Hippocampal sparing radiotherapy for glioblastoma patients: a planning study using volumetric modulated arc therapy

Background: The purpose of this study is to investigate the potential to reduce exposure of the contralateral hippocampus in radiotherapy for glioblastoma using volumetric modulated arc therapy (VMAT). Methods: Datasets of 27 patients who had received 3D conformal radiotherapy (3D-CRT) for glioblastoma with a prescribed dose of 60Gy in fractions of 2Gy were included in this planning study. VMAT plans were optimized with the aim to reduce the dose to the contralateral hippocampus as much as possible without compromising other parameters. Hippocampal dose and treatment parameters were compared to the 3D-CRT plans using the Wilcoxon signed-rank test. The influence of tumour location and PTV size on the hippocampal dose was investigated with the Mann-Whitney-U-test and Spearman's rank correlation coefficient. Results: The median reduction of the contralateral hippocampus generalized equivalent uniform dose (gEUD) with VMAT was 36 % compared to the original 3D-CRT plans (p < 0.05). Other dose parameters were maintained or improved. The median V30Gy brain could be reduced by 17.9 % (p < 0.05). For VMAT, a parietal and a non-temporal tumour localisation as well as a larger PTV size were predictors for a higher hippocampal dose (p < 0.05). Conclusions: Using VMAT, a substantial reduction of the radiotherapy dose to the contralateral hippocampus for patients with glioblastoma is feasible without compromising other treatment parameters. For larger PTV sizes, less sparing can be achieved. Whether this approach is able to preserve the neurocognitive status without compromising the oncological outcome needs to be investigated in the setting of prospective clinical trials

Multifocal high-grade glioma radiotherapy safety and efficacy

BACKGROUND Multifocal manifestation of high-grade glioma is a rare disease with very unfavourable prognosis. The pathogenesis of multifocal glioma and pathophysiological differences to unifocal glioma are not fully understood. The optimal treatment of patients suffering from multifocal high-grade glioma is not defined in the current guidelines, therefore individual case series may be helpful as guidance for clinical decision-making. METHODS Patients with multifocal high-grade glioma treated with conventionally fractionated radiation therapy (RT) in our institution with or without concomitant chemotherapy between April 2011 and April 2019 were retrospectively analysed. Multifocality was neuroradiologically assessed and defined as at least two independent contrast-enhancing foci in the MRI T1 contrast-enhanced sequence. IDH mutational status and MGMT methylation status were assessed from histopathology records. GTV, PTV as well as the V30Gy, V45Gy and D2% volumes of the brain were analysed. Overall and progression-free survival were calculated from the diagnosis until death and from start of radiation therapy until diagnosis of progression of disease in MRI for all patients. RESULTS 20 multifocal glioma cases (18 IDH wild-type glioblastoma cases, one diffuse astrocytic glioma, IDH wild-type case with molecular features of glioblastoma and one anaplastic astrocytoma, IDH wild-type case) were included into the analysis. Resection was performed in two cases and stereotactic biopsy only in 18 cases before the start of radiation therapy. At the start of radiation therapy patients were 61~years old in median (range 42-84~years). Histopathological examination showed IDH wild-type in all cases and MGMT promotor methylation in 11 cases (55%). Prescription schedules were 60~Gy (2~Gy × 30), 59.4~Gy (1.8~Gy × 33), 55~Gy (2.2~Gy × 25) and 50~Gy (2.5~Gy × 20) in 15, three, one and one cases, respectively. Concomitant temozolomide chemotherapy was applied in 16 cases, combined temozolomide/lomustine chemotherapy was applied in one case and concomitant bevacizumab therapy in one case. Median number of GTVs was three. Median volume of the sum of the GTVs was 26 cm3. Median volume of the PTV was 425.7 cm3 and median PTV to brain ratio 32.8 percent. Median D2% of the brain was 61.5~Gy (range 51.2-62.7) and median V30Gy and V45 of the brain were 59.9 percent (range 33-79.7) and 40.7 percent (range 14.9-64.1), respectively. Median survival was eight months (95% KI 3.6-12.4~months) and median progression free survival after initiation of RT five months (95% CI 2.8-7.2~months). Grade 2 toxicities were detected in eight cases and grade 3 toxicities in four cases consisting of increasing edema in three cases and one new-onset seizure. One grade 4 toxicity was detected, which was febrile neutropenia related to concomitant chemotherapy. CONCLUSION Conventionally fractionated RT with concomitant chemotherapy could safely be applied in multifocal high-grade glioma in this case series despite large irradiation treatment fields

