Hypofractionated accelerated radiotherapy (HART) with concurrent and adjuvant temozolomide in newly diagnosed glioblastoma: a phase II randomized trial (HART-GBM trial)
Maximal safe surgical resection followed by adjuvant chemoradiation has been standard for newly diagnosed glioblastoma multiforme (GBM). Hypofractionated accelerated radiotherapy (HART) has the potential to improve outcome as it reduces the overall treatment time and increases the biological effective dose.
Between October 2011 and July 2017, a total of 89 newly diagnosed GBM patients were randomized to conventional fractionated radiotherapy (CRT) or HART. Radiotherapy was delivered in all patients with a three-dimensional conformal radiotherapy technique in CRT arm (60 Gy in 30 fractions over 6 weeks @ 2 Gy/per fraction) or simultaneous integrated boost intensity modulated radiotherapy in HART arm (60 Gy in 20 fractions over 4 weeks @ 3 Gy/per fraction to high-risk planning target volume (PTV) and 50 Gy in 20 fractions over 4 weeks @ 2.5 Gy/per fraction to low-risk PTV). The primary endpoint of the trial was overall survival (OS).
After a median follow-up of 11.4 months (Range: 2.9–42.5 months), 26 patients died and 39 patients had progression of the disease. Median OS for the entire cohort was 23.4 months. Median OS in the CRT and HART arms were 18.07 months (95% CI 14.52-NR) and 25.18 months (95% CI 12.89-NR) respectively, p = 0.3. Median progression free survival (PFS) for the entire cohort was 13.5 months (Range: 11.7–15.7 months). In multivariate analysis patients younger than 40 years of age, patients with a gross total resection of tumor and a mutated IDH-1 had significantly better OS. PFS was significantly better for patients with a gross total resection of tumor and a mutated IDH-1. All patients included in the trial completed the planned course of radiation. Only two patients required hospital admission for features of raised intracranial tension. One patient in the HART arm required treatment interruption.
HART is comparable to CRT in terms of survival outcome. HART arm had no excess treatment interruption and minimal toxicity. Dose escalation, reduction in overall treatment time, is the advantages with use of HART.
KeywordsGlioblastoma Hypofractionated radiotherapy Accelerated radiotherapy Temozolomide Surgery
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Stupp R, Hegi ME, Mason WP, van den Bent MJ 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):434–435CrossRefGoogle Scholar
- 4.Minniti G, Amelio D, Amichetti M, Salvati M, Muni R, BozzaoA et al (2010) 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 97(3):377–381CrossRefGoogle Scholar
- 7.Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H et al (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase III trial. Lancet Oncol 13(9):916–926CrossRefGoogle Scholar
- 10.Panet-Raymond V, Souhami L, Roberge D, Kavan P, Shakibnia L, Muanza T et al (2009) Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastomamultiforme: a safety and efficacy analysis. Int J Radiat Oncol Biol Phys 73(2):473–478CrossRefGoogle Scholar
- 12.The National Cancer Institute (2009) Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0).Google Scholar
- 18.Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK et al (2014) 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 III trial. Lancet Oncol 15:1100–1108CrossRefGoogle Scholar
- 19.Westphal M, Heese O, Steinbach JP, Schnell O, Schackert G, Mehdorn M et al (2015) 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 51:522–532CrossRefGoogle Scholar
- 23.Stummer W, Reulen HJ, Meinel T, Pichlmeier U et al. (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–566Google Scholar