective analysis of the AV Aglio trial. J Clin Oncol 2015. pii: JCO.2015.61.5005. [Epub ahead of print].
- 12 Kovic B, Xie F. Economic evaluation of bevacizumab for the first-line treatment of newly diagnosed glioblastoma multiforme. J Clin Oncol 2015;33:2296-302.
- 13 Taphoorn MJ, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, et al. Health-related quality of life in a randomized phase III study of bevacizumab, temozolomide, and radiotherapy in newly diagnosed glioblastoma. J Clin Oncol 2015;33:2166-75.
- 14 Smith JW. Cilengitide merck. Curr Opin Investig Drugs 2003;4:741-5.
- 15 Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1100-8.
- 16 Hatanpaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: Signal transduction, neuropathology, imaging, and radioresistance. Neoplasia 2010;12:675-84.
- 17 Talavera A, Friemann R, Gómez-Puerta S, Martinez-Fleites C, Garrido G, Rabasa A, et al. Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res 2009;69:5851-9.
- 18 Westphal M, Heese O, Steinbach JP, Schnell O, Schackert G, Mehdorn M, et al. A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer 2015;51:522-32.
- 19 Puumalainen AM, Vapalahti M, Agrawal RS, Kossila M, Laukkanen J, Lehtolainen P, et al. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 1998;9:1769-74.
- 20 Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, et al. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncol 2013;14:823-33.
- 21 Minniti G, Amelio D, Amichetti M, Salvati M, Muni R, Bozzao A, et al. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol 2010;97:377-81.
- 22 Omuro A, Beal K, Gutin P, Karimi S, Correa DD, Kaley TJ, et al. Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res 2014;20:5023-31.
- 23 Iuchi T, Hatano K, Kodama T, Sakaida T, Yokoi S, Kawasaki K, et al. Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 2014;88:793-800.
- 24 Reddy K, Gaspar LE, Kavanagh BD, Waziri A, Damek DM, Ney D, et al. Prospective evaluation of health-related quality of life in patients with glioblastoma multiforme treated on a phase II trial of hypofractionated IMRT with temozolomide. J Neurooncol 2013;114:111-6.
- 25 Cho KH, Kim JY, Lee SH, Yoo H, Shin SH, Moon SH, et al. Simultaneous integrated boost intensity-modulated radiotherapy in patients with high-grade gliomas. Int J Radiat Oncol Biol Phys 2010;78:390-7.
- 26 Panet-Raymond V, Souhami L, Roberge D, Kavan P, Shakibnia L, Muanza T, et al. Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: A safety and efficacy analysis. Int J Radiat Oncol Biol Phys 2009;73:473-8.
- 27 Kim IH, Park CK, Heo DS, Kim CY, Rhee CH, Nam DH, et al. Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: A prospective randomized controlled multicenter phase III trial. J Neurooncol 2011;103:595-602.
- 28 Shibui S, Narita Y, Mizusawa J, Beppu T, Ogasawara K, Sawamura Y, et al. Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). Cancer Chemother Pharmacol 2013;71:511-21.
- 29 Lee SX, Tunkyi A, Wong E, Swanson KD. Mitosis interference of cancer cells during anaphase by electric field from NovoTTF-100A: An update. J Clin Oncol 2012, 30 (suppl; abstr e21078).
- 30 Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, et al. NovoTTF-100A versus physician′s choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality. Eur J Cancer 2012;48:2192-202.
- 31 Kanner AA, Wong ET, Villano JL, Ram Z; EF - Investigators. Post-hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician′s choice chemotherapy. Semin Oncol 2014;41 Suppl 6:S25-34.
- 32 Srivastava A, Jain A, Jha P, Suri V, Sharma MC, Mallick S, et al. MGMT gene promoter methylation in pediatric glioblastomas. Childs Nerv Syst 2010;26:1613-8.
- 33 Jha P, Agrawal R, Pathak P, Kumar A, Purkait S, Mallik S, et al. Genome-wide small noncoding RNA profiling of pediatric high-grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII-52 and delineates H3F3A and TP53 mutant-specific miRNAs and snoRNAs. Int J Cancer 2015;137:2343-53.
- 34 Pathak P, Jha P, Purkait S, Sharma V, Suri V, Sharma MC, et al. Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM. J Neurooncol 2015;121:489-97.
- 35 Jha P, Pia Patric IR, Shukla S, Pathak P, Pal J, Sharma V, et al. Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation. Neuro Oncol 2014;16:1607-17.
- 36 Mallick S, Gandhi AK, Joshi NP, Kumar A, Puri T, Sharma DN, et al. Outcomes of pediatric glioblastoma treated with adjuvant chemoradiation with temozolomide and correlation with prognostic factors. Indian J Med Paediatr Oncol 2015;36:99-104.
- 37 Jalali R, Rishi A, Goda JS, Sridhar E, Gurav M, Sharma P, et al. Clinical outcome and molecular characterization of pediatric glioblastoma treated with postoperative radiotherapy with concurrent and adjuvant temozolomide: A single institutional study of 66 children. Neurooncol Pract 2015. [Article in press; doi:10.1093/nop/npv024].
- 38 Chan AS, Leung SY, Wong MP, Yuen ST, Cheung N, Fan YW, et al. Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol 1998;22:816-26.
- 39 Butowski N, Chang SM, Lamborn KR, Polley MY, Pieper R, Costello JF, et al. Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma. Neuro Oncol 2010;12:1167-72.
- 40 Wick W, Steinbach JP, Platten M, Hartmann C, Wenz F, von Deimling A, et al. Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. Neuro Oncol 2013;15:1405-12.
- 41 Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610-22.
- 42 Alexander BM, Wang M, Yung WK, Fine HA, Donahue BA, Tremont IW, et al. A phase II study of conventional radiation therapy and thalidomide for supratentorial, newly-diagnosed glioblastoma (RTOG 9806). J Neurooncol 2013;111:33-9.
- 43 Ducassou A, Uro-Coste E, Verrelle P, Filleron T, Benouaich-Amiel A, Lubrano V, et al. αvβ3 Integrin and fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase III clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma. Eur J Cancer 2013;49:21619.
- 44 Chakravarti A, Wang M, Robins HI, Lautenschlaeger T, Curran WJ, Brachman DG, et al. RTOG 0211: A phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys 2013;85:1206-11.
- 45 Baselga J, Campone M, Piccart M, Burris HA 3 rd , Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9.
- 46 Hainsworth JD, Shih KC, Shepard GC, Tillinghast GW, Brinker BT, Spigel DR. Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma. Clin Adv Hematol Oncol 2012;10:240-6.
- 47 Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010;17:98-110.
- 48 Gupta T, Nair V, Paul SN, Kannan S, Moiyadi A, Epari S, et al. Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma? J Neurooncol 2012;109:195-203.