Radiotherapy For Primary Brain Tumors Research Articles

Late-onset vascular complications of radiotherapy for primary brain tumors: a case–control and cross-sectional analysis

PurposeRadiotherapy (RT) is a recognized risk factor for cerebrovascular (CV) disease in children and in adults with head and neck cancer. We aimed to investigate whether cerebral RT increases the risk of CV disease in adults with primary brain tumors (PBT).MethodsWe retrospectively identified adults with a supratentorial PBT diagnosed between 1975 and 2006 and with at least 10 years follow-up after treatment. We analyzed demographic, clinical, and radiological features with special attention to CV events. We also described CV events, vascular risk factors, and intracranial artery modifications in a cross-sectional study of irradiated patients alive at the time of the study.ResultsA total of 116 patients, treated with RT (exposed group), and 85 non-irradiated patients (unexposed group) were enrolled. Stroke was more frequent in irradiated PBT patients than in the unexposed group (42/116 (36%) vs 7/85 (8%); p < 0.001), with higher prevalence of both ischemic (27/116 (23%) vs 6/85 (7%); p = 0.004) and hemorrhagic (12/116 (10%) vs 1/85 (1%); p = 0.02) stroke. In the irradiated group, patients with tumors near the Willis Polygon were more likely to experience stroke (p < 0.016). Fourty-four alive irradiated patients were included in the cross-sectional study. In this subgroup, intracranial arterial stenosis was more prevalent (11/45, 24%) compared to general population (9%).ConclusionsStroke prevalence is increased in long-surviving PBT patients treated with cranial RT.Implications for cancer survivorsCV events are frequent in long survivors of PBT treated with cerebral RT. We propose a check list to guide management of late CV complications in adults treated with RT for PBT.

Dose reduction of hippocampus using HyperArc planning in postoperative radiotherapy for primary brain tumors.

To compare dosimetric parameters for the hippocampus, organs at risk (OARs), and targets of volumetric modulated arc therapy (VMAT), noncoplanar VMAT (NC-VMAT), and HyperArc (HA) plans in patients undergoing postoperative radiotherapy for primary brain tumors. For 20 patients, HA plans were generated to deliver 40.05 to 60 Gy for the planning target volume (PTV). In addition, doses for the hippocampus and OARs were minimized. The VMAT and NC-VMAT plans were retrospectively generated using the same optimization parameters as those in the HA plans. For the hippocampus, the equivalent dose to be administered in 2 Gy fractions (EQD2) was calculated assuming α/β = 2. Dosimetric parameters for the PTV, hippocampus, and OARs in the VMAT, NC-VMAT, and HA plans were compared. For PTV, the HA plans provided significantly lower Dmax and D1% than the VMAT and NC-VMAT plans (p < 0.05), whereas the D99% and Dmin were significantly higher (p < 0.05). For the contralateral hippocampus, the dosimetric parameters in the HA plans (8.1 ± 9.6, 6.5 ± 7.2, 5.6 ± 5.8, and 4.8 ± 4.7 Gy for D20%, D40%, D60% and D80%, respectively) were significantly smaller (p < 0.05) than those in the VMAT and NC-VMAT plans. Except for the optic chiasm, the Dmax in the HA plans (brainstem, lens, optic nerves, and retinas) was the smallest (p < 0.05). In addition, the doses in the HA plans for the brain and skin were the smallest (p < 0.05) among the 3 plans. HA planning, instead of coplanar and noncoplanar VMAT, significantly reduces the dosage to which the contralateral hippocampus as well as other OARs are exposed without compromising on target coverage.

