Simulation and experimental benchmarking of a proton pencil beam scanning nozzle model for development of MR-integrated proton therapy.

BACKGROUND: MR-integrated proton therapy is under development. It consists of the unique challenge of integrating a proton pencil beam scanning (PBS) beam line nozzle with an magnetic resonance imaging (MRI) scanner. The magnetic interaction between these two components is deemed high risk as the MR images can be degraded if there is cross-talk during beam delivery and image acquisition. PURPOSE: To create and benchmark a self-consistent proton PBS nozzle model for empowering the next stages of MR-integrated proton therapy development, namely exploring and de-risking complete integrated prototype system designs including magnetic shielding of the PBS nozzle. MATERIALS AND METHODS: Magnetic field (COMSOL Multiphysics ${\text{Multiphysics}}$ ) and radiation transport (Geant4) models of a proton PBS nozzle located at OncoRay (Dresden, Germany) were developed according to the manufacturers specifications. Geant4 simulations of the PBS process were performed by using magnetic field data generated by the COMSOL Multiphysics ${\text{Multiphysics}}$ simulations. In total 315 spots were simulated which consisted of a 40 × 30 cm 2 $40\times 30\,{\text{cm}}^{2}$ scan pattern with 5 cm spot spacings and for proton energies of 70, 100, 150, 200, and 220 MeV. Analysis of the simulated deflection at the beam isocenter plane was performed to determine the self-consistency of the model. The magnetic fringe field from a sub selection of 24 of the 315 spot simulations were directly compared with high precision magnetometer measurements. These focused on the maximum scanning setting of ± $\pm$  20 cm beam deflection as generated from the second scanning magnet in the PBS for a proton beam energy of 220 MeV. Locations along the beam line central axis (CAX) were measured at beam isocenter and downstream of 22, 47, 72, 97, and 122 cm. Horizontal off-axis positions were measured at 22 cm downstream of isocenter ( ± $\pm$  50, ± $\pm$  100, and ± $\pm$  150 cm from CAX). RESULTS: The proton PBS simulations had good spatial agreement to the theoretical values in all 315 spots examined at the beam line isocenter plane (0-2.9 mm differences or within 1.5 % of the local spot deflection amount). Careful analysis of the experimental measurements were able to isolate the changes in magnetic fields due solely to the scanning magnet contribution, and showed 1.9  ± $\pm$  1.2 µ T $\bf{\mu} {\text{T}}$ -9.4 ± $\pm$  1.2 µ T $\bf{\mu} {\text{T}}$ changes over the range of measurement locations. Direct comparison with the equivalent simulations matched within the measurement apparatus and setup uncertainty in all but one measurement point. CONCLUSIONS: For the first time a robust, accurate and self-consistent model of a proton PBS nozzle assembly has been created and successfully benchmarked for the purposes of advancing MR-integrated proton therapy research. The model will enable confidence in further simulation based work on fully integrated designs including MRI scanners and PBS nozzle magnetic shielding in order to de-risk and realize the full potential of MR-integrated proton therapy.

Prediction of radiation pneumonitis using the effective α/ß of lungs and heart in NSCLC patients treated with proton beam therapy.

PURPOSE: Radiation pneumonitis (RP) remains a major complication in non-small cell lung cancer (NSCLC) patients undergoing radiochemotherapy (RCHT). Traditionally, the mean lung dose (MLD) and the volume of the total lung receiving at least 20 Gy (V20Gy) are used to predict RP in patients treated with normo-fractionated photon therapy. However, other models, including the actual dose-distribution in the lungs using the effective α/ß model or a combination of radiation doses to the lungs and heart, have been proposed for predicting RP. Moreover, the models established for photons may not hold for patients treated with passively-scattered proton therapy (PSPT). Therefore, we here tested and validated novel predictive parameters for RP in NSCLC patient treated with PSPT. METHODS: Data on the occurrence of RP, structure files and dose-volume histogram parameters for lungs and heart of 96 NSCLC patients, treated with PSPT and concurrent chemotherapy, was retrospectively retrieved from prospective clinical studies of two international centers. Data was randomly split into a training set (64 patients) and a validation set (32 patients). Statistical analyses were performed using binomial logistic regression. RESULTS: The biologically effective dose (BED) of the'lungs - GTV' significantly predicted RP ≥ grade 2 in the training-set using both a univariate model (p = 0.019, AUCtrain = 0.72) and a multivariate model in combination with the effective α/ß parameter of the heart (pBED = 0.006, [Formula: see text] = 0.043, AUCtrain = 0.74). However, these results did not hold in the validation-set (AUCval = 0.52 andAUCval = 0.50, respectively). Moreover, these models were found to neither outperform a model built with the MLD (p = 0.015, AUCtrain = 0.73, AUCval = 0.51), nor a multivariate model additionally including the V20Gy of the heart (pMLD = 0.039, pV20Gy,heart = 0.58, AUCtrain = 0.74, AUCval = 0.53). CONCLUSION: Using the effective α/ß parameter of the lungs and heart we achieved similar performance to commonly used models built for photon therapy, such as MLD, in predicting RP ≥ grade 2. Therefore, prediction models developed for photon RCHT still hold for patients treated with PSPT.

