User Tools

Site Tools


Recurrent glioblastoma (GBM)

Glioblastoma has an unfavorable prognosis mainly due to its high propensity for tumor recurrence. It has been suggested that GBM recurrence is inevitable after a median survival time of 32 to 36 weeks 1) 2).

Natural history

The natural history of recurrent GBM, is largely undefined for the following reasons:

1) Lack of uniform definition and criteria for tumor recurrence

2) Institutional variability in treatment philosophy

3) The heterogeneous nature of the disease, including location of recurrence and distinct mechanisms believed to contribute to known subtypes of GBM.

The criteria used to define recurrent glioblastoma GBM remain ambiguous due to the varied presentation of new lesions. First, the infiltrative nature of GBM cells makes it difficult to eliminate microscopic disease despite macroscopic gross-total resection. Studies have shown that GBM recurrence most often occurs in the form of a local continuous growth within 2 to 3 cm from the border of the original lesion 3) 4) 5).


One of the factors that cause recurrence is the strong migratory capacity of GBM cells. Wanibuchi et al., reported that actin, alpha, cardiac muscle 1 (ACTC1) could serve as a marker to detect GBM migration in clinical cases 6).

Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells (CSC) that contributes to tumor propagation, maintenance, and treatment resistance.

These cells are associated with vascular niches which regulate glioma stem cells (GSC) self-renewal and survival.

Studies suggest that while blood vessels support glioma stem cells, these tumor cells in turn may regulate and contribute to the tumor vasculature by transdifferentiating into endothelial cells directly or through the secretion of regulatory growth factors such as vascular endothelial growth factor (VEGF) and hepatoma derived growth factor (HDGF) 7).

Intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of GBM and its propensity to recur in patients 8) 9).


Generally, glioma recurrence is detected using imaging technology, such as computed tomography (CT) and magnetic resonance imaging (MRI).

Diagnosis of progression is complex given the possibility of pseudoprogression in glioblastoma. The Response Assessment in Neurooncology criteria increase the sensitivity for detecting progression.

Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease.

Increase in FLAIR signal of the fluid within the resection cavity is described as a highly specific and early sign for tumor recurrence in gliomas.

An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. 10).

Relative cerebral blood volume, as measured by T2 weighted image dynamic susceptibility contrast MRI imaging, represents the most robust and widely used perfusion MR imaging metric in neurooncology.

see Apparent diffusion coefficient

see Intravoxel incoherent motion

Visually imperceptible imaging patterns discovered via multiparametric pattern analysis methods (T1, T1-gadolinium, T2-weighted, T2-weighted fluid-attenuated inversion recovery, diffusion tensor imaging, and dynamic susceptibility contrast-enhanced magnetic resonance images) were found to estimate the extent of infiltration and location of future tumor recurrence, paving the way for improved targeted treatment 11).

Differential Diagnosis

Radiation necrosis and other normal responses associated with surgical treatment may lead to mimicking of tumor recurrence, also known as pseudoprogression in glioblastoma.

Single-photon emission computed tomography (SPECT), positron emission tomography (PET), perfusion CT, diffusion MRI, perfusion MRI, and magnetic resonance spectroscopy (MRS) are the imaging modalities in the clinical setting.

Determining whether glioblastoma multiforme (GBM) is progressing despite treatment is challenging due to the pseudoprogression in glioblastoma phenomenon seen on conventional MRIs, but relative cerebral blood volume (CBV) has been shown to be helpful.

Adding perfusion MRI imaging to the combination of Dynamic contrast enhanced MRI CE contrast enhanced T1-weighted imaging and Diffusion weighted magnetic resonance imaging significantly improves the prediction of recurrent glioblastoma; however, selection of perfusion MRI method does not affect the diagnostic performance 12).

The multiparametric 3-T MR assessment based on Proton magnetic resonance spectroscopic imaging (1H-MRSI), diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI) in addition to MRI is a useful tool to discriminate tumour recurrence/progression from radiation effects 13).

The regional cerebral blood volume (rCBVmax) in Perfusion MRI differentiates tumor progression from Treatment-related changes (TRC) in unselected recurrent glioblastomas, but it is not predictive for the overall survival (OS) 14).

Adding and combining proton MR spectroscopic imaging (1H-MRSI), diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) information at 3 Tesla facilitate such discrimination 15).


Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade.

Despite aggressive investigation, glioblastoma multiforme (GBM) remains one of the deadliest cancers, with low progression free survival (PFS) and high one-year mortality.

In the series of Tejada y col., recurrence pattern was local only in 65.5 % of patients and non-local in 34.5 %. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences 16).

Survival after repeat surgery was decreased in patients with recurrent GBM involving the subventricular zone SVZ at recurrence (p = 0.022). No other prognostic factors for survival after repeat surgery were identified. This finding may have prognostic and therapeutic significance 17).


Case series

Case reports

Corns et al. describe the case of a patient with recurrent glioblastoma encroaching on Broca's area. Gross total resection of the tumour was achieved by combining two techniques, awake craniotomy to prevent damage to eloquent brain and 5 aminolevulinic acid fluorescence guided resection to maximise the extent of tumour resection. This technique led to gross total resection of all T1-contrast enhancement tumour with the avoidance of neurological deficit. They recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery 18).

Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery. 1987 Nov;21(5):607-14. PubMed PMID: 2827051.
Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, Wilson CB. Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg. 1986 Nov;65(5):654-8. PubMed PMID: 3021931.
Durmaz R, Erken S, Arslantas A, et al: Management of glioblastoma multiforme: with special reference to recurrence. Clin Neurol Neurosurg 99:117–123, 1997
Halperin EC, Burger PC, Bullard DE: The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 15:505–509, 1988
Lee SW, Fraass BA, Marsh LH, et al: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43:79-88,1999
Wanibuchi M, Ohtaki S, Ookawa S, Kataoka-Sasaki Y, Sasaki M, Oka S, Kimura Y, Akiyama Y, Mikami T, Mikuni N, Kocsis JD, Honmou O. Actin, alpha, cardiac muscle 1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. J Neurol Sci. 2018 Jul 17;392:117-121. doi: 10.1016/j.jns.2018.07.013. [Epub ahead of print] PubMed PMID: 30055382.
Jhaveri N, Chen TC, Hofman FM. Tumor vasculature and glioma stem cells: contributions to glioma progression. Cancer Lett. 2014 Dec 16. pii: S0304-3835(14)00783-6. doi: 10.1016/j.canlet.2014.12.028. [Epub ahead of print] PubMed PMID: 25527451.
Cancer Genome Atlas Research Network: Comprehensive ge- nomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068, 2008
Nickel GC, Barnholtz-Sloan J, Gould MP, McMahon S, Cohen A, Adams MD, et al: Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. PLoS ONE 7:e35262, 2012
Bette S, Gempt J, Wiestler B, Huber T, Specht H, Meyer B, Zimmer C, Kirschke JS, Boeckh-Behrens T. Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? Rofo. 2017 Jan;189(1):63-70. doi: 10.1055/s-0042-119686. PubMed PMID: 28002859.
Akbari H, Macyszyn L, Da X, Bilello M, Wolf RL, Martinez-Lage M, Biros G, Alonso-Basanta M, OʼRourke DM, Davatzikos C. Imaging Surrogates of Infiltration Obtained Via Multiparametric Imaging Pattern Analysis Predict Subsequent Location of Recurrence of Glioblastoma. Neurosurgery. 2016 Apr;78(4):572-80. doi: 10.1227/NEU.0000000000001202. PubMed PMID: 26813856.
Kim HS, Goh MJ, Kim N, Choi CG, Kim SJ, Kim JH. Which combination of MR imaging modalities is best for predicting recurrent glioblastoma? Study of diagnostic accuracy and reproducibility. Radiology. 2014 Dec;273(3):831-43. doi: 10.1148/radiol.14132868. Epub 2014 May 30. PubMed PMID: 24885857.
Di Costanzo A, Scarabino T, Trojsi F, Popolizio T, Bonavita S, de Cristofaro M, Conforti R, Cristofano A, Colonnese C, Salvolini U, Tedeschi G. Recurrent glioblastoma multiforme versus radiation injury: a multiparametric 3-T MR approach. Radiol Med. 2014 Jan 10. [Epub ahead of print] PubMed PMID: 24408041.
Blasel S, Zagorcic A, Jurcoane A, Bähr O, Wagner M, Harter PN, Hattingen E. Perfusion MRI in the Evaluation of Suspected Glioblastoma Recurrence. J Neuroimaging. 2015 Apr 24. doi: 10.1111/jon.12247. [Epub ahead of print] PubMed PMID: 25907688.
Di Costanzo A, Scarabino T, Trojsi F, Popolizio T, Bonavita S, de Cristofaro M, Conforti R, Cristofano A, Colonnese C, Salvolini U, Tedeschi G. Recurrent glioblastoma multiforme versus radiation injury: a multiparametric 3-T MR approach. Radiol Med. 2014 Jan 10. [Epub ahead of print] PubMed PMID: 24408041.
Tejada S, Díez-Valle R, Aldave G, Marigil M, de Gallego J, Domínguez PD. Factors associated with a higher rate of distant failure after primary treatment for glioblastoma. J Neurooncol. 2014 Jan;116(1):169-75. doi:10.1007/s11060-013-1279-z. Epub 2013 Oct 18. PubMed PMID: 24135848; PubMed Central PMCID: PMC3889292.
Sonoda Y, Saito R, Kanamori M, Kumabe T, Uenohara H, Tominaga T. The Association of Subventricular Zone Involvement at Recurrence with Survival after Repeat Surgery in Patients with Recurrent Glioblastoma. Neurol Med Chir (Tokyo). 2013 Dec 27. [Epub ahead of print] PubMed PMID: 24390189.
Corns R, Mukherjee S, Johansen A, Sivakumar G. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme. BMJ Case Rep. 2015 Jul 15;2015. pii: bcr2014208575. doi: 10.1136/bcr-2014-208575. PubMed PMID: 26177997.
recurrent_glioblastoma.txt · Last modified: 2018/12/19 19:12 by administrador