Radiotherapy For Brain Tumors Research Articles

Protection Of Neurocognitive Function During Cranial Irradiation Of Brain Tumors

Although radiation therapy can be effective against cancer, potential damage to normal tissues limits the amount that can be safely administered. In the central nervous system (CNS), radiation damage to normal tissues is associated with cognitive impairments. Chronic oxidative stress, neuroinflammation, suppressed hippocampal neurogenesis, and down regulation of the brain-derived neurotrophic factor (BDNF) have been identified as the causes for cognitive impairments following radiation therapy of the CNS. Based on these mechanisms, we tested two experimental drugs, each targeting a different pathway, for their ability to preserve normal tissue functions in experimental animals following cranial irradiation. The Mn porphyrin (MnP)-based redox active drug, MnTnBuOE-2-PyP5+ (MnBuOE), is able to cross the blood brain barrier and has been shown to protect normal tissues from radiation damage. Administration of MnBuOE for one week before cranial irradiation and continued for one week afterwards supported production and long-term survival of newborn neurons in the hippocampal dentate gyrus. However, prolonged administration of MnBuOE following cranial irradiation did not increase the efficacy further, suggesting the best therapeutic window for redox active drugs is centered around the time of irradiation. The small flavonoid compound 7,8-dihydroxyflavone (7,8-DHF) has been shown to activate the high affinity BDNF receptor, TrkB, and enhance dendrite outgrowth and neuronal survival. Chronic treatment with 7,8-DHF following cranial irradiation significantly restored spatial, contextual, and working memory, and this was achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity during the recovery phase following cranial irradiation. Given the different biological effects of the two experimental drugs, strategic use during their optimal therapeutic windows before and after cranial radiation therapy may achieve the best efficacy in preserving normal tissue functions.

Imaging and clinical end points in brain metastases trials.

Imaging and clinical end points in brain metastases trials.

Initial Investigation into Microbleeds and White Matter Signal Changes following Radiotherapy for Low-Grade and Benign Brain Tumors Using Ultra-High-Field MRI Techniques

External beam radiation therapy is a common treatment for many brain neoplasms. While external beam radiation therapy adheres to dose limits to protect the uninvolved brain, areas of high dose to normal tissue still occur. Patients treated with chemoradiotherapy can have adverse effects such as microbleeds and radiation necrosis, but few studies exist of patients treated without chemotherapy. Ten patients were treated for low-grade or benign neoplasms with external beam radiation therapy only and scanned within 12-36 months following treatment with a 7T MR imaging scanner. A multiecho gradient-echo sequence was acquired and postprocessed into SWI, quantitative susceptibility mapping, and apparent transverse relaxation maps. Six patients returned for follow-up imaging approximately 18 months following their first research scan and were imaged with the same techniques. At the first visit, 7/10 patients had microbleeds evident on SWI, quantitative susceptibility mapping, and apparent transverse relaxation. All microbleeds were within a dose region of >45 Gy. Additionally, 4/10 patients had asymptomatic WM signal changes evident on standard imaging. Further analysis with our technique revealed that these lesions were venocentric, suggestive of a neuroinflammatory process. There exists a potential for microbleeds in patients treated with external beam radiation therapy without chemotherapy. This finding is of clinical relevance because it could be a precursor of future neurovascular disease and indicates that additional care should be taken when using therapies such as anticoagulants. Additionally, the appearance of venocentric WM lesions could be suggestive of a neuroinflammatory mechanism that has been suggested in diseases such as MS. Both findings merit further investigation in a larger population set.

Contraintes de dose en radiothérapie conformationnelle fractionnée et en radiothérapie stéréotaxique dans les hippocampes, le tronc cérébral et l’encéphale : limites et perspectives

Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of α/β ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain.

Cataract incidence and severity after therapeutic radiation for brain tumors

To determine the incidence of cataract formation and requirement for cataract surgery in a pediatric population receiving therapeutic radiation for brain tumors (SJMB03). A lower risk group (LR), without known metastasis, received 23.4 Gy and a higher risk (HR), with known metastatic disease, received 36-39.6 Gy.

