Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM.
Methods
This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day.
Results
The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS.
Conclusions
To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.
MauerMStuppRTaphoornMJThe prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study. Br J Cancer.2007;97 (3):302–307.
2.
StuppRHegiMEMasonWPEuropean Organisation for Research and Treatment of Cancer Brain Tumour 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 EORTC-NCIC trial. Lancet Oncol.2009;10 (5): 459–466.
3.
StuppRMasonWPvan den BentMJEuropean Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.2005;352 (10): 987–996.
4.
FilippiniGFalconeCBoiardiABrain Cancer Register of the Fondazione IRCCS (Istituto Ricovero e Cura a Carattere Scientifico) Istituto Neurologico Carlo Besta. Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma. Neuro-oncol.2008;10 (1):79–87.
5.
GonzálezDGMentenJBoschDAAccelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study. Radiother Oncol.1994;32 (2):98–105.
6.
HoriotJCvan den BogaertWAngKKEuropean Organization for Research on Treatment of Cancer trials using radiotherapy with multiple fractions per day. A 19781987 survey. Front Radiat Ther Oncol.1988;22:149–161.
7.
IuchiTHatanoKNaritaYKodamaTYamakiTOsatoKHypofractionated high-dose irradiation for the treatment of malignant astrocytomas using simultaneous integrated boost technique by IMRT. Int J Radiat Oncol Biol Phys.2006;64 (5): 1317–1324.
8.
LevinVAMaorMHThallPFPhase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme. Int J Radiat Oncol Biol Phys.1995;33 (2):357–364.
9.
NiederCAndratschkeNWiedenmannNBuschRGrosuALMollsMRadiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol.2004; 180 (7):401–407.
10.
BotturiMFariselliLClinical results of unconventional fractionation radiotherapy in central nervous system tumors. Tumori.1998;84 (2):176–187.
11.
AndersKGrabenbauerGGSchuchardtUAccelerated radiotherapy with concomitant ACNU/Ara-C for the treatment of malignant glioma. J Neurooncol.2000;48 (1):63–73.
12.
CaoJQFisherBJBaumanGSMegyesiJFWatlingCJMacdonaldDRHypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience. J Neurooncol.2012;107 (2):395–405.
13.
GuckenbergerMMayerMButtmannMVinceGHSweeneyRAFlentjeMProlonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme. Strahlenther Onkol.2011;187 (9):548–554.
14.
Panet-RaymondVSouhamiLRobergeDAccelerated 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):473–478.
15.
RaoRDThoméSDOFallonJEarleJDDinapoliRPBucknerJCSafety of thrice-daily hyperfractionated radiation and BCNU for high-grade gliomas. Int J Radiat Oncol Biol Phys.2002;53 (2): 376–384.
16.
AngKKvan der SchuerenENotterGSplit course multiple daily fractionated radiotherapy schedule combined with misonidazole for the management of grade III and IV gliomas. A pilot feasibility study of the Radiotherapy Group of the EORTC. Int J Radiat Oncol Biol Phys.1982;8 (10):1657–1664.
17.
NakajimaMNakasuSMorikawaSInubushiTEstimation of volume doubling time and cell loss in an experimental rat glioma model in vivo. Acta Neurochir (Wien).1998;140 (6):607–612, discussion 612-613.
18.
MarcuLGAltered fractionation in radiotherapy: from radiobiological rationale to therapeutic gain. Cancer Treat Rev.2010;36 (8): 606–614.
19.
FariselliLPinziVMilanesiIShort-course radiotherapy in elderly patients with glioblastoma: feasibility and efficacy of results from a single centre. Strahlenther Onkol.2013;189 (6):456–461.
MacdonaldDRCascinoTLScholdSCJrCairncrossJGResponse criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol.1990;8 (7):1277–1280.
22.
SimonROptimal two-stage designs for phase II clinical trials. Control Clin Trials.1989;10 (1):1–10.
23.
KaplanELMeierPNon parametric estimation for incomplete observation. J Am Stat Assoc.1958;53 (282):457–481.
24.
CoxDRRegression models and life tables. J R Stat Soc (Ser A).1972;34:187–202.
25.
BrandesAATosoniAFranceschiERecurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol.2009;27 (8):1275–1279.
26.
ChakravartiAErkkinenMGNestlerUTemozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res.2006;12 (15):4738–4746.
27.
ZhangMChakravartiANovel radiation-enhancing agents in malignant gliomas. Semin Radiat Oncol.2006;16 (1):29–37.
28.
BaoSWuQMcLendonREGlioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature.2006;444 (7120):756–760.
29.
JonesBSangheraPEstimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma. Int J Radiat Oncol Biol Phys.2007;68 (2):441–448.
30.
PaulssonAKMcMullenKPPeifferAMLimited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma. Am J Clin Oncol.2014;37 (2): 177–181.
31.
McDonaldMWShuHKCurranWJJrCrockerIRPattern of failure after limited margin radiotherapy and temozolomide for glioblastoma. Int J Radiat Oncol Biol Phys.2011;79 (1):130–136.
32.
HauEShenHClarkCGrahamPHKohESMcDonaldK.LThe evolving roles and controversies of radiotherapy in the treatment of glioblastoma. J Med Radiat Sci.2016;63 (2):114–123.
33.
IuchiTHatanoKKodamaTPhase 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 (4):793–800.
34.
ReddyKGasparLEKavanaghBDChenCHypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy may alter the patterns of failure in patients with glioblastoma multiforme. J Med Imaging Radiat Oncol.2014;58 (6):714–721.
35.
GebhardtBJDobelbowerMCEnnisWHBagAKMarkertJMFiveashJBPatterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide. Radiat Oncol.2014;9 (1):130.
36.
BlochOSafaeeMSunMZDisseminated progression of glioblastoma after treatment with bevacizumab. Clin Neurol Neurosurg.2013;115 (9):1795–1801.
37.
CanazzaACalatozzoloCFumagalliLIncreased migration of a human glioma cell line after in vitro CyberKnife irradiation. Cancer Biol Ther.2011;12 (7):629–633.
38.
BrandsmaDStalpersLTaalWSminiaPvan den BentMJClinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol.2008; 9 (5):453–461.
39.
ReulenHJPoepperlGGoetzCLong-term outcome of patients with WHO Grade III and IV gliomas treated by fractionated intracavitary radioimmunotherapy. J Neurosurg.2015;123 (3): 760–770.
40.
WenPYMacdonaldDRReardonDAUpdated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol.2010;28 (11):1963–1972.
