Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide
ABSTRACT To analyze the recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with conformal radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ), and to compare the patterns of failure according to different target volume delineations.
One hundred and five patients with GBM which recurred after three-dimensional (3D) conformal RT plus TMZ were evaluated. The clinical target volume (CTV) used for our treatment planning (S'Andrea plans) consisted of residual tumor and resection cavity plus 2-cm margins according to recent randomized trials of the European Organisation for Research and Treatment of Cancer (EORTC). MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. For each patient a theoretical plan based on the addition of postoperative edema plus 2-cm margins according to current guidelines of Radiation Therapy Oncology Group (RTOG) was created and patterns of failure were evaluated.
The median overall survival and progression-free survival were 14.2 months and 7.5 months, respectively. Recurrences were central in 79 patients, in-field in 6 patients, marginal in 6 patients, and distant in 14 patients. Analysis of O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred central/in-field and outside in 64% and 31% of methylated patients, and in 91% and 5.4% of unmethylated patients, respectively (P=0.01). Patterns of failure were similar between the different treatment plans, however the median volume percent of brain irradiated to high doses was significantly smaller for our plans than for RTOG plans (P=0.0001).
Most of patients treated with RT plus concomitant and adjuvant RT have central recurrences, however distant new lesions may occur in more than 10% of patients. The use of target delineation using postoperative residual tumor and cavity plus 2-cm margins is associated with smaller volumes of normal brain irradiated to high doses as compared with plans including expanded edema, without a significant increase of the risk of marginal recurrences. Future clinical randomized studies need to compare the different planning methods in terms of efficacy and risk of late radiation-induced toxicity.
- SourceAvailable from: Muna Aryal
- "This tumor is highly infiltrative, and recurrence after localized treatments such as conformal radiotherapy or surgery is common. This relapse usually occurs within a few cm of the treated region   . The introduction of temozolomide, a small molecule chemotherapy agent that has some penetration across the BBB, has improved clinical outcomes , but this improvement has been modest. "
Dataset: Aryal 2013 JCR
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- "More recently, Farace et al.  showed that huge changes in oedema are observed between pre-and postoperative MRI, which may be a consequence of steroid treatment and changes in mass effect and does not support the deliberate inclusion of the T2 abnormality in the CTV. In the modern era of radiotherapy with temozolomide, Minniti et al.  analysed 105 patients with recurrent GBM treated to a CTV comprising enhancing tumour plus 2 cm. They also constructed theoretical plans, including peritumoural oedema with a 2 cm margin, and concluded that treating the smaller volumes (without intentional inclusion of oedema) reduced the brain volumes treated to a high dose without a significant increase in the "
ABSTRACT: Here we review current practices in target volume delineation for radical radiotherapy planning for gliomas. Current radiotherapy planning margins for glioma are informed by historic data of recurrence patterns using radiological imaging or post-mortem studies. Radiotherapy planning for World Health Organization grade II-IV gliomas currently relies predominantly on T1-weighted contrast-enhanced magnetic resonance imaging (MRI) and T2/fluid-attenuated inversion recovery sequences to identify the gross tumour volume (GTV). Isotropic margins are added empirically for each tumour type, usually without any patient-specific individualisation. We discuss novel imaging techniques that have the potential to influence radiotherapy planning, by improving definition of the tumour extent and its routes of invasion, thus modifying the GTV and allowing anisotropic expansion to a clinical target volume better reflecting areas at risk of recurrence. Identifying the relationships of tumour boundaries to important white matter pathways and eloquent areas of cerebral cortex could lead to reduced normal tissue complications. Novel magnetic resonance approaches to identify tumour extent and invasion include: (i) diffusion-weighted magnetic resonance metrics; (ii) diffusion tensor imaging; and (iii) positron emission tomography, using radiolabelled amino acids methyl-11C-L-methionine and 18F-fluoroethyltyrosine. Novel imaging techniques may also have a role together with clinical characteristics and molecular genetic markers in predicting response to therapy. Most significant among these techniques is dynamic contrast-enhanced MRI, which uses dynamic acquisition of images after injection of intravenous contrast. A number of studies have identified changes in diffusion and microvascular characteristics occurring during the early stages of radiotherapy as powerful predictive biomarkers of outcome.Clinical Oncology 05/2014; 26(7). DOI:10.1016/j.clon.2014.04.026 · 2.83 Impact Factor
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- "Despite aggressive surgical resections followed by the currently available therapeutic interventions, such as radiation therapy and chemotherapeutical protocols, improvement in glioma patients' outcomes is still quite limited. The median survival rates of patients with the most malignant glioma, glioblastoma multiforme is within the range of 12–14 months after diagnosis (Adamson et al., 2009; Gerstein et al., 2010; Minniti et al., 2010). Therefore, it is imperative to further study the molecular mechanisms underlying gliomagenesis for the development of novel therapies that effectively target the pathological alterations. "
ABSTRACT: Glioma is the most common highly malignant primary brain tumor. The molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found microRNA-107 (miR-107) was downregulated in glioma tissues and cell lines. Our results revealed miR-107 overexpression suppressed cell proliferation in glioma cells, whereas miR-107 knockdown promoted cell growth in MO59K. miR-107 expression induced apoptosis in glioma cells possibly through the increase in Fas (TNFRSF6)-associated via death domain (FADD) expression and activation of caspases-8 and -3/7. Moreover, the activity of caspase-8 in miR-107-overexpressing SHG44 cells was suppressed with FADD knockdown. The tumor growth in nude mice bearing miR-107-overexpressing SHG44 cells was blocked through apoptosis induction. Sal-like 4 (Drosophila) (SALL4) level was reduced upon miR-107 overexpression in glioma cells, and the inverse was observed upon miR-107 knockdown in MO59K. Using a luciferase reporter system, SALL4 3'-UTR-dependent luciferase activity was reduced by miR-107 mimics or increased by an inhibitor of miR-107. In SHG44, SALL4 downregulation triggered growth inhibition and activated FADD-mediated cell apoptosis pathway. The caspase-8 activity in miR-107-overexpressing SHG44 cells was suppressed with SALL4 upregulation. Furthermore, primary glioma tumors with low miR-107 expression show elevated SALL4 level. An obvious inverse correlation was observed between miR-107 expression and SALL4 level in clinical glioma samples. Therefore, our results demonstrate upregulation of miR-107 suppressed glioma cell growth through direct targeting of SALL4, leading to the activation of FADD/caspase-8/caspase-3/7 signaling pathway of cell apoptosis. These data suggest miR-107 is a potential therapeutic target against glioma.The international journal of biochemistry & cell biology 06/2013; 45(9). DOI:10.1016/j.biocel.2013.06.008 · 4.24 Impact Factor