Reduction of intrafraction pancreas motion using an abdominal corset compatible with proton therapy and MRI.

Background and purpose: Motion mitigation is of crucial importance in particle therapy (PT) of patients with abdominal tumors to ensure high-precision irradiation. Magnetic resonance imaging (MRI) is an excellent modality for target volume delineation and motion estimation of mobile soft-tissue tumors. Thus, the aims of this study were to develop an MRI- and PT-compatible abdominal compression device, to investigate its effect on pancreas motion reduction, and to evaluate patient tolerability and acceptance. Materials and methods: In a prospective clinical study, 16 patients with abdominal tumors received an individualized polyethylene-based abdominal corset. Pancreas motion was analyzed using time- and phase resolved MRI scans (orthogonal 2D-cine and 4D MRI) with and without compression by the corset. The pancreas was manually segmented in each MRI data set and the population-averaged center-of-mass motion in inferior-superior (IS), anterior-posterior (AP) and left-right (LR) directions was determined. A questionnaire was developed to investigate the level of patient acceptance of the corset, which the patients completed after acquisition of the planning computed tomography (CT) and MRI scans. Results: The corset was found to reduce pancreas motion predominantly in IS direction by on average 47 % - 51 % as found in the 2D-cine and 4D MRI data, respectively, while motion in the AP and LR direction was not significantly reduced. Most patients reported no discomfort when wearing the corset. Conclusion: An MRI- and PT-compatible individualized abdominal corset was presented, which substantially reduced breathing-induced pancreas motion and can be safely applied with no additional discomfort for the patients. The corset has been successfully integrated into our in-house clinical workflow for PT of tumors of the upper abdomen.

Technical Note: ADAM PETer - An anthropomorphic, deformable and multimodality pelvis phantom with positron emission tomography extension for radiotherapy.

OBJECTIVE: To develop an anthropomorphic, deformable and multimodal pelvis phantom with positron emission tomography extension for radiotherapy (ADAM PETer). METHODS: The design of ADAM PETer was based on our previous pelvis phantom (ADAM) and extended for compatibility with PET and use in 3T magnetic resonance imaging (MRI). The formerly manually manufactured silicon organ surrogates were replaced by three-dimensional (3D) printed organ shells. Two intraprostatic lesions, four iliac lymph node metastases and two pelvic bone metastases were added to simulate prostate cancer as multifocal and metastatic disease. Radiological properties [computed tomography (CT) and 3T MRI] of cortical bone, bone marrow and adipose tissue were simulated by heavy gypsum, a mixture of Vaseline and K2 HPO4 and peanut oil, respectively. For soft tissues, agarose gels with varying concentrations of agarose, gadolinium (Gd) and sodium fluoride (NaF) were developed. The agarose gels were doped with patient-specific activity concentrations of a Fluorine-18 labelled compound and then filled into the 3D printed organ shells of prostate lesions, lymph node and bone metastases. The phantom was imaged at a dual energy CT and a 3T PET/MRI scanner. RESULTS: The compositions of the soft tissue surrogates are the following (given as mass fractions of agarose[w%]/NaF[w%]/Gd[w%]): Muscle (4/1/0.027), prostate (1.35/4.2/0.011), prostate lesions (2.25/4.2/0.0085), lymph node and bone metastases (1.4/4.2/0.025). In all imaging modalities, the phantom simulates human contrast. Intraprostatic lesions appear hypointense as compared to the surrounding normal prostate tissue in T2-weighted MRI. The PET signal of all tumors can be localized as focal spots at their respective site. Activity concentrations of 12.0 kBq/mL (prostate lesion), 12.4 kBq/mL (lymph nodes) and 39.5 kBq/mL (bone metastases) were measured. CONCLUSION: The ADAM PETer pelvis phantom can be used as multimodal, anthropomorphic model for CT, 3T-MRI and PET measurements. It will be central to simulate and optimize the technical workflow for the integration of PET/MRI-based radiation treatment planning of prostate cancer patients.