Compulsory military service as a measure of later physical and cognitive performance in male survivors of childhood cancer

Background: Compromised physical fitness and cognitive difficulties have been reported as late effects of cancer treatment during childhood. To assess this issue, the military rankings of cancer survivors in medical checkups at call-up, and conscripts’ physical and cognitive performance during the first weeks of compulsory military education were compared to those of matched population controls without a history of cancer.Material and methods: A total of 1680 male patients born between 1960 and 1992 with a malignancy diagnosed before the age of 16 who were alive at the call-up age (18 years) were identified using the Finnish Cancer Registry, and five age, sex and place of residence matched controls for each patient using the Population Register Centre. Data on military service were gathered from Finnish Defense Forces. A conditional logistic regression analysis, the GEE-method with the cumulative logit link function, the chi-square test, the chi-square test for trend and a one-way analysis of variance were used in different analyses.Results: Cancer survivors were exempted from military service more often than the controls (p < .001). The fit-for-service frequency was highest for survivors of kidney tumors (68%) and lowest after irradiated brain tumors (19%). In service, the results of the 12-min running test were poorer than those of controls for leukemia/non-Hodgkin lymphoma (p = .03) and brain tumor (p = .01) survivors. Interestingly, the standing long-jump test was the only muscle test for which survivor groups performed worse than controls. Performance on cognitive tests only differed from controls in brain tumor survivors.Conclusions: Exemption from service is still common under the current guidelines, but fit-for-service survivors do well in military education. These results can be used for reassuring survivors that completion of military service is possible for those fulfilling the national general guidelines for military fitness.

Impact of parametric uncertainty on estimation of the energy deposition into an irradiated brain tumor

Predictions of the total energy deposited into a brain tumor through X-ray irradiation are notoriously error-prone. We investigate how this predictive uncertainty is affected by uncertainty in both the location of the region occupied by a dose-enhancing iodinated contrast agent and the agent's concentration. This is done within the probabilistic framework in which these uncertain parameters are modeled as random variables. We employ the stochastic collocation (SC) method to estimate statistical moments of the deposited energy in terms of statistical moments of the random inputs, and the global sensitivity analysis (GSA) to quantify the relative importance of uncertainty in these parameters on the overall predictive uncertainty. A nonlinear radiation–diffusion equation dramatically magnifies the coefficient of variation of the uncertain parameters, yielding a large coefficient of variation for the predicted energy deposition. This demonstrates that accurate prediction of the energy deposition requires a proper treatment of even small parametric uncertainty. Our analysis also reveals that SC outperforms standard Monte Carlo, but its relative efficiency decreases as the number of uncertain parameters increases from one to three. A robust GSA ameliorates this problem by reducing this number.

Quality of life of irradiated brain tumor survivors treated with donepezil or placebo: Results of the WFU CCOP research base protocol 91105.

The health-related quality of life (HRQL) and fatigue of brain cancer survivors treated with donepezil or placebo for cognitive symptoms after radiation therapy were examined. One hundred ninety-eight patients who completed >30 Gy fractionated whole or partial brain irradiation at least 6 months prior to enrollment were randomized to either placebo or donepezil (5 mg for 6 weeks followed by 10 mg for 18 weeks) in a phase 3 trial. A neurocognitive battery, the Functional Assessment of Cancer Therapy-Brain (FACT-Br) and the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, was administered at baseline, 12 weeks, and 24 weeks. At 12 weeks, donepezil resulted in improvements in only emotional functioning (P = .04), with no significant effects at week 24. Associations by level of baseline cognitive symptoms (above or below the median score of the baseline FACT-Br "additional concerns/brain" subscale), indicated that participants with more baseline symptoms who received donepezil versus placebo, showed improvements in social (P = .02) and emotional well-being (P = .038), other concerns/brain (P = .003) and the FACT-Br total score (P = .004) at 12 weeks, but not 24 weeks. However, participants with fewer baseline symptoms randomized to donepezil versus placebo reported lower functional well-being at both 12 (P = .015) and 24 weeks (P = .009), and greater fatigue (P = .02) at 24 weeks. The positive impact of donepezil on HRQL was greater in survivors reporting more baseline cognitive symptoms. Donepezil had significantly worse effects on fatigue and functional well-being among participants with fewer baseline symptoms. Future interventions with donepezil should target participants with more baseline cognitive complaints to achieve greater therapeutic impact and lessen potential side effects of treatment.

