BACKGROUND: The current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp's landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp's trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy.The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing. CONCLUSIONS: In conjunction with new treatment approaches such as tumor-treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Comprehensive Cancer Care Faculty of Medicine Masaryk University Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Neurosurgery St Anne's University Hospital Brno Brno Czech Republic

Department of Neurosurgery St Anne's University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Nuclear Medicine and PET Center Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Radiation Oncology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Radiation Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Faculty of Medicine Masaryk University Brno Czech Republic

Regional Center for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Zobrazit více v PubMed

Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A. et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22:1583–8. doi: 10.1200/JCO.2004.06.082. PubMed DOI

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. doi: 10.1016/S1470-2045(12)70265-6. PubMed DOI

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. doi: 10.1016/S1470-2045(12)70164-X. PubMed DOI

Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C. et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376:1027–37. doi: 10.1056/NEJMoa1611977. PubMed DOI

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;352:997–1003. PubMed

Wick W, Platten M, Wick A, Hertenstein A, Radbruch A, Bendszus M. et al. Current status and future directions of anti-angiogenic therapy for gliomas. Neuro Oncol. 2016;18:315–28. doi: 10.1093/neuonc/nov180. PubMed DOI PMC

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. doi: 10.1056/NEJMoa1308345. PubMed DOI

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. doi: 10.1056/NEJMoa1308573. PubMed DOI PMC

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, 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. doi: 10.1016/S1470-2045(09)70025-7. PubMed DOI

Uhm JH, Porter AB.. Treatment of Glioma in the 21st Century: An exciting decade of postsurgical treatment advances in the molecular era. Mayo Clin Proc. 2017;92:995–1004. doi: 10.1016/j.mayocp.2017.01.010. PubMed DOI

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. doi: 10.1056/NEJMoa043330. PubMed DOI

Alexander BM, Cloughesy TF.. Adult glioblastoma. J Clin Oncol. 2017;35:2402–09. doi: 10.1200/JCO.2017.73.0119. PubMed DOI

Halasz BLM, Soltys SG, Breneman JC, Chan MD, Laack NN, Minniti G. et al. Treatment of gliomas: a changing landscape. Int J Radiat Oncol Biol Phys. 2017;98:255–8. doi: 10.1016/j.ijrobp.2017.02.223. PubMed DOI

Hottinger AF, Pacheco P, Stupp R.. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro Oncol. 2016;18:1338–49. doi: 10.1093/neuonc/now182. PubMed DOI PMC

Mehta M, Wen P, Nishikawa R, Reardon D, Peters K.. Critical Reviews in Oncology / Hematology Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Rev Oncol Hematol. 2017;111:60–5. doi: 10.1016/j.critrevonc.2017.01.005. PubMed DOI

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA. et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma. JAMA. 2015;314:2535–43. doi: 10.1001/jama.2015.16669. PubMed DOI

Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B. et al. Effect of Tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 2017;318:2306–16. doi: 10.1001/jama.2017.18718. PubMed DOI PMC

Wick W.. TTFields: Where does all the skepticism come from? Neuro Oncol. 2016;18:303–5. doi: 10.1093/neuonc/now012. PubMed DOI PMC

Zhu JJ, Demireva P, Kanner AA, Pannullo S, Mehdorn M, Avgeropoulos N. et al. Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. 2017 Aug 28; doi: 10.1007/s11060-017-2601-y. [Epub ahead of print] PubMed DOI PMC

Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18:1373–85. doi: 10.1016/S1470-2045(17)30517-X. PubMed DOI

Corso CD, Bindra RS, Mehta MP.. The role of radiation in treating glioblastoma: here to stay. J Neurooncol. 2017 Mar 7; doi: 10.1007/s11060-016-2348-x. [Epub ahead of print] PubMed DOI

Roth P, Gramatzki D, Weller M.. Management of elderly patients with glioblastoma. Curr Neurol Neurosci Rep. 2017;17:35. doi: 10.1007/s11910-017-0740-3. PubMed DOI

Walker MD, Strike TA, Sheline GE.. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5:1725–31. doi: 10.1016/0360-3016(79)90553-4. PubMed DOI

Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S. et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983;52:997–1007. PubMed