CT-based attenuation correction of whole-body radiotherapy treatment positioning devices in PET/MRI hybrid imaging.

OBJECTIVE: To implement computed tomography (CT)-based attenuation maps of radiotherapy (RT) positioning hardware and radiofrequency (RF) coils to enable hybrid positron emission tomography/magnetic resonance imaging (PET/MRI)-based RT treatment planning. MATERIALS AND METHODS: The RT positioning hardware consisted of a flat RT table overlay, coil holders for abdominal scans, coil holders for head and neck scans and an MRI compatible hip and leg immobilization device. CT images of each hardware element were acquired on a CT scanner. Based on the CT images, attenuation maps of the devices were created. Validation measurements were performed on a PET/MR scanner using a 68Ge phantom (48 MBq, 10 min scan time). Scans with each device in treatment position were performed. Then, reference scans containing only the phantom were taken. The scans were reconstructed online (at the PET/MRI scanner) and offline (via e7tools on a PC) using identical reconstruction parameters. Average reconstructed activity concentrations of the device and reference scans were compared. RESULTS: The device attenuation maps were successfully implemented. The RT positioning devices caused an average decrease of reconstructed PET activity concentration in the range between -8.3 ± 2.1% (mean ± SD) (head and neck coil holder with coils) to -1.0 ± 0.5% (abdominal coil holder). With attenuation correction taking into account RT hardware, these values were reduced to -2.0 ± 1.2% and -0.6 ± 0.5%, respectively. The results of the offline and online reconstructions were nearly identical, with a difference of up to 0.2%. CONCLUSION: The decrease in reconstructed activity concentration caused by the RT positioning devices is clinically relevant and can successfully be corrected using CT-based attenuation maps. Both the offline and online reconstruction methods are viable options.

First application of a high-resolution silicon detector for proton beam Bragg peak detection in a 0.95 T magnetic field.

PURPOSE: To report on experimental results of a high spatial resolution silicon-based detector exposed to therapeutic quality proton beams in a 0.95 T transverse magnetic field. These experimental results are important for the development of accurate and novel dosimetry methods in future potential real-time MRI-guided proton therapy systems. METHODS: A permanent magnet device was utilized to generate a 0.95 T magnetic field over a 4 × 20 × 15 cm3 volume. Within this volume, a high-resolution silicon diode array detector was positioned inside a PMMA phantom of 4 × 15 × 12 cm3 . This detector contains two orthogonal strips containing 505 sensitive volumes spaced at 0.2 mm apart. Proton beams collimated to a circle of 10 mm diameter with nominal energies of 90 MeV, 110 MeV, and 125 MeV were incident on the detector from an edge-on orientation. This allows for a measurement of the Bragg peak at 0.2 mm spatial resolution in both the depth and lateral profile directions. The impact of the magnetic field on the proton beams, that is, a small deflection was also investigated. A Geant4 Monte Carlo simulation was performed of the experimental setup to aid in interpretation of the results. RESULTS: The nominal Bragg peak for each proton energy was successfully observed with a 0.2 mm spatial resolution in the 0.95 T transverse magnetic field in both a depth and lateral profiles. The proton beam deflection (at 0.95 T) was a consistent 2 ±0.5 mm at the center of the magnetic volume for each beam energy. However, a pristine Bragg peak was not observed for each energy. This was caused by the detector packaging having small air gaps between layers of the phantom material surrounding the diode array. These air gaps act to degrade the shape of the Bragg peak, and further to this, the nonwater equivalent silicon chip acts to separate the Bragg peak into multiple peaks depending on the proton path taken. Overall, a promising performance of the silicon detector array was observed, however, with a qualitative assessment rather than a robust quantitative dosimetric evaluation at this stage of development. CONCLUSIONS: For the first time, a high-resolution silicon-based radiation detector has been used to measure proton beam Bragg peak deflections in a phantom due to a strong magnetic field. Future efforts are required to optimize the detector packaging to strengthen the robustness of the dosimetric quantities obtained from the detector. Such high-resolution silicon diode arrays may be useful in future efforts in MRI-guided proton therapy research.

