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