Chan JL, Lee SW, Fraass BA, Normolle DP, Greenberg HS, Junck LR. et al. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol. 2002;20:1635–42. PubMed

Selker RG, Shapiro WR, Burger P, Blackwood MS, Arena VC, Gilder JC. et al. The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery. 2002;51:343–57. PubMed

Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R. et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60:853–60. doi: 10.1016/j.ijrobp.2004.04.011. PubMed DOI

Werner-Wasik M, Scott CB, Nelson DF, Gaspar LE, Murray KJ, Fischbach JA. et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02. Cancer. 1996;77:1535–43. PubMed

Badiyan SN, Markovina S, Simpson JR, Robinson CG, DeWees T, Tran DD. et al. Radiation therapy dose escalation for glioblastoma multiforme in the era of temozolomide. Int J Radiat Oncol Biol Phys. 2014;90:877–85. doi: 10.1016/j.ijrobp.2014.07.014. PubMed DOI

Kelly PJ, Daumas-Duport C, Scheithauer BW, Kall BA KD.. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62:450–9. PubMed

Dunet V, Pomoni A, Hottinger A, Nicod-Lalonde M, Prior JO.. Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis. Neuro Oncol. 2016;18:426–34. doi: 10.1093/neuonc/nov148. PubMed DOI PMC

Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM. et al. Response assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro Oncol. 2016;18:1199–208. doi: 10.1093/neuonc/now058. PubMed DOI PMC

Whitfield GA, Kennedy SR, Djoukhadar IK, Jackson A.. Imaging and target volume delineation in glioma. Clin Oncol (R Coll Radiol) 2014;26:364–76. doi: 10.1016/j.clon.2014.04.026. PubMed DOI

Pafundi DH, Laack NN, Youland RS, Parney IF, Lowe VJ, Giannini C. et al. Biopsy validation of 18 F-DOPA PET and planning and radiotherapy target delineation: results of a prospective pilot study. Neuro Oncol. 2013;15:1058–67. doi: 10.1093/neuonc/not002. PubMed DOI PMC

Mills SJ, Du Plessis D, Pal P, Thompson G, Buonacorrsi G, Soh C. et al. Mitotic activity in glioblastoma correlates with estimated extravascular extracellular space derived from dynamic contrast-enhanced MR imaging. Am J Neuroradiol. 2016;37:811–7. doi: 10.3174/ajnr.A4623. PubMed DOI PMC

Brindle KM, Izquierdo-García JL, Lewis DY, Mair RJ, Wright AJ.. Brain tumor imaging. J Clin Oncol. 2017;35:2432–8. doi: 10.1200/JCO.2017.72.7636. PubMed DOI

Niyazi M, Geisler J, Siefert A, Schwarz SB, Ganswindt U, Garny S. et al. FET-PET for malignant glioma treatment planning. Radiother Oncol. 2011;99:44–8. doi: 10.1016/j.radonc.2011.03.001. PubMed DOI

Sulman EP, Ismaila N, Armstrong TS, Tsien C, Batchelor TT, Cloughesy T. et al. Radiation therapy for glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline. J Clin Oncol. 2017;35:361–9. doi: 10.1200/JCO.2016.70.7562. PubMed DOI

Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A. et al. ESTRO-ACROP guideline “target delineation of glioblastomas.”. Radiother Oncol. 2016;118:35–42. doi: 10.1016/j.radonc.2015.12.003. PubMed DOI

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. doi: 10.1016/j.radonc.2010.08.020. PubMed DOI

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella D, Webster B. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20. doi: 10.1007/s00401-016-1545-1. PubMed DOI

Chan MF, Schupak K, Burman C, Chui C-S, Ling CC.. Comparison of intensity-modulated radiotherapy with three-dimensional conformal radiation therapy planning for glioblastoma multiforme. Med Dosim. 2003;28:261–5. doi: 10.1016/j.meddos.2003.08.004. PubMed DOI

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. doi: 10.1016/j.ijrobp.2008.04.030. PubMed DOI

Shenouda G, Souhami L, Petrecca K, Owen S, Panet-Raymond V, Guiot M-C. et al. A phase 2 trial of neoadjuvant temozolomide followed by hypofractionated accelerated radiation therapy with concurrent and adjuvant temozolomide for patients with glioblastoma. Int J Radiat Oncol Biol Phys. 2017;97:487–94. doi: 10.1016/j.ijrobp.2016.11.006. PubMed DOI