Image-based data mining applies to data collected from children

PurposeImage-based data mining (IBDM) is a novel voxel-based method for analyzing radiation dose responses that has been successfully applied in adult data. Because anatomic variability and side effects of interest differ for children compared to adults, we investigated the feasibility of IBDM for pediatric analyses. MethodsWe tested IBDM with CT images and dose distributions collected from 167 children (aged 10 months to 20 years) who received proton radiotherapy for primary brain tumors. We used data from four reference patients to assess IBDM sensitivity to reference selection. We quantified spatial-normalization accuracy via contour distances and deviations of the centers-of-mass of brain substructures. We performed dose comparisons with simplified and modified clinical dose distributions with a simulated effect, assessing their accuracy via sensitivity, positive predictive value (PPV) and Dice similarity coefficient (DSC). ResultsSpatial normalizations and dose comparisons were insensitive to reference selection. Normalization discrepancies were small (average contour distance < 2.5 mm, average center-of-mass deviation < 6 mm). Dose comparisons identified differences (p < 0.01) in 81% of simplified and all modified clinical dose distributions. The DSCs for simplified doses were high (peak frequency magnitudes of 0.9–1.0). However, the PPVs and DSCs were low (maximum 0.3 and 0.4, respectively) in the modified clinical tests. ConclusionsIBDM is feasible for childhood late-effects research. Our findings may inform cohort selection in future studies of pediatric radiotherapy dose responses and facilitate treatment planning to reduce treatment-related toxicities and improve quality of life among childhood cancer survivors.

Modelling Neurocognitive Change Using Brain Substructure Dosimetry In Adults With Primary Brain Tumors

The contribution of radiotherapy (RT) dose to brain substructures on neurocognitive function in adults is unclear, beyond the known role of the hippocampus. The goal of this study was to identify brain substructures associated with neurocognitive decline in adults treated with RT for primary brain tumors. In this retrospective cohort study, adults with a primary brain tumor treated with fractionated photon RT at a single institution were included if they had ≥2 neurocognitive assessments (with ≥1 done post-RT) and had accessible RT dosimetry (i.e. 2004 and later). Neurocognitive assessments performed after recurrence were excluded. Neurocognitive tests were scored according to published criteria, converted to z-scores (mean 0, SD 1) and averaged to create nine cognitive domains (language, visual-spatial, attention, working memory, speed, executive function, verbal/visual memory, motor dexterity). Brain substructures (whole brain, infratentorial region, left/right (L/R) ventral/dorsal frontal, subcortical, L/R parieto-occipital, L/R temporal, L/R hippocampi regions) were contoured and dosimetric parameters (mean, D40, D50) were collected. Multivariable linear mixed effects models were used to model cognitive domain endpoints, with time from RT and dose to different brain regions as fixed effects and patient-specific random intercepts. Thirty patients met eligibility criteria. Patients had a median of two neurocognitive assessments (range, 2-4). Median neurocognitive follow-up was 3.9 years (range, 0.5-13.8; time between first and last evaluation). Median time from first assessment to RT was 0.05 years (range, 0.15 years before to 0.80 years after). Diagnoses included meningioma (n = 11), medulloblastoma (n = 5), germinoma (n = 2), craniopharyngioma (n = 2), low-grade glioma (n = 2), high-grade glioma (n = 2), and other (n = 6). Median age at RT was 41 years (17-71). 63% of patients were treated with focal RT; the remainder had whole brain (WB) or craniospinal irradiation. WB/CSI doses ranged from 25-54 Gy while total brain doses ranged from 40-70 Gy. Neurocognitive endpoints associated with RT dosimetry were visual memory (mean dose to left ventral-frontal region, p = 0.030; mean dose to subcortical region, p = 0.032) and motor dexterity (mean dose to left parieto-occipital region, p = 0.032). This is one of the few studies to evaluate correlations between neurocognitive function in adults with primary brain tumors and dosimetry to specific brain substructures, beyond the hippocampus and memory. These findings will guide suggested avoidance structures during RT planning as well as quantify the neurocognitive benefit of conformal RT methods, such as proton therapy.

