Hypofractionated radiation therapy versus chemotherapy with temozolomide in patients affected by RPA class V and VI glioblastoma: a randomized phase II trial

  • Sara Pedretti
  • Laura Masini
  • Enrico Turco
  • Luca TriggianiEmail author
  • Marco Krengli
  • Bruno Meduri
  • Luigi Pirtoli
  • Paolo Borghetti
  • Ludovica Pegurri
  • Nada Riva
  • Roberto Gatta
  • Vincenzo Fusco
  • Silvia Scoccianti
  • Alessio Bruni
  • Umberto Ricardi
  • Riccardo Santoni
  • Stefano M. Magrini
  • Michela Buglione
Clinical Study



In RPA V-VI glioblastoma patients both hypofractionated radiotherapy and exclusive temozolomide can be used; the purpose of this trial is to compare these treatment regimens in terms of survival and quality of life.


Patients with histologic diagnosis of glioblastoma were randomized to hypofractionated radiotherapy (RT–30 Gy in 6 fractions) and exclusive chemotherapy (CHT–emozolomide 200 mg/m2/day 5 days every 28 days). Overall (OS) and progression free survival (PFS) were evaluated with Kaplan Maier curves and correlated with prognostic factors. Quality- adjusted survival (QaS) was evaluated according to the Murray model (Neurological Sign and Symptoms–NSS)


From 2010 to 2015, 31 pts were enrolled (CHT: 17 pts; RT: 14pts). Four pts were excluded from the analysis. RPA VI (p = 0.048) and absence of MGMT methylation (p = 0.001) worsened OS significantly. Biopsy (p = 0.048), RPA class VI (p = 0.04) and chemotherapy (p = 0.007) worsened PFS. In the two arms the initial NSS scores were overlapping (CHT: 12.23 and RT: 12.30) and progressively decreased in both group and became significantly worse after 5 months in CHT arm (p = 0.05). Median QaS was 104 days and was significantly better in RT arm (p = 0.01).


The data obtained are limited by the poor accrual. Both treatments were well tolerated. Patients in RT arm have a better PFS and QaS, without significant differences in OS. The deterioration of the NSS score would seem an important parameter and coincide with disease progression rather than with the toxicity of the treatment.


Glioblastoma Poor prognosis patients Quality of life Hypofractionated radiotherapy Temozolomide 



On behalf of Brain Study Group of the Italian Association of Radiation Oncology (AIRO).

