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.
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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; · 2.83 Impact Factor
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ABSTRACT: Diffusion tensor imaging (DTI) is an MR-based technique that may better detect the peritumoural region than MRI. Our aim was to explore the feasibility of using DTI for target volume delineation in glioblastoma patients. MR tensor tracts and maps of the isotropic (p) and anisotropic (q) components of water diffusion were coregistered with CT in 13 glioblastoma patients. An in-house image processing program was used to analyse water diffusion in each voxel of interest in the region of the tumour. Tumour infiltration was mapped according to validated criteria and contralateral normal brain was used as an internal control. A clinical target volume (CTV) was generated based on the T1-weighted image obtained using contrast agent (T1Gd), tractography and the infiltration map. This was compared to a conventional T2-weighted CTV (T2-w CTV). Definition of a diffusion-based CTV that included the adjacent white matter tracts proved highly feasible. A statistically significant difference was detected between the DTI-CTV and T2-w CTV volumes (p < 0.005, t = 3.480). As the DTI-CTVs were smaller than the T2-w CTVs (tumour plus peritumoural oedema), the pq maps were not simply detecting oedema. Compared to the clinical planning target volume (PTV), the DTI-PTV showed a trend towards volume reduction. These diffusion-based volumes were smaller than conventional volumes, yet still included sites of tumour recurrence. Extending the CTV along the abnormal tensor tracts in order to preserve coverage of the likely routes of dissemination, whilst sparing uninvolved brain, is a rational approach to individualising radiotherapy planning for glioblastoma patients.Strahlentherapie und Onkologie 05/2014; · 2.73 Impact Factor
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ABSTRACT: Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rate and acceptable toxicity with the use of fractionated stereotactic radiosurgery in this patient population. Our primary objective was to determine the efficacy and toxicity of fractionated stereotactic radiosurgery combined with concurrent temozolomide chemotherapy as a salvage treatment for recurrent glioblastoma multiforme. We prospectively collected treatment and outcome data for patients having fractionated stereotactic radiosurgery for locally recurrent glioblastoma multiforme after radical radiotherapy. Eligible patients had a maximum recurrence diameter of 60 mm without causing significant mass effect. The gross tumor volume was defined as the enhancing lesion on an enhanced fine-slice T1 (spin-lattice) magnetic resonance imaging, and a circumferential setup margin of 1 mm was used to define the planning target volume. All patients were treated using robotic radiosurgery with three dose/fractionation schedules ranging from 25 to 35 Gy in five fractions, depending on the maximum tumor diameter. Concurrent temozolomide 75 mg/m(2) was prescribed to all patients. Tumor response was judged using the Macdonald criteria, and toxicity was assessed using the CTCAE (Common Terminology Criteria for Adverse Events). A total of 31 patients were enrolled in this study. The median overall survival was 9 months, and progression-free survival was 7 months. The 6-month progression-free survival was 60% with a 95% confidence interval of 43%-77%. The a priori stratification factor of small tumor diameter was shown to predict overall survival, while time to recurrence was not predictive of progression-free or overall survival. Three patients experienced grade 3 acute toxicity that responded to increased steroid dosing. One patient experienced a grade 4 acute toxicity that did not respond to increased steroids but did respond to anti-angiogenic therapy. Fractionated stereotactic radiosurgery with concurrent temozolomide has shown good short-term clinical and radiologic control with manageable acute toxicity. This regimen appears to provide superior efficacy to either temozolomide or fractionated radiosurgery alone. The results of this study support the continued evaluation of this regimen.OncoTargets and Therapy 01/2014; 7:485-90. · 1.34 Impact Factor