Exercise training improves physical function and fitness in long-term paediatric brain tumour survivors treated with cranial irradiation

AimsWe examined the efficacy of exercise training for improving physical functioning and cardiopulmonary fitness in survivors of paediatric brain tumours (BTs) treated with cranial irradiation. MethodsWe conducted a controlled clinical trial with crossover of exercise training versus no training in the community in either a group or combined group/home setting. A volunteer sample of 28 children treated with cranial irradiation for brain tumours completed training (mean age = 11.53 years; mean time since diagnosis = 5.25 years). end-points were physical functioning assessed by four subtests from the Bruininks–Oseretsky Test of motor performance (BOT-2) and pro-rated work rate from a cycle ergometer. Linear mixed modelling was used to evaluate time, training, training setting, and carryover effects. ResultsAdherence to training was 84%. Performance on the BOT-2 was below average for all assessments. However, training resulted in improvement in bilateral coordination (F (1, 30) = 6.59, p = 0.02), irrespective of training setting and improved performance was maintained even approximately 12°weeks after training had ended (F (1, 24) = 9.60, p = 0.005). Training resulted in increased pro-rated work rate for participants in the group training setting only (F (1, 25) = 4.57, p = 0.04) and these participants maintained their improved work rate approximately 12°weeks after training had ended (F (1, 20) = 8.38, p = 0.01). ConclusionExercise training improves physical functioning and fitness in paediatric BT survivors. Exercise interventions that ameliorate adverse physical effects and promote health in long-term survivors are highly recommended in this vulnerable population. (ClinicalTrials.gov, NCT01944761).

Zero echo time MRI-only treatment planning for radiation therapy of brain tumors after resection

Using magnetic resonance imaging (MRI) as the sole imaging modality for patient modeling in radiation therapy (RT) is a challenging task due to the need to derive electron density information from MRI and construct a so-called pseudo-computed tomography (pCT) image. We have previously published a new method to derive pCT images from head T1-weighted (T1-w) MR images using a single-atlas propagation scheme followed by a post hoc correction of the mapped CT numbers using local intensity information. The purpose of this study was to investigate the performance of our method with head zero echo time (ZTE) MR images. To evaluate results, the mean absolute error in bins of 20 HU was calculated with respect to the true planning CT scan of the patient. We demonstrated that applying our method using ZTE MR images instead of T1-w improved the correctness of the pCT in case of bone resection surgery prior to RT (that is, an example of large anatomical difference between the atlas and the patient).

Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain.

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed.

PO-0894: Comparing the spatial integrity of 7 T and 3 T MR images for image-guided radiotherapy of brain tumors

PO-0894: Comparing the spatial integrity of 7 T and 3 T MR images for image-guided radiotherapy of brain tumors

Orthostatic myoclonus after brain tumor radiation: Insights from two lesional cases

IntroductionOrthostatic myoclonus (OM) is a recognized syndrome of gait unsteadiness accompanied by lower limb myoclonus provoked by the assumption of an upright posture. OM typically affects the elderly and is often associated with neurodegenerative disease. We sought to review the clinical and electrophysiologic characteristics of OM due to brain tumor treatment, the first reported lesional cases of this rare disorder. MethodsThe database of the Mayo Clinic Rochester Movement Disorders Laboratory was searched for all patients diagnosed with OM from January 2007 to December 2016. All available clinical, radiographic, and surface electromyographic data were reviewed, and patients with a history of primary or metastatic brain tumor were analyzed. ResultsTwo patients with OM and brain tumor were identified; both had undergone tumor resection and targeted brain radiation. Both patients complained of unsteadiness while walking and recurrent falls. Tumor pathology (atypical meningioma, gliosarcoma) was centered in the frontal lobe and extended to the supplementary motor area (SMA), pre-SMA, or prefrontal cortex. Medications did not improve gait. ConclusionTwo cases of brain tumor-related OM suggest that degeneration of frontal motor programming circuits underlies the pathophysiology of OM.