Comparison of pancreatic respiratory motion management with three abdominal corsets for particle radiation therapy: Case study.

BACKGROUND AND PURPOSE: Abdominal organ motion seriously compromises the targeting accuracy for particle therapy in patients with pancreatic adenocarcinoma. This study compares three different abdominal corsets regarding their ability to reduce pancreatic motion and their potential usability in particle therapy. MATERIALS AND METHODS: A patient-individualized polyurethane (PU), a semi-individualized polyethylene (PE), and a patient-individualized three-dimensional-scan based polyethylene (3D-PE) corset were manufactured for one healthy volunteer. Time-resolved volumetric four-dimensional-magnetic resonance imaging (4D-MRI) and single-slice two-dimensional (2D) cine-MRI scans were acquired on two consecutive days to compare free-breathing motion patterns with and without corsets. The corset material properties, such as thickness variance, material homogeneity in Hounsfield units (HU) on computed tomography (CT) scans, and manufacturing features were compared. The water equivalent ratio (WER) of corset material samples was measured using a multi-layer ionization chamber for proton energies of 150 and 200 MeV. RESULTS: All corsets reduced the pancreatic motion on average by 9.6 mm in inferior-superior and by 3.2 mm in anterior-posterior direction. With corset, the breathing frequency was approximately doubled and the day-to-day motion variations were reduced. The WER measurements showed an average value of 0.993 and 0.956 for the PE and 3DPE corset, respectively, and of 0.298 for the PU corset. The PE and 3DPE corsets showed a constant thickness of 2.8 ± 0.2 and 3.8 ± 0.2 mm, respectively and a homogeneous material composition with a standard deviation (SD) of 31 and 32 HU, respectively. The PU corset showed a variable thickness of 4.2 - 25.6 mm and a heterogeneous structure with air inclusions with an SD of 113 HU. CONCLUSION: Abdominal corsets may be effective devices to reduce pancreatic motion. For particle therapy, PE-based corsets are preferred over PU-based corset due to their material homogeneity and constant thickness.

Detectability and structural stability of a liquid fiducial marker in fresh ex vivo pancreas tumour resection specimens on CT and 3T MRI.

PURPOSE: To test the detectability of a liquid fiducial marker injected into ex vivo pancreas tumour tissue on magnetic resonance imaging (MRI) and computed tomography (CT). Furthermore, its injection performance using different needle sizes and its structural stability after fixation in formaldehyde were investigated. METHODS: Liquid fiducial markers with a volume of 20-100 µl were injected into freshly resected pancreas specimens of three patients with suspected adenocarcinoma. X­ray guided injection was performed using different needle sizes (18 G, 22 G, 25 G). The specimens were scanned on MRI and CT with clinical protocols. The markers were segmented on CT by signal thresholding. Marker detectability in MRI was assessed in the registered segmentations. Marker volume on CT was compared to the injected volume as a measure of backflow. RESULTS: Markers with a volume ≥20 µl were detected as hyperintensity on X­ray and CT. On T1- and T2-weighted 3T MRI, marker sizes ranging from 20-100 µl were visible as hypointensity. Since most markers were non-spherical, MRI detectability was poor and their differentiation from hypointensities caused by air cavities or surgical clips was only feasible with a reference CT. Marker backflow was only observed when using an 18-G needle. A volume decrease of 6.6 ± 13.0% was observed after 24 h in formaldehyde and, with the exception of one instance, no wash-out occurred. CONCLUSIONS: The liquid fiducial marker injected in ex vivo pancreatic resection specimen was visible as hyperintensity on kV X­ray and CT and as hypointensity on MRI. The marker's size was stable in formaldehyde. A marker volume of ≥50 µL is recommended in clinically used MRI sequences. In vivo injection is expected to improve the markers sphericity due to persisting metabolism and thereby enhance detectability on MRI.

Characterizing geometrical accuracy in clinically optimised 7T and 3T magnetic resonance images for high-precision radiation treatment of brain tumours.