Ataman F, Poortmans P, Stupp R, Fisher B, Mirimanoff RO.. Quality assurance of the EORTC 26981/22981; NCIC CE3 intergroup trial on radiotherapy with or without temozolomide for newly-diagnosed glioblastoma multiforme: the individual case review. Eur J Cancer. 2004;40:1724–30. doi: 10.1016/j.ejca.2004.03.026. PubMed DOI

Kazda T, Jancalek R, Pospisil P, Sevela O, Prochazka T, Vrzal M. et al. Why and how to spare the hippocampus during brain radiotherapy: the developing role of hippocampal avoidance in cranial radiotherapy. Radiat Oncol. 2014;9:139. doi: 10.1186/1748-717X-9-139. PubMed DOI PMC

Gondi V, Hermann BP, Mehta MP, Tomé WA.. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85:348–54. doi: 10.1016/j.ijrobp.2012.11.031. PubMed DOI

Gzell C, Back M, Wheeler H, Bailey D, Foote M.. Radiotherapy in glioblastoma: the past, the present and the future. Clin Oncol (R Coll Radiol) 2017;29:15–25. doi: 10.1016/j.clon.2016.09.015. PubMed DOI

Smith AW, Mehta MP, Wernicke AG.. Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma. J Neurooncol. 2016;128:1–10. doi: 10.1007/s11060-016-2123-z. PubMed DOI

Chen L, Chaichana KL, Kleinberg L, Ye X, Quinones-Hinojosa A, Redmond K.. Glioblastoma recurrence patterns near neural stem cell regions. Radiother Oncol. 2015;116:294–300. doi: 10.1016/j.radonc.2015.07.032. PubMed DOI PMC

Khalifa J, Tensaouti F, Lusque A, Plas B, Lotterie J-A, Benouaich-Amiel A. et al. Subventricular zones: new key targets for glioblastoma treatment. Radiat Oncol. 2017;12:67. doi: 10.1186/s13014-017-0791-2. PubMed DOI PMC

Nourallah B, Digpal R, Jena R, Watts C.. Irradiating the subventricular zone in glioblastoma patients: is there a case for a clinical trial? Clin Oncol (R Coll Radiol) 2017;29:26–33. doi: 10.1016/j.clon.2016.09.005. PubMed DOI

Pospisil P, Kazda T, Hynkova L, Bulik M, Dobiaskova M, Burkon P. et al. Post-WBRT cognitive impairment and hippocampal neuronal depletion measured by in vivo metabolic MR spectroscopy: results of prospective investigational study. Radiother Oncol. 2017;122:373–9. doi: 10.1016/j.radonc.2016.12.013. PubMed DOI

Flechl B, Sax C, Ackerl M, Crevenna R, Woehrer A, Hainfellner J. et al. The course of quality of life and neurocognition in newly diagnosed patients with glioblastoma. Radiother Oncol. 2017;125:228–33. doi: 10.1016/j.radonc.2017.07.027. PubMed DOI

Weller M, Roth P, Preusser M, Wick W, Reardon DA, Platten M. et al. Vaccine-based immunotherapeutic approaches to gliomas and beyond. Nat Rev Neurol. 2017;13:363–74. doi: 10.1038/nrneurol.2017.64. PubMed DOI

Sampson JH, Maus MV, June CH.. Immunotherapy for brain tumors. J Clin Oncol. 2017;35:2450–6. doi: 10.1200/JCO.2017.72.8089. PubMed DOI

Reznik E, Smith AW, Taube S, Mann J, Yondorf MZ, Parashar B. et al. Radiation and immunotherapy in high-grade gliomas. Am J Clin Oncol. 2017 Sep 12; doi: 10.1097/COC.0000000000000406. [Epub ahead of print] PubMed DOI

11C-methionine in the diagnostics and management of glioblastoma patients with rapid early progression: nonrandomized, open label, prospective clinical trial (GlioMET)

Pre-Radiotherapy Progression after Surgery of Newly Diagnosed Glioblastoma: Corroboration of New Prognostic Variable

Real-World Evidence in Glioblastoma: Stupp's Regimen After a Decade