Compliance with ethical standards

Conflict of interest

Al the authors declared that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Stupp R, Hegi ME, Mason WP et al (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):459–466CrossRefGoogle Scholar
  2. 2.
    Curran WJ Jr, Scott CB, Horton J et al (1993) Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85(9):704–710CrossRefGoogle Scholar
  3. 3.
    Scott CB, Scarantino C, Urtasun R et al (1998) Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06. Int J Radiat Oncol Biol Phys 40(1):51–55CrossRefGoogle Scholar
  4. 4.
    Scoccianti S, Magrini SM, Ricardi U et al (2010) Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (italian Association of Radiation Oncology). Neurosurgery 67(2):446–458CrossRefGoogle Scholar
  5. 5.
    Magrini SM, Ricardi U, Santoni R et al (2006) Patterns of practice and survival in a retrospective analysis of 1722 adult astrocytoma patients treated between 1985 and 2001 in 12 Italian radiation oncology centers. Int J Radiat Oncol Biol Phys 65(3):788–799CrossRefGoogle Scholar
  6. 6.
    Medical Research Council (1990) Prognostic factors for high-grade malignant glioma. Prognostic factors for high-grade malignant glioma development of a prognostic index. A Report of the Medical Research Council Brain Tumour Working Party. J Neuroncol 9:47–55CrossRefGoogle Scholar
  7. 7.
    Thomas R, James N, Guerrero D et al (1994) Hypofractionated radiotherapy as palliative treatment in poor prognosis patients with high grade glioma. Radiother Oncol 33(2):113–116CrossRefGoogle Scholar
  8. 8.
    Roa W, Brasher PM, Bauman G et al (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22(9):1583–1588CrossRefGoogle Scholar
  9. 9.
    Hoegler DB, Davey P (1997) A prospective study of short course radiotherapy in elderly patients with malignant glioma. J Neurooncol 33(3):201–204CrossRefGoogle Scholar
  10. 10.
    Buglione M, Spiazzi L, Saiani F et al (2014) Three-dimensional conformal radiotherapy, static intensity-modulated and helical intensity-modulated radiotherapy in glioblastoma. Dosimetric comparison in patients with overlap between target volumes and organs at risk. Tumori. 100(3):272–277Google Scholar
  11. 11.
    Glantz M, Chamberlain M, Liu Q et al (2003) Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Cancer 97(9):2262–2266CrossRefGoogle Scholar
  12. 12.
    Taphoorn MJ, Stupp R, Coens C et al (2005) Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 6(12):937–944CrossRefGoogle Scholar
  13. 13.
    Sizoo EM, Pasman HRW, Buttolo J et al (2012) Decision-making in the end-of-life phase of high-grade glioma patients. Eur J Cancer 4(8):226–232CrossRefGoogle Scholar
  14. 14.
    Buglione M, Borghetti P, Pedretti S et al (2015) Post-surgical therapeutic approaches to glioblastoma patients submitted to biopsy (BA) or "partial" resection (PR): the possibilities to treat also them without renunciations. Study from the Brescia Neuro-Oncology Group. Radiol Med 120(10):975–981CrossRefGoogle Scholar
  15. 15.
    Mathiesen T (2013) To operate or not–the impact of a lecture on radical glioblastoma surgery and different treatment options on decision-making for oneself and patients. Acta Neurochir (Wien) 155(8):1425–1429CrossRefGoogle Scholar
  16. 16.
    Kesselheim JC, Norden AD, Wen PY, Joffe S (2011) Discontinuing bevacizumab in patients with glioblastoma: an ethical analysis. Oncologist 16(10):1435–1439CrossRefGoogle Scholar
  17. 17.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280CrossRefGoogle Scholar
  18. 18.
    Murray KJ, Nelson DF, Scott C et al (1995) Quality-adjusted survival analysis of malignant glioma. Patients treated with twice-daily radiation (RT) and carmustine: A report of radiation therapy oncology group (RTOG) 83–02. Int J Radiat Oncol Biol Phys 31(3):453–459CrossRefGoogle Scholar
  19. 19.
    Chinot L, Barrie M, Frauger E et al (2004) Phase II Study of Temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly population. Cancer 100(10):2208–2214CrossRefGoogle Scholar
  20. 20.
    Karsy M, Yoon N, Boettcher L et al (2018) Surgical treatment of glioblastoma in the elderly: the impact of complications. J Neurooncol 138(1):123–132CrossRefGoogle Scholar
  21. 21.
    McAleese JJ, Stenning SP, Ashley S et al (2003) Hypofractionated radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls. Radiother Oncol 67:177–182CrossRefGoogle Scholar
  22. 22.
    Slotman BJ, Kralendonk JH, van Alphen HA et al (1996) Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors. Int J Radiat Oncol Biol Phys 34:895–898CrossRefGoogle Scholar
  23. 23.
    Phillips C, Guiney M, Smith J et al (2003) A randomized trial comparing 35 Gy in ten fractions with 60Gy in 30 fractions of cerebral irradiation for glioblastoma multiforme and older patients with anaplastic astrocytoma. Radiother Oncol 68:23–26CrossRefGoogle Scholar
  24. 24.
    Chibbaro S, Benvenuti L, Caprio A et al (2004) Temozolamide as first line agent in treating high-grade gliomas: phase II study. J Neurooncol 67(1–2):77–81CrossRefGoogle Scholar
  25. 25.
    Malmström A, Grønberg BH, Marosi C et al (2012) 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 13(9):916–926CrossRefGoogle Scholar
  26. 26.
    Guedes de Castro D, Matiello J, Roa W et al (2017) Survival outcomes with short-course radiation therapy in elderly patients with glioblastoma: data from a randomized phase 3 trial. Int J Radiat Oncol Biol Phys 98(4):931–938CrossRefGoogle Scholar
  27. 27.
    Reifenberger G, Hentschel B, Felsberg J et al (2012) Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer 131(6):1342–1350CrossRefGoogle Scholar
  28. 28.
    Wick W, Platten M, Meisner C et al (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13(7):707–715CrossRefGoogle Scholar
  29. 29.
    Perry JR, Laperriere N, O'Callaghan CJ et al (2017) Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med. 376(11):1027–1037CrossRefGoogle Scholar
  30. 30.
    Sulman EP, Ismaila N, Armstrong TS et al (2017) Radiation therapy for glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline. J Clin Oncol 35(3):361–369CrossRefGoogle Scholar
  31. 31.
    Weller M, van den Bent M, Hopkins K et al (2014) EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 15(9):e395–403CrossRefGoogle Scholar
  32. 32.
    Song K, Amatya B, Voutier C, Khan F (2016) Advance care planning in patients with primary malignant brain tumors: a systematic review. Front Oncol 6:223CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Radiation Oncology DepartmentASST Spedali Civili BresciaBresciaItaly
  2. 2.Radiation Oncology DepartmentAOU Maggiore Della Carità, East Piedmont UniversityNovaraItaly
  3. 3.Radiation Oncology DepartmentAOU Policlinico Di ModenaModenaItaly
  4. 4.Radiation Oncology DepartmentBrescia UniversityBresciaItaly
  5. 5.Radiation Oncology DepartmentAOUS, Siena UniversitySienaItaly
  6. 6.Radiation Oncology DepartmentIRST IRCSSMeldolaItaly
  7. 7.Radiation Oncology DepartmentiIRCSSRionero in VultureItaly
  8. 8.Radiation Oncology DepartmentFlorence University and AUOC Ospedale CareggiFirenzeItaly
  9. 9.Radiation Oncology DepartmentAO Città Della Salute E Della ScienzaTurinItaly
  10. 10.Radiation Oncology DepartmentFondazione Policlinico Tor VergataRomeItaly

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