BACKGROUND AND PURPOSE: In neuro-oncology, high spatial accuracy is needed for clinically acceptable high-precision radiation treatment planning (RTP). In this study, the clinical applicability of anatomically optimised 7-Tesla (7T) MR images for reliable RTP is assessed with respect to standard clinical imaging modalities. MATERIALS AND METHODS: System- and phantom-related geometrical distortion (GD) were quantified on clinically-relevant MR sequences at 7T and 3T, and on CT images using a dedicated anthropomorphic head phantom incorporating a 3D grid-structure, creating 436 points-of-interest. Global GD was assessed by mean absolute deviation (MADGlobal). Local GD relative to the magnetic isocentre was assessed by MADLocal. Using 3D displacement vectors of individual points-of-interest, GD maps were created. For clinically acceptable radiotherapy, 7T images need to meet the criteria for accurate dose delivery (GD < 1 mm) and present comparable GD as tolerated in clinically standard 3T MR/CT-based RTP. RESULTS: MADGlobal in 7T and 3T images ranged from 0.3 to 2.2 mm and 0.2-0.8 mm, respectively. MADLocal increased with increasing distance from the isocentre, showed an anisotropic distribution, and was significantly larger in 7T MR sequences (MADLocal = 0.2-1.2 mm) than in 3T (MADLocal = 0.1-0.7 mm) (p < 0.05). Significant differences in GD were detected between 7T images (p < 0.001). However, maximum MADLocal remained ≤1 mm within 68.7 mm diameter spherical volume. No significant differences in GD were found between 7T and 3T protocols near the isocentre. CONCLUSIONS: System- and phantom-related GD remained ≤1 mm in central brain regions, suggesting that 7T MR images could be implemented in radiotherapy with clinically acceptable spatial accuracy and equally tolerated GD as in 3T MR/CT-based RTP. For peripheral regions, GD should be incorporated in safety margins for treatment uncertainties. Moreover, the effects of sequence-related factors on GD needs further investigation to obtain RTP-specific MR protocols.

Ano-rectal wall dose-surface maps localize the dosimetric benefit of hydrogel rectum spacers in prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: To evaluate spatial differences in dose distributions of the ano-rectal wall (ARW) using dose-surface maps (DSMs) between prostate cancer patients receiving intensity-modulated radiation therapy with and without implantable rectum spacer (IMRT+IRS; IMRT-IRS, respectively), and to correlate this with late gastro-intestinal (GI) toxicities using validated spatial and non-spatial normal-tissue complication probability (NTCP) models. MATERIALS AND METHODS: For 26 patients DSMs of the ARW were generated. From the DSMs various shape-based dose measures were calculated at different dose levels: lateral extent, longitudinal extent, and eccentricity. The contiguity of the ARW dose distribution was assessed by the contiguous-DSH (cDSH). Predicted complication rates between IMRT+IRS and IMRT-IRS plans were assessed using a spatial NTCP model and compared against a non-spatial NTCP model. RESULTS: Dose surface maps are generated for prostate radiotherapy using an IRS. Lateral extent, longitudinal extent and cDSH were significantly lower in IMRT+IRS than for IMRT-IRS at high-dose levels. Largest significant differences were observed for cDSH at dose levels >50 Gy, followed by lateral extent at doses >57 Gy, and longitudinal extent in anterior and superior-inferior directions. Significant decreases (p = 0.01) in median rectal and anal NTCPs (respectively, Gr 2 late rectal bleeding and subjective sphincter control) were predicted when using an IRS. CONCLUSIONS: Local-dose effects are predicted to be significantly reduced by an IRS. The spatial NTCP model predicts a significant decrease in Gr 2 late rectal bleeding and subjective sphincter control. Dose constraints can be improved for current clinical treatment planning.

Integrating a low-field open MR scanner with a static proton research beam line: proof of concept.

On-line image guidance using magnetic resonance (MR) imaging is expected to improve the targeting accuracy of proton therapy. However, to date no combined system exists. In this study, for the first time a low-field open MR scanner was integrated with a static proton research beam line to test the feasibility of simultaneous irradiation and imaging. The field-of-view of the MR scanner was aligned with the beam by taking into account the Lorentz force induced beam deflection. Various imaging sequences for extremities were performed on a healthy volunteer and on a patient with a soft-tissue sarcoma of the upper arm, both with the proton beam line switched off. T 1-weighted spin echo images of a tissue-mimicking phantom were acquired without beam, with energised beam line magnets and during proton irradiation. Beam profiles were acquired for the MR scanner's static magnetic field alone and in combination with the dynamic gradient fields during the acquisition of different imaging sequences. It was shown that MR imaging is feasible in the electromagnetically contaminated environment of a proton therapy facility. The observed quality of the anatomical MR images was rated to be sufficient for target volume definition and positioning. The tissue-mimicking phantom showed no visible beam-induced image degradation. The beam profiles depicted no influence due to the dynamic gradient fields of the imaging sequences. This study proves that simultaneous irradiation and in-beam MR imaging is technically feasible with a low-field MR scanner integrated with a static proton research beam line.

