Rasim MERAL, Şefika Arzu ERGEN, Musa ALTUN

Late Radiation Outcomes of Patients with Newly Diagnosed Glioblastoma Treated with Accelerated Hyperfractionated Radiotherapy and Temozolomide

This study aimed to evaluate the late radiation outcomes in patients with glioblastoma who were treatedwith accelerated hyperfractionated radiotherapy (AHRT) and concurrent plus adjuvant temozolomide(TMZ).METHODSBetween 2006 and 2007, 32 consecutive patients with glioblastoma were treated with AHRT and TMZ.The total dose of 66 Gy was administered in 33 fractions within 6 weeks. In phase I, PTV1 received 40Gy (2 Gy per fraction, five times per week). In phase II, 26 Gy was delivered to PTV2 by adding a seconddaily fraction at intervals of 8 hours once every 3 days. All patients received chemotherapy according tothe Stupp protocol. Toxicities were evaluated based on the CTCAE v3.0.RESULTSThe median follow-up period was 18 months. A total of 28 patients completed the planned radiotherapy schedule, and 20 patients received six cycles of adjuvant TMZ. Median overall survival (OS) andprogression-free survival (PFS) were 17 and 10 months, respectively. In univariate analysis, age, performance status, and RPA classes III–IV were found significant for OS. Multivariate analysis showed thatsix cycles of TMZ administration affected both OS and PFS. Late grade-4 central nervous system (CNS)toxicities were observed in five patients.CONCLUSIONIt was observed that it is both feasible and effective to administer AHRT with TMZ in a selected group ofpatients. It provides better short-term survival advantage than the standard treatment regimen.