Clinical observation of radiotherapy combined with temozolomide in non-small cell lung cancer patients with brain metastases

Objective To investigate the recent curative effect and adverse reactions of radiotherapy combined with temozolomide in non-small cell lung cancer (NSCLC) patients with brain metastases. Methods The clinical date of 51 NSCLC patients with brain metastases were retrospective analyzed in Department of Radiation Oncology of Affiliated Hospital of Hebei University. Patients were divided into experimental group (n=26) and control group (n=25) according to the different treatment methods. The experimental group underwent whole brain and local tumor radiotherapy plus temozolomide. The control group only received whole brain and local tumor radiotherapy. The recent curative effect and adverse reactions of the two groups were analyzed. Results The Karnofsky performance status score of patients in the experimental group was obviously improved than that in the control group (76.2±6.4 vs. 72.8±5.3), with a significant difference (t=2.06, P=0.04). The total effective rate in the experimental group was higher than that in the control group (80.8% vs. 64.0%), but there was no statistically significant difference (χ2=1.80, P=0.18). Compared with the control group, the incidences of nausea and vomiting (80.8% vs. 28.0%) and bone marrow suppression (84.6% vs. 24.0%) in the experimental group were significantly higher, with significant differences (χ2=14.33, P=0.00; χ2=18.91, P=0.00). There were similar incidences of headache (69.2% vs. 60.1%), liver and kidney damage (73.1% vs. 64.0%) in the two groups, with no significant differences (χ2=0.47, P=0.49; χ2=0.47, P=0.49). Conclusion Radiotherapy combined with temozolomide can improve the quality of life in NSCLC patients with brain metastases, which has controllable and tolerable adverse reactions. Key words: Carcinoma, non-small-cell lung; Radiotherapy; Neoplasm metastases; Temozolomide

P03.20 Comparison of histopathology profiles in surgically resected cerebral radiation necrosis with recurrent irradiated brain tumor

P03.20 Comparison of histopathology profiles in surgically resected cerebral radiation necrosis with recurrent irradiated brain tumor

Microbleeds and cavernomas after radiotherapy for paediatric primary brain tumours

BackgroundWith the expected growth and aging of the population of primary central nervous system tumours (PCNST) survivors, attention to the radiation-induced late brain injury is fundamental. Late focal hemosiderin deposition (FHD) lesions, namely microbleeds and cavernomas, are among the presumable late cerebrovascular complications associated with radiotherapy for PCNST. ObjectiveTo explore association between PCNST radiotherapy and the occurrence FHD lesions and to address the correlation between the topographic location of these microvascular lesions with the focal radiotherapy location. MethodsRetrospective cohort study of 190 paediatric patients being followed for PCNST in a single referral oncological centre. The frequency of FHD lesions was compared between paediatric PCNST treated (n=132) and not treated (n=58) with brain radiation. Microbleed Anatomical Rating Scale (MARS) was used for systematic identification of these cerebrovascular lesions and to address the consistency between the topographic location of each lesion and the location of the focal radiotherapy area. Univariate analysis to address the role of variables such as tumour histology, location, gender and age of children at the beginning of radiotherapy, duration of follow-up and chemotherapy was performed. ResultsFHD lesions (microbleeds and cavernomas) occurred exclusively and in a high percentage (41.6%) in PCNST survivors treated with brain radiation. Younger age at the diagnosis (p=0.031), duration of follow-up (p=0.010) and embryonal histology (p=0.003) positively correlated with the occurrence FHD lesions. FHD lesions were topographically concordant with the brain focal irradiation area in 3/19 (15.8%) patients from the focal RT subgroup and in 22/111 (19.8%) patients from the WBRT plus focal RT subgroup. ConclusionOur study, which is one of the largest to date on the topic, shows that FHD lesions are a common complication after radiotherapy for childhood PCNST. The young brain is probably more susceptible to radiation-induced late cerebrovascular injury. Diffuse small vessel disease and ceiling effect may account for the low topographic concordance we found. The clinical implications of FHD lesions in this specific population are yet to be clarified.

Fractionated stereotactic radiotherapy for metastatic brain tumors that recurred after gamma knife radiosurgery results in acceptable toxicity and favorable local control.

To treat local recurrence of brain metastases after gamma knife radiosurgery (GKS), we have used fractionated stereotactic radiotherapy (SRT). The purpose of this study was to evaluate the efficacy and toxicity of SRT in these patients. Fifty locally recurrent metastatic brain tumors in 47 patients were treated with SRT. The median prescribed dose of GKS was 20Gy at the periphery. The median interval between the GKS (the last session in cases in which multiple GKS procedures were performed) and recurrence was 7.5 (range 1-33) months. Several dose-fractionation protocols were used for SRT, depending on the size and location of the tumor and previous GKS dose. The median prescribed dose of the SRT at the isocenter was 30Gy with a median of ten fractions. Among the 50 lesions treated with SRT, 26 did not recur locally before the patient's death or the last follow-up examination, and 24 recurred locally. The median follow-up period for the surviving patients was 24months after the first GKS procedure, and the overall survival rate was 80% at 1year and 57% at 2years. The median time to local re-recurrence after the SRT (16months) was significantly longer than the median interval between the last GKS and recurrence (7.5months; P<0.001). Only two patients developed ≥grade 2 radiation necrosis. Stereotactic radiotherapy appeared to be an effective treatment for recurrent metastatic brain tumors and yielded relatively good local control. The associated adverse events were generally acceptable.