External validation of an NTCP model for acute esophageal toxicity in locally advanced NSCLC patients treated with intensity-modulated (chemo-)radiotherapy.

BACKGROUND AND PURPOSE: We externally validated a previously established multivariable normal-tissue complication probability (NTCP) model for Grade ≥2 acute esophageal toxicity (AET) after intensity-modulated (chemo-)radiotherapy or volumetric-modulated arc therapy for locally advanced non-small cell lung cancer. MATERIALS AND METHODS: A total of 603 patients from five cohorts (A-E) within four different Dutch institutes were included. Using the NTCP model, containing predictors concurrent chemoradiotherapy, mean esophageal dose, gender and clinical tumor stage, the risk of Grade ≥2 AET was estimated per patient and model discrimination and (re)calibration performance were evaluated. RESULTS: Four validation cohorts (A, B, D, E) experienced higher incidence of Grade ≥2 AET compared to the training cohort (49.3-70.2% vs 35.6%; borderline significant for one cohort, highly significant for three cohorts). Cohort C experienced lower Grade ≥2 AET incidence (21.7%, p < 0.001). For three cohorts (A-C), discriminative performance was similar to the training cohort (area under the curve (AUC) 0.81-0.89 vs 0.84). In the two remaining cohorts (D-E) the model showed poor discriminative power (AUC 0.64 and 0.63). Reasonable calibration performance was observed in two cohorts (A-B), and recalibration further improved performance in all three cohorts with good discrimination (A-C). Recalibration for the two poorly discriminating cohorts (D-E) did not improve performance. CONCLUSIONS: The NTCP model for AET prediction was successfully validated in three out of five patient cohorts (AUC ≥0.80). The model did not perform well in two cohorts, which included patients receiving substantially different treatment. Before applying the model in clinical practice, validation of discrimination and (re)calibration performance in a local cohort is recommended.

Technical Note: Experimental verification of magnetic field-induced beam deflection and Bragg peak displacement for MR-integrated proton therapy.

PURPOSE: Given its sensitivity to anatomical variations, proton therapy is expected to benefit greatly from integration with magnetic resonance imaging for online anatomy monitoring during irradiation. Such an integration raises several challenges, as both systems mutually interact. The proton beam will experience quasi-continuous energy loss and energy-dependent electromagnetic deflection at the same time, giving rise to a deflected beam trajectory and an altered dose distribution with a displaced Bragg peak. So far, these effects have only been predicted using Monte Carlo and analytical models, but no clear consensus has been reached and experimental benchmark data are lacking. We measured proton beam trajectories and Bragg peak displacement in a homogeneous phantom placed inside a magnetic field and compared them to simulations. METHODS: Planar dose distributions of proton pencil beams (80-180 MeV) traversing the field of a 0.95 T NdFeB permanent magnet while depositing energy in a PMMA slab phantom were measured using EBT3 radiochromic films and simulated using the Geant4 toolkit. Deflected beam trajectories and the Bragg peak displacement were extracted from the measured planar dose distributions and compared against the simulations. RESULTS: The lateral beam deflection was clearly visible on the EBT3 films and ranged from 1 to 10 mm for 80 to 180 MeV, respectively. Simulated and measured beam trajectories and Bragg peak displacement agreed within 0.8 mm for all studied proton energies. CONCLUSIONS: These results prove that the magnetic field-induced Bragg peak displacement is both measurable and accurately predictable in a homogeneous phantom at 0.95 T, and allows Monte Carlo simulations to be used as gold standard for proton beam trajectory prediction in similar frameworks for MR-integrated proton therapy.

Evidence on the efficacy of primary radiosurgery or stereotactic radiotherapy for drug-resistant non-neoplastic focal epilepsy in adults: A systematic review.