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1. Lassman AB, Schifter D, Corn BW. High-Grade Gliomas. In: Gunderson LL, Tepper JE, editors. Clinical Radiation Oncology. 3th edition. Philadelphia: Elsevier Churchill Livingstone; 2012. p. 461–72.
2. Wick W, Osswald M, Wick A, Winkler F. Treatment of glioblastoma in adults. Ther Adv Neurol Disord 2018;11:1–13.
3. Laperriere N, Zuraw L, Cairncross G; Cancer Care Ontario Practice Guidelines Initiative Neuro-Oncology Disease Site Group. Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Radiother Oncol 2002;64(3):259–73.
4. Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978;49(3):333–43.
5. Scally TS, Lin C, Beriwal S, Brady LW. Central Nervous System Tumors. In: Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK, editors. Principles and Practise of Radiation Oncology. 4th edition. Philadelphia: Lippincoth Williams & Wilkins; 2004. p. 810–5.
6. Shapiro WR, Young DF. Treatment of malignant glioma. A controlled study of chemotherapy and irradiation. Arch Neurol 1976;33(7):494–500.
7. Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980;303(23):1323–9.
8. Sandberg-Wollheim M, Malmström P, Strömblad LG, Anderson H, Borgström S, Brun A, et al. A randomized study of chemotherapy with procarbazine, vincristine and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4. Cancer 1991;68(1):22–9.
9. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71(8):2585–97.
10.Stupp R, Mason WP, Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. for the European organization for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institue of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Eng J Med 2005;352(10):987–95.
11. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. 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 EORTCNCIC trial. Lancet Oncol 2009;10(5):459–66.
12.Raymond VP, 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(2):473–8.
13.Tsien CI, Brown D, Normolle D, Schipper M, Piert M, Junck L, et al. Concurrent temozolomide and dose-escalated ıntensity modulated radiation therapy in newly diagnosed glioblastoma. Clin Cancer Res 2012;18(1):273–9.
14.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(2):390–7.
15.Ciammella P, Galeandro M, D’Abbiero N, Podgornii A, Pisanello A, Botti A, et al. Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: a 6 year single institutional experience. Clin Neurol Neurosurg 2015;115(9):1609–14.
16.Massaccesi M, Ferro M, Cilla S, Balducci M, Deodato F, Macchia G, et al. Accelerated intensity-modulated radiotherapy plus temozolomide in patients with glioblastoma: a phase I dose-escalation study (ISIDEBT-1). Int J Clin Oncol 2013;18:784–91.
17.Reddy K, Damek D, Gaspar LE, Ney D, Waziri A, Lillehei K, et al. Phase II trial of hypofractioated IMRT with temozolomide for patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2012;84(3):655–60.
18.Watkins JM, Marshall DT, Patel S, Giglio P, Herrin AE, Garret-Mayer E, et al. High dose radiotherapy to 78 Gy with or without temozolomide for high grade gliomas. J Neurooncol 2009;93(3):343–8.
19.Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidencebased review of the role of radiosurgery for malignant glioma. In. J Radiat Oncol Biol Phys 2005;63(1):47–55.
20.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(3):853–60.
21.CTCAEv3.0. The revised common toxicity criteria: Version 3.0. 2006. Available at: https://ctep.cancer.gov/ protocoldevelopment/electronic_applications/docs/ ctcaev3.pdf. Accessed February 15, 2019.
22.Nitta T, Sato K. Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer 1995;75(11):2727–31.
23.Fults DW. Neurosurgeons still wanted. Neuro Oncol 2018;20(9):1150–1.
24.Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, Fisher B, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981- NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24(16):2563–9.
25.Taghian A, Dubois W, Budach W, Baumann M, Freeman J, Suit H. Invivo radiation sensitivity of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1995;32:99–104.
26.Walker MD, Strike TS, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5(10):1725–31.
27.Reni M, Cozzarini C, Panucci MG, Ceresoli GL, Ferreri AJ, Fiorino C, et al. Irradiation fields and doses in glioblastoma multiforme: are current standards adequate? Tumori 2001;87(2):85–90.
28.Sherriff J, Tamangani J, Senthil L, Cruickshank G, Spooner D, Jones B, et al. Patterns of relapse in glioblastoma multiforme following concomitant chemoradiotherapy with temozolomide. Br J Radiol 2013;86(1022):20120414.
29.Wick W, Stupp R, Beule AC, Bromberg J, Wick A, Ernemann U, et al; European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group. A novel tool to analyse MRI recurrence patterns in glioblastoma. Neuro Oncol 2008;10(6):1019–24.
30. Shrieve DC, Alexander E 3rd, Black PM, Wen PY, Fine HA, Kooy HM, et al. Treatment of patients with primary glioblastoma multiforme with standart postoperative radiotherapy and radiosurgical boost: prognostic factors and long term outcome. J Neurosurg 1999;90(1):72–7.
31.Prisco FE, Weltman E, de Hanriot RM, Brandt RA. Radiosurgical boost for primary high-grade gliomas. J NeuroOncol 2002;57(2):151–60.
32.Fariselli L, Cuppini L, Gaviani P, Marchetti M, Pinzi V, Milanesi I, et al. Short course radiotherapy concomitant with temozolomide in GBM patients: a phase II study. Tumori. 2017;103(5):457–63.
33.Scoccianti S, Krengli M, Marrazzo L, Magrini SM, Detti B, Fusco V, et al. Hypofractionated radiotherapy with simultaneous integrated boost (SIB) plus temozolomide in good prognosis patients with glioblastoma: a multicenter phase II study by the Brain Study Group of the Italian Association of Radiation Oncology (AIRO). Radiol Med 2018;123(1):48–62.
34.Monjazeb AM, Ayala D, Jensen C, Case LD, Bourland JD, Ellis TL, et al. A phase I dose escalation study of hypofractionated IMRT field-in-field boost for newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2012;82(2):743–8.
35.Nelson DF, Curran WJ Jr., Scott C, Nelson JS, Weinstein AS, Ahmad K, et al. Hyperfractioned radiation therapy and bischlorethyl nitrosourea in the treatment of malignant glioma-possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys 1993;25(2):193–207.
36.Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS. Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr 1988;(6):279–84.
37.Murray KJ, Nelson DF, Scott C, Fishbach J, Porter A, Farnan N, et al. 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 1995;31(3):453–9.
38.Nieder C, Nestle U, Ketter R, Kolles H, Gentner SJ, Steudel WI, et al. Hyperfractionated and acceleratedhyperfractionated radiotherapy for glioblastoma multiforme. Radiat Oncol Invest 1999;7(1):36–41.
39.Fitzek MM, Thornton AF, Rabinov JD, Lev MH, Pardo FS, Munzenrider JE, et al. Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: Results of a phase II prospective trial. J Neurosurg 1999;91(1):251–60.
40.Kaul D, Florange J, Badakhshi H, Grün A, Ghadjar P, Exner S, et al. Accelerated hyperfractionation plus temozolomide in glioblastoma. Radiat Oncol 2016;11:70–7.
41.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(4):877–80.
42.Mizumoto M, Tsuboi K, Igaki H, Yamamoto T, Takano S, Oshiro Y, et al. Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2010;77(1):98–105.
43.Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85(9):704–10.
44.Buatti JM, Marcus RB, Mendenhall WM, Friedman WA, Bova FJ. Accelerated hyperfractionated radiotherapy for malignant gliomas. Int J Radiat Oncol Biol Phy 1996;34(4):785–92.
45.Brada M, Sharpe G, Rajan B, Britton J, Wilkins PR, Guerrero D, et al. Modifying radical radiotherapy in high grade gliomas; shortening the treatment time through acceleration. Int J Radiat Oncol Biol Phys 1999;43(2):287–92.
46.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(1):35–42.
47.Lorentini S, Amelio D, Giri MG, Fellin F, Meliado G, Rizzotti A, et al. IMRT or 3D-CRT in glioblastoma? A dosimetric criterion for patient selection. Technol Cancer Res Treat 2013;12(5):411–20.
48.Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys 2006;65(2):499–508.
49.Rusthoven KE, Olsen C, Franklin W, KleinschmidtDeMasters BK, Kavanagh BD, Gaspar LE, et al. Favorable prognosis in patients with high-grade glioma with radiation necrosis: The University of Colorado reoperation series. Int J Radiat Oncol Biol Phys 2011;81(1):211–7.
50.Peca C, Pacelli R, Elefante A, Del Basso De Caro ML, Vergara P, Mariniello G, et al. early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: Tumour progression or radionecrosis? Clin Neurol Neurosurg 2009;111(4):331–3.