Personalized Radiotherapy Planning Based on a Computational Tumor Growth Model

In this article, we propose a proof of concept for the automatic planning of personalized radiotherapy for brain tumors. A computational model of glioblastoma growth is combined with an exponential cell survival model to describe the effect of radiotherapy. The model is personalized to the magnetic resonance images (MRIs) of a given patient. It takes into account the uncertainty in the model parameters, together with the uncertainty in the MRI segmentations. The computed probability distribution over tumor cell densities, together with the cell survival model, is used to define the prescription dose distribution, which is the basis for subsequent Intensity Modulated Radiation Therapy (IMRT) planning. Depending on the clinical data available, we compare three different scenarios to personalize the model. First, we consider a single MRI acquisition before therapy, as it would usually be the case in clinical routine. Second, we use two MRI acquisitions at two distinct time points in order to personalize the model and plan radiotherapy. Third, we include the uncertainty in the segmentation process. We present the application of our approach on two patients diagnosed with high grade glioma. We introduce two methods to derive the radiotherapy prescription dose distribution, which are based on minimizing integral tumor cell survival using the maximum a posteriori or the expected tumor cell density. We show how our method allows the user to compute a patient specific radiotherapy planning conformal to the tumor infiltration. We further present extensions of the method in order to spare adjacent organs at risk by re-distributing the dose. The presented approach and its proof of concept may help in the future to better target the tumor and spare organs at risk.

P53 regulates disruption of neuronal development in the adult hippocampus after irradiation.

Inhibition of hippocampal neurogenesis is implicated in neurocognitive dysfunction after cranial irradiation for brain tumors. How irradiation results in impaired neuronal development remains poorly understood. The Trp53 (p53) gene is known to regulate cellular DNA damage response after irradiation. Whether it has a role in disruption of late neuronal development remains unknown. Here we characterized the effects of p53 on neuronal development in adult mouse hippocampus after irradiation. Different bromodeoxyuridine incorporation paradigms and a transplantation study were used for cell fate mapping. Compared with wild-type mice, we observed profound inhibition of hippocampal neurogenesis after irradiation in mice deficient in p53 despite the absence of acute apoptosis of neuroblasts. The putative neural stem cells were apoptosis resistant after irradiation regardless of p53 genotype. Cell fate mapping using different bromodeoxyuridine incorporation paradigms revealed enhanced activation of neural stem cells and their consequential exhaustion in the absence of p53 after irradiation. Both p53-knockout and wild-type mice demonstrated similar extent of microglial activation in the hippocampus after irradiation. Impairment of neuronal differentiation of neural progenitors transplanted in irradiated hippocampus was not altered by p53 genotype of the recipient mice. We conclude that by inhibiting neural progenitor activation, p53 serves to mitigate disruption of neuronal development after irradiation independent of apoptosis and perturbation of the neural stem cell niche. These findings suggest for the first time that p53 may have a key role in late effects in brain after irradiation.

Diffusion and perfusion weighted magnetic resonance imaging for tumor volume definition in radiotherapy of brain tumors

Accurate target volume delineation is crucial for the radiotherapy of tumors. Diffusion and perfusion magnetic resonance imaging (MRI) can provide functional information about brain tumors, and they are able to detect tumor volume and physiological changes beyond the lesions shown on conventional MRI. This review examines recent studies that utilized diffusion and perfusion MRI for tumor volume definition in radiotherapy of brain tumors, and it presents the opportunities and challenges in the integration of multimodal functional MRI into clinical practice. The results indicate that specialized and robust post-processing algorithms and tools are needed for the precise alignment of targets on the images, and comprehensive validations with more clinical data are important for the improvement of the correlation between histopathologic results and MRI parameter images.