PURPOSE: Although the majority of adult epilepsy patients respond well to the current antiepileptic drug treatment, 20-40% of them are drug-resistant. In these patients, resective epilepsy surgery is a curative treatment option, for which, however, only a limited number of patients is eligible. The purpose is to summarize the outcome of radiotherapy for drug-resistant non-neoplastic focal epilepsy and to elucidate its efficacy for seizure outcome and long-term toxicity in adults. METHOD: A systematic literature search was performed in Pubmed, Ovid Medline, Cochrane library, Embase and Web of Science. The methodological quality was evaluated using an adapted QUADAS checklist. RESULTS: Sixteen out of 170 initially identified studies were included in this systematic literature study (n = 170 patients). Twelve of the 16 studies described a positive effect of radiotherapy on seizure frequency reduction, with 98 of the patients (on average 58%, range 25%-95%) reporting no or rare seizures (defined as radiotherapy-adapted Engel class [RAEC] I and II. In total, 20% (34 patients) of the patients needed subsequent surgery due to radionecrosis, cysts formation, edema, and intracranial hypertension or remaining seizures. A dose-effect model was fitted to the available response data in an attempt to derive a relationship between prescribed dose and RAEC frequency. CONCLUSIONS: Radiotherapy is a possible non-invasive treatment option for patients with drug-resistant focal non-neoplastic epilepsy. This systematic review showed that there is only level 4 evidence of primary radiotherapy reducing seizure frequency in adult patients. Prospective randomized trials are needed to determine its exact value compared to other treatment approaches.

Improved effectiveness of stereotactic radiosurgery in large brain metastases by individualized isotoxic dose prescription: an in silico study.

INTRODUCTION: In large brain metastases (BM) with a diameter of more than 2 cm there is an increased risk of radionecrosis (RN) with standard stereotactic radiosurgery (SRS) dose prescription, while the normal tissue constraint is exceeded. The tumor control probability (TCP) with a single dose of 15 Gy is only 42%. This in silico study tests the hypothesis that isotoxic dose prescription (IDP) can increase the therapeutic ratio (TCP/Risk of RN) of SRS in large BM. MATERIALS AND METHODS: A treatment-planning study with 8 perfectly spherical and 46 clinically realistic gross tumor volumes (GTV) was conducted. The effects of GTV size (0.5-4 cm diameter), set-up margins (0, 1, and 2 mm), and beam arrangements (coplanar vs non-coplanar) on the predicted TCP using IDP were assessed. For single-, three-, and five-fraction IDP dose-volume constraints of V12Gy = 10 cm3, V19.2 Gy = 10 cm3, and a V20Gy = 20 cm3, respectively, were used to maintain a low risk of radionecrosis. RESULTS: In BM of 4 cm in diameter, the maximum achievable single-fraction IDP dose was 14 Gy compared to 15 Gy for standard SRS dose prescription, with respective TCPs of 32 and 42%. Fractionated SRS with IDP was needed to improve the TCP. For three- and five-fraction IDP, a maximum predicted TCP of 55 and 68% was achieved respectively (non-coplanar beams and a 1 mm GTV-PTV margin). CONCLUSIONS: Using three-fraction or five-fraction IDP the predicted TCP can be increased safely to 55 and 68%, respectively, in large BM with a diameter of 4 cm with a low risk of RN. Using IDP, the therapeutic ratio of SRS in large BM can be increased compared to current SRS dose prescription.

Inclusion of Incidental Radiation Dose to the Cardiac Atria and Ventricles Does Not Improve the Prediction of Radiation Pneumonitis in Advanced-Stage Non-Small Cell Lung Cancer Patients Treated With Intensity Modulated Radiation Therapy.

PURPOSE: To evaluate whether inclusion of incidental radiation dose to the cardiac atria and ventricles improves the prediction of grade ≥3 radiation pneumonitis (RP) in advanced-stage non-small cell lung cancer (AS-NSCLC) patients treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: Using a bootstrap modeling approach, clinical parameters and dose-volume histogram (DVH) parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction in 188 AS-NSCLC patients. RESULTS: After a median follow-up of 18.4 months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3 Gy vs 13.7 Gy for the RP and non-RP group, respectively; P=.004). The MLD showed the highest Spearman correlation coefficient (Rs) for RP (Rs = 0.21; P<.01). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters. After predictive modeling using a bootstrap procedure, the MLD was always included in the predictive model for grade ≥3 RP, whereas the heart DVH parameters were seldom included in the model. CONCLUSION: Incidental dose to the cardiac atria and ventricles did not improve RP risk prediction in our cohort of 188 AS-NSCLC patients treated with IMRT or VMAT.

Esophageal wall dose-surface maps do not improve the predictive performance of a multivariable NTCP model for acute esophageal toxicity in advanced stage NSCLC patients treated with intensity-modulated (chemo-)radiotherapy.