Epworth Sleepiness Scale- a novel tool to assess somnolence syndrome in patients receiving radiotherapy to the brain

Purpose: Radiation to brain causes early, early-delayed, and delayed side effects. There is paucity of literature regarding early-delayed effects like somnolence syndrome. Existing studies use general symptom assessment and visual analog scales. Epworth Sleepiness Scale (ESS) is a time tested tool to assess daytime sleepiness in various conditions. In this study, the ESS has been used to determine the occurrence of somnolence in patients receiving cranial radiotherapy for primary and metastatic brain tumors. Thus the ESS has been used in a novel setting in our study. The ESS is a simple to administer questionnaire and may be useful in grading the severity of somnolence. To our knowledge, this is the second study to determine post radiation somnolence using ESS. Methods: This prospective study was conducted in 23 patients with primary and metastatic brain tumor. Patient demographics and tumor type and grade was noted. Those with Karnofsky Performance Scale (KPS) less than 70 and with pre-existing sleep disorders were excluded. Radiotherapy regimen included palliative whole brain radiation for brain metastases and conformal adjuvant radiotherapy for primary brain tumors as per standard guidelines. All subjects included were administered ESS at baseline and weekly thereafter during and for 6 weeks after radiation. Results: All 23 patients (median age 50 years) completed the planned questionnaires until 6 weeks post radiation. Twenty (87%) patients had primary brain tumors whereas three (13%) patients had metastatic lesions in brain. Of the 23 patients, 14 patients (60.86%) had abnormal or increased daytime sleepiness; of which 3 had ESS scores greater than 16. Conclusion: Somnolence was noted in 60.86% of the patients, which is in accordance with existing literature. Epworth sleepiness scale is an effective tool to detect and quantify somnolence, However, it does not consider other symptoms of somnolence syndrome and hence should be combined with visual analog scale to get complete information.

Automated delineation of brain structures in patients undergoing radiotherapy for primary brain tumors: From atlas to dose–volume histograms

PurposeTo implement and evaluate a magnetic resonance imaging atlas-based automated segmentation (MRI-ABAS) procedure for cortical and sub-cortical grey matter areas definition, suitable for dose-distribution analyses in brain tumor patients undergoing radiotherapy (RT). Patients and methods3T-MRI scans performed before RT in ten brain tumor patients were used. The MRI-ABAS procedure consists of grey matter classification and atlas-based regions of interest definition. The Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm was applied to structures manually delineated by four experts to generate the standard reference. Performance was assessed comparing multiple geometrical metrics (including Dice Similarity Coefficient – DSC). Dosimetric parameters from dose–volume-histograms were also generated and compared. ResultsCompared with manual delineation, MRI-ABAS showed excellent reproducibility [median DSCABAS=1 (95% CI, 0.97–1.0) vs. DSCMANUAL=0.90 (0.73–0.98)], acceptable accuracy [DSCABAS=0.81 (0.68–0.94) vs. DSCMANUAL=0.90 (0.76–0.98)], and an overall 90% reduction in delineation time. Dosimetric parameters obtained using MRI-ABAS were comparable with those obtained by manual contouring. ConclusionsThe speed, reproducibility, and robustness of the process make MRI-ABAS a valuable tool for investigating radiation dose–volume effects in non-target brain structures providing additional standardized data without additional time-consuming procedures.

Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base

To analyze clinical concepts, toxicity and treatment outcome in patients with brain and skull base tumors treated with photons and particle therapy. Material and methods. In total 260 patients with brain tumors and tumors of the skull base were treated at the Heidelberg Ion Therapy Center (HIT). Patients enrolled in and randomized within prospective clinical trials as well as bony or soft tissue tumors are not included in this analysis. Treatment was delivered as protons, carbon ions, or combinations of photons and a carbon ion boost. All patients are included in a tight follow-up program. The median follow-up time is 12 months (range 2–39 months). Results. Main histologies included meningioma (n = 107) for skull base lesions, pituitary adenomas (n = 14), low-grade gliomas (n = 51) as well as high-grade gliomas (n = 55) for brain tumors. In all patients treatment could be completed without any unexpected severe toxicities. No side effects > CTC Grade III were observed. To date, no severe late toxicities were observed, however, for endpoints such as secondary malignancies or neurocognitive side effects follow-up time still remains too short. Local recurrences were mainly seen in the group of high-grade gliomas or atypical meningiomas; for benign skull base meningiomas, to date, no recurrences were observed during follow-up. Conclusion. The specific benefit of particle therapy will potentially reduce the risk of secondary malignancies as well as improve neurocognitive outcome and quality of life (QOL); thus, longer follow-up will be necessary to confirm these endpoints. Indication-specific trials on meningiomas and gliomas are underway to elucidate the role of protons and carbon ions in these indications.

Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts

BackgroundParticle irradiation was established at the University of Heidelberg 2 years ago. To date, more than 400 patients have been treated including patients with primary brain tumors. In malignant glioma (WHO IV) patients, two clinical trials have been set up-one investigating the benefit of a carbon ion (18 GyE) vs. a proton boost (10 GyE) in addition to photon radiotherapy (50 Gy), the other one investigating reirradiation with escalating total dose schedules starting at 30 GyE. In atypical meningioma patients (WHO °II), a carbon ion boost of 18 GyE is applied to macroscopic tumor residues following previous photon irradiation with 50 Gy.This study was set up in order to investigate toxicity and response after proton and carbon ion therapy for gliomas and meningiomas.Methods33 patients with gliomas (n = 26) and meningiomas (n = 7) were treated with carbon ion (n = 26) and proton (n = 7) radiotherapy. In 22 patients, particle irradiation was combined with photon therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients with gliomas. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and PET imaging. Response was assessed by MRI examinations, and progression was diagnosed according to the Macdonald criteria. Toxicity was classified according to CTCAE v4.0.ResultsTreatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial nerve symptoms (6%) and single episodes of seizures (6%). At first and second follow-up examinations, mean maximum tumor diameters had slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively. Nine glioma patients suffered from tumor relapse, among these 5 with infield relapses, causing death in 8 patients. There was no progression in any meningioma patient.ConclusionsParticle radiotherapy is safe and feasible in patients with primary brain tumors. It is associated with little toxicity. A positive response of both gliomas and meningiomas, which is suggested in these preliminary data, must be evaluated in further clinical trials.

164. 1H-MR Spectroscopy of normal brain tissue before and after postoperative radiotherapy for primary brain tumors

Purpose The aim of the study was to reveal the impact of postoperative radiotherapy (pRT) on normai brain tissue metabolism and find out, if proton magnetic resonance spectroscopy (1 HMRS) can help in delineating tumor recurrence area. Methods and Material Spectra of 43 patients treated with pRT for glial tumors assessed by 1H-MRS were analyzed. Patients were treated with conformal 3D techniques using 6–20 MV photons to the total dose dr 60 Gy given in 30 fractions. Control group consisted of spectra registered for 30 healthy volunteers. Spectra were taken from tumor bed and from control region before pRT and from a 3 uninvolved regions 9–12 months after the end of pRT. Voxels were located in the region of low, medium and high total dose. Relative intensities of the signals due to N-acetyl aspartate (NAA), choline based compounds (Cho), mio-lnositol (ml), lactate (Lac) and lipids (Lip) were obtained. The statistical difference between means was calculated using Mann-Whitney U-test for independent samples or paired Wilcoxon test for the different dose levels for one patient. Results Spectra taken after pRT were significantly different from those obtained from healthy volunteers and those acquired before radiotherapy. The lactate and lipids signals were strong and not correlated with absorbed dose. NAA/Cr ratios were significantly lower than before pRT even for the low dose regions. These differences were increasing with radiation dose. Cho/Cr and Cho/NAA ratios increased significantly in medium and high dose area. Conclusion 1H-MRS can not help in delineating tumor recurrence area after pRT. Surgery and pRT cause alteration of brain metabolism even in regions far from the postoperative tumor bed that received relatively low total radiation dose.

Radiotherapy for primary brain tumors in very young children.

Ninety-one children younger than age five years have been treated with radiotherapy for primary intracranial tumors. Patients with cerebellar astrocytomas and optic chiasm gliomas did relatively well, whereas brain stem tumors, extensive posterior fossa tumors and cerebral gliomas had a poor prognosis. Medulloblastomas, ependymomas, and midbrain tumors were of intermediate prognosis. There was no definite correlation between age at diagnosis and survival, although patients over 24 months of age seemed to do slightly better. Tumor doses of at least 4000 rad seem necessary for any likelihood of control. Of 63 children diagnosed over five years ago, 27 (43%) survived at least five years. The majority of long-term survivors are leading normal lives, although many have mild impairments.