Simultaneous stereotactic radiosurgery of multiple brain metastases using single-isocenter dynamic conformal arc therapy: a prospective monocentric registry trial

BACKGROUND Single-isocenter dynamic conformal arc (SIDCA) therapy is a~technically efficient way of delivering stereotactic radiosurgery (SRS) to multiple metastases simultaneously. This study reports on the safety and feasibility of linear accelerator (LINAC) based SRS with SIDCA for patients with multiple brain metastases. METHODS All patients who received SRS with this technique between November 2017 and June 2019 within a~prospective registry trial were included. The patients were irradiated with a~dedicated planning tool for multiple brain metastases using a~LINAC with a~5 mm multileaf collimator. Follow-up was performed every 3~months, including clinical and radiological examination with cranial magnetic resonance imaging (MRI). These early data were analyzed using descriptive statistics and the Kaplan-Meier method. RESULTS A total of 65~patients with 254 lesions (range 2-12) were included in this analysis. Median beam-on time was 23 min. The median follow-up at the time of analysis was 13~months (95% CI 11.1-14.9). Median overall survival and median intracranial progression-free survival was 15~months (95% CI 7.7-22.3) and 7~months (95% CI 3.9-10.0), respectively. Intracranial and local control after 1~year was 64.6~and 97.5%, respectively. During follow-up, CTCAE grade~I adverse effects (AE) were experienced by 29~patients (44.6%; 18~of them therapy related, 27.7%), CTCAE grade~II~AEs by four patients (6.2%; one of them therapy related, 1.5%), and CTCAE grade~III~by three patients (4.6%; none of them therapy related). Two lesions (0.8%) in two patients (3.1%) were histopathologically proven to be radiation necrosis. CONCLUSION Simultaneous SRS using SIDCA seems to be a~feasible and safe treatment for patients with multiple brain metastases