In our previous work, a multivariable normal-tissue complication probability (NTCP) model for acute esophageal toxicity (AET) Grade ⩾2 after highly conformal (chemo-)radiotherapy for non-small cell lung cancer (NSCLC) was developed using multivariable logistic regression analysis incorporating clinical parameters and mean esophageal dose (MED). Since the esophagus is a tubular organ, spatial information of the esophageal wall dose distribution may be important in predicting AET. We investigated whether the incorporation of esophageal wall dose-surface data with spatial information improves the predictive power of our established NTCP model. For 149 NSCLC patients treated with highly conformal radiation therapy esophageal wall dose-surface histograms (DSHs) and polar dose-surface maps (DSMs) were generated. DSMs were used to generate new DSHs and dose-length-histograms that incorporate spatial information of the dose-surface distribution. From these histograms dose parameters were derived and univariate logistic regression analysis showed that they correlated significantly with AET. Following our previous work, new multivariable NTCP models were developed using the most significant dose histogram parameters based on univariate analysis (19 in total). However, the 19 new models incorporating esophageal wall dose-surface data with spatial information did not show improved predictive performance (area under the curve, AUC range 0.79-0.84) over the established multivariable NTCP model based on conventional dose-volume data (AUC = 0.84). For prediction of AET, based on the proposed multivariable statistical approach, spatial information of the esophageal wall dose distribution is of no added value and it is sufficient to only consider MED as a predictive dosimetric parameter.

Prediction and compensation of magnetic beam deflection in MR-integrated proton therapy: a method optimized regarding accuracy, versatility and speed.

The integration of magnetic resonance imaging (MRI) and proton therapy for on-line image-guidance is expected to reduce dose delivery uncertainties during treatment. Yet, the proton beam experiences a Lorentz force induced deflection inside the magnetic field of the MRI scanner, and several methods have been proposed to quantify this effect. We analyze their structural differences and compare results of both analytical and Monte Carlo models. We find that existing analytical models are limited in accuracy and applicability due to critical approximations, especially including the assumption of a uniform magnetic field. As Monte Carlo simulations are too time-consuming for routine treatment planning and on-line plan adaption, we introduce a new method to quantify and correct for the beam deflection, which is optimized regarding accuracy, versatility and speed. We use it to predict the trajectory of a mono-energetic proton beam of energy E 0 traversing a water phantom behind an air gap within an omnipresent uniform transverse magnetic flux density B 0. The magnetic field induced dislocation of the Bragg peak is calculated as function of E 0 and B 0 and compared to results obtained with existing analytical and Monte Carlo methods. The deviation from the Bragg peak position predicted by Monte Carlo simulations is smaller for the new model than for the analytical models by up to 2 cm. The model is faster than Monte Carlo methods, less assumptive than the analytical models and applicable to realistic magnetic fields. To compensate for the predicted Bragg peak dislocation, a numerical optimization strategy is introduced and evaluated. It includes an adjustment of both the proton beam entrance angle and energy of up to 25° and 5 MeV, depending on E 0 and B 0. This strategy is shown to effectively reposition the Bragg peak to its intended location in the presence of a magnetic field.

Comparison of toxicity and outcome in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy using IMRT or VMAT.

Retrospective evaluation of 188 advanced stage non-small cell lung cancer patients treated with IMRT or VMAT revealed a limited increase of moderate to severe acute esophageal toxicity after VMAT. Acute pulmonary toxicity and severe late toxicity were low. Overall survival did not differ between the IMRT and VMAT groups.

Who will benefit most from hydrogel rectum spacer implantation in prostate cancer radiotherapy? A model-based approach for patient selection.

BACKGROUND AND PURPOSE: Previous studies confirmed that implantable rectum spacers (IRS) decreased acute gastro-intestinal (GI) toxicity in a significant percentage of prostate cancer patients undergoing intensity modulated radiation therapy (IMRT). We developed decision rules based on clinical risk factors (CRFs) to select those patients who are expected to benefit most from IRS implantation. MATERIALS AND METHODS: For 26 patients dose distributions with (IMRT+IRS) and without (IMRT-IRS) IRS were calculated. Validated nomograms based on CRFs and dosimetric criteria (anorectal V40Gy and V75Gy) were used to predict probabilities for grade 2-3 (G2-3) acute GI toxicity, G2