Quantification and management of uncertainties in radiation therapy

For the therapeutic success of radiotherapy treatment it is crucial that the actual dose distribution delivered to a patient coincides as precisely as possible with the planned distribution, since deviations might lead to unexpected treatment toxicities or tumor recurrences. In this cumulative dissertation, an approach for patient positioning to manage the impact of anatomical changes in photon therapy is evaluated, and a framework for quantitative analyses of various types of uncertainty in proton therapy is developed. In the first project, an existing algorithm for scatter correction of cone beam computed tomography (CBCT) images is used to enable a dose recalculation on the changed patient anatomy. This is combined with a software tool for multi-criterial optimization of the patient position based on dosimetric parameters. The feasibility of the approach is shown for two clinical datasets of head and neck cancer patients, and potential benefits in comparison with the clinical standard - a rigid registration of the CBCT to the planning images - are evaluated. It is concluded that the approach offers increased control over target coverage and organ-at-risk (OAR) doses, since in many cases target coverage or OAR dose could be improved compared to the rigid image registration approach. However, for pronounced anatomical changes, both approaches were unable to restore an acceptable target coverage. In the second project of this thesis, a framework for variance-based sensitivity analysis of uncertainties in proton therapy was developed. With a fast, GPU-based pencil beam algorithm, a large number of error scenarios for a proton therapy treatment plan can be calculated. In these scenarios, patient position, proton range and relative biological effectiveness (RBE) model parameters are varied simultaneously and independently within their assumed uncertainty distributions. With this Monte Carlo approach, also interactions between multiple types of uncertainty are taken into account. For the dose distribution and dosimetric parameters such as dose volume histogram (DVH) quantiles for target structures and OARs the overall uncertainty as well as sensitivity indices are calculated. These indices allow for a ranking of the individual input uncertainties with respect to their impact on the overall uncertainty. The feasibility and the capabilities of the framework are shown with two clinical patient datasets. In a further step, the framework is extended to include IOV in target definition. In a study with ten patients and 10 observers, the impact of IOV in comparison with setup and range uncertainty on clinical target volume (CTV) coverage is evaluated. For two out of ten patients, a relevant impact of IOV was found. In future studies, this framework might help to determine which types of uncertainty are driving the overall uncertainty of clinically relevant dosimetric parameters and might help to prioritize research attempts aiming at the reduction of uncertainty.Für den Therapieerfolg in der Strahlentherapie ist es von essentieller Bedeutung, dass die applizierte Dosisverteilung möglichst genau mit der geplanten übereinstimmt, da Abweichungen zu unerwarteten Nebenwirkungen oder Rezidiven führen können. Die vorliegende kumulative Arbeit befasst sich mit einem Konzept zur Positionierungkorrektur in der Photonentherapie zur Minimierung des dosimetrischen Einflusses von anatomischen Veränderungen in der Photonentherapie und mit der quantitativen Analyse des Zusammenspiels verschiedener Quellen von dosimetrischer Unsicherheit in der Protonentherapie. In ersterem Projekt wird ein bestehender Algorithmus zur Streuungskorrektur von CBCT-Bildern dazu verwendet, eine Dosisneuberechnung auf der aktuellen Patientenanatomie durchzuführen. Dies wird kombiniert mit einem Softwaretool zur multikriteriellen Optimierung der Patientenposition basierend auf dosimetrischen Parametern. Die Machbarkeit des Ansatzes wird für Patienten mit Kopf-Hals-Tumoren gezeigt, und potentielle Vorteile gegenüber dem klinischen Standard für die Positionskorrektur - einer rigiden Registrierung des CBCT auf die Planungsbildgebung - werden anhand von klinischen Bilddaten untersucht. Es wurde gezeigt, dass der Ansatz machbar ist und verbesserte Kontrolle über Dosis im Zielvolumen und Risikoorganen bietet. Meist konnte Zielvolumenabdeckung oder Dosis in Risikoorganen gegenüber der rigiden Bilderegistrierung verbessert werden, jedoch konnte für beide Methoden im Falle zu ausgeprägter anatomischer Veränderungen keine ausreichende Zielvolumenabdeckung mehr hergestellt werden. Im zweiten Teil der Arbeit wurde ein Framework zur Anwendung der statistischen Methode der varianzbasierten Sensitivitätsanalyse auf dosimetrische Unsicherheiten in der Protonentherapie entwickelt. Dieses ermöglicht mit Hilfe eines GPU-basierten Pencil-Beam-Algorithmus die schnelle Berechnung einer großen Zahl an Fehlerszenarien für einen bestehenden Bestrahlungsplan. Während der Berechnung werden Patientenposition, Protonenreichweite und Parameter der Modelle zur Berechnung der relativen biologischen Wirksamkeit der Strahlung gleichzeitig und unabhängig voneinander innerhalb der für sie angenommenen Unsicherheiten variiert. In diesem Monte-Carlo-Ansatz können durch die gleichzeitige Variation aller Parameter auch Wechselwirkungen zwischen verschiedenen Quellen von Unsicherheit berücksichtigt werden. Für die Dosisverteilung und relevante dosimetrische Parameter (DVH-Quantile für Zielvolumina und Risikoorgane) können sowohl die Gesamtunsicherheit als auch Sensitivitätsindizes bestimmt werden. Diese Indizes ermöglichen eine Quantifizierung des Einflusses der einzelnen Eingangsunsicherheiten auf die Gesamtunsicherheit. Die Machbarkeit und die Möglichkeiten des Frameworks werden anhand von zwei klinischen Datensätzen gezeigt. Schließlich wird das Framework erweitert, um zusätzlich noch Inter-Observer-Variabilität in der Definition der Zielvolumina berücksichtigen zu können. In einer Studie mit zehn Patienten und vier Observern wird der Einfluss der Inter-Observer-Variabilität im Vergleich mit Reichweiten- und Setupunsicherheit auf die Abdeckung des klinischen Zielvolumens untersucht. Für zwei von zehn Patienten ergab sich hierbei ein relevanter Einfluss der Inter-Observer-Variabilität. Zukünftige Studien mit dem Framework könnten Aufschluss darüber geben, für welche Parameter eine Reduktion der Unsicherheit den größten Einfluss auf die Gesamtunsicherheit klinisch relevanter Parameter hat und dadurch helfen, entsprechende Forschungsvorhaben zu priorisieren

Hippocampal sparing radiotherapy for glioblastoma patients: a planning study using volumetric modulated arc therapy

Background: The purpose of this study is to investigate the potential to reduce exposure of the contralateral hippocampus in radiotherapy for glioblastoma using volumetric modulated arc therapy (VMAT). Methods: Datasets of 27 patients who had received 3D conformal radiotherapy (3D-CRT) for glioblastoma with a prescribed dose of 60Gy in fractions of 2Gy were included in this planning study. VMAT plans were optimized with the aim to reduce the dose to the contralateral hippocampus as much as possible without compromising other parameters. Hippocampal dose and treatment parameters were compared to the 3D-CRT plans using the Wilcoxon signed-rank test. The influence of tumour location and PTV size on the hippocampal dose was investigated with the Mann-Whitney-U-test and Spearman's rank correlation coefficient. Results: The median reduction of the contralateral hippocampus generalized equivalent uniform dose (gEUD) with VMAT was 36 % compared to the original 3D-CRT plans (p < 0.05). Other dose parameters were maintained or improved. The median V30Gy brain could be reduced by 17.9 % (p < 0.05). For VMAT, a parietal and a non-temporal tumour localisation as well as a larger PTV size were predictors for a higher hippocampal dose (p < 0.05). Conclusions: Using VMAT, a substantial reduction of the radiotherapy dose to the contralateral hippocampus for patients with glioblastoma is feasible without compromising other treatment parameters. For larger PTV sizes, less sparing can be achieved. Whether this approach is able to preserve the neurocognitive status without compromising the oncological outcome needs to be investigated in the setting of prospective clinical trials

Combining inter-observer variability, range and setup uncertainty in a variance-based sensitivity analysis for proton therapy

Margin concepts in proton therapy aim to ensure full dose coverage of the clinical target volume (CTV) in presence of setup and range uncertainty. Due to inter-observer variability (IOV), the CTV itself is uncertain. We present a framework to evaluate the combined impact of IOV, setup and range uncertainty in a variance-based sensitivity analysis (SA). For ten patients with skull base meningioma, the mean calculation time to perform the SA including 1.6 x 10(4) dose recalculations was 59 min. For two patients in this dataset, IOV had a relevant impact on the estimated CTV D-95% uncertainty

Continuous time-resolved estimated synthetic 4D-CTs for dose reconstruction of lung tumor treatments at a 0.35 T MR-linac

Objective. To experimentally validate a method to create continuous time-resolved estimated synthetic 4D-computed tomography datasets (tresCTs) based on orthogonal cine MRI data for lung cancer treatments at a magnetic resonance imaging (MRI) guided linear accelerator (MR-linac). Approach. A breathing porcine lung phantom was scanned at a CT scanner and 0.35 T MR-linac. Orthogonal cine MRI series (sagittal/coronal orientation) at 7.3 Hz, intersecting tumor-mimicking gelatin nodules, were deformably registered to mid-exhale 3D-CT and 3D-MRI datasets. The time-resolved deformation vector fields were extrapolated to 3D and applied to a reference synthetic 3D-CT image (sCT(ref)), while accounting for breathing phase-dependent lung density variations, to create 82 s long tresCTs at 3.65 Hz. Ten tresCTs were created for ten tracked nodules with different motion patterns in two lungs. For each dataset, a treatment plan was created on the mid-exhale phase of a measured ground truth (GT) respiratory-correlated 4D-CT dataset with the tracked nodule as gross tumor volume (GTV). Each plan was recalculated on the GT 4D-CT, randomly sampled tresCT, and static sCT(ref) images. Dose distributions for corresponding breathing phases were compared in gamma (2%/2 mm) and dose-volume histogram (DVH) parameter analyses. Main results. The mean gamma pass rate between all tresCT and GT 4D-CT dose distributions was 98.6%. The mean absolute relative deviations of the tresCT with respect to GT DVH parameters were 1.9%, 1.0%, and 1.4% for the GTV D-98%, D-50%, and D-2%, respectively, 1.0% for the remaining nodules D-50%, and 1.5% for the lung V-20Gy. The gamma pass rate for the tresCTs was significantly larger (p &lt; 0.01), and the GTV D-50% deviations with respect to the GT were significantly smaller (p &lt; 0.01) than for the sCT(ref). Significance. The results suggest that tresCTs could be valuable for time-resolved reconstruction and intrafractional accumulation of the dose to the GTV for lung cancer patients treated at MR-linacs in the future

Statistical breathing curve sampling to quantify interplay effects of moving lung tumors in a 4D Monte Carlo dose calculation framework

Purpose: The interplay between respiratory tumor motion and dose application by intensity modulated radio-therapy (IMRT) techniques can potentially lead to undesirable and non-intuitive deviations from the planned dose distribution. We developed a 4D Monte Carlo (MC) dose recalculation framework featuring statistical breathing curve sampling, to precisely simulate the dose distribution for moving target volumes aiming at a comprehensive assessment of interplay effects. Methods: We implemented a dose accumulation tool that enables dose recalculations of arbitrary breathing curves including the actual breathing curve of the patient. This MC dose recalculation framework is based on linac log-files, facilitating a high temporal resolution up to 0.1 s. By statistical analysis of 128 different breathing curves, interplay susceptibility of different treatment parameters was evaluated for an exemplary patient case. To facilitate prospective clinical application in the treatment planning stage, in which patient breathing curves or linac log-files are not available, we derived a log-file free version with breathing curves generated by a random walk approach. Interplay was quantified by standard deviations sigma in D-5%, D(50% )and D-95%. Results: Interplay induced dose deviations for single fractions were observed and evaluated for IMRT and volumetric arc therapy (sigma(D95%) up to 1.3 %) showing a decrease with higher fraction doses and an increase with higher MU rates. Interplay effects for conformal treatment techniques were negligible (sigma < 0.1%). The log-file free version and the random walk generated breathing curves yielded similar results (deviations in sigma < 0.1 %) and can be used as substitutes for interplay assessment. Conclusion: It is feasible to combine statistically sampled breathing curves with MC dose calculations. The universality of the presented framework allows comprehensive assessment of interplay effects in retrospective and prospective clinically relevant scenarios

Dose-guided patient positioning in proton radiotherapy using multicriteria-optimization

Proton radiotherapy (PT) requires accurate target alignment before each treatment fraction, ideally utilizing 3D in-room X-ray computed tomography (CT) imaging. Typically, the optimal patient position is determined based on anatomical landmarks or implanted markers. In the presence of non-rigid anatomical changes, however, the planning scenario cannot be exactly reproduced and positioning should rather aim at finding the optimal position in terms of the actually applied dose. In this work, dose-guided patient alignment, implemented as multicriterial optimization (MCO) problem, was investigated in the scope of intensity-modulated and double-scattered PT (IMPT and DSPT) for the first time. A method for automatically determining the optimal patient position with respect to pre-defined clinical goals was implemented. Linear dose interpolation was used to access a continuous space of potential patient shifts. Fourteen head and neck (H&N) and eight prostate cancer patients with up to five repeated CTs were included. Dose interpolation accuracy was evaluated and the potential dosimetric advantages of dose-guided over bony-anatomy-based patient alignment investigated by comparison of clinically relevant target and organ-at-risk (OAR) dose-volume histogram (DVH) parameters. Dose interpolation was found sufficiently accurate with average pass-rates of 90% and 99% for an exemplary H&N and prostate patient, respectively, using a 2% dose-difference criterion. Compared to bony-anatomy-based alignment, the main impact of automated MCO-based dose-guided positioning was a reduced dose to the serial OARs (spinal cord and brain stem) for the H&N cohort. For the prostate cohort, under-dosage of the target structures could be efficiently diminished. Limitations of dose-guided positioning were mainly found in reducing target over-dosage due to weight loss for H&N patients, which might require adaptation of the treatment plan. Since labor-intense online quality-assurance is not required for dose-guided patient positioning, it might, nevertheless, be considered an interesting alternative to full online re-planning for initially mitigating the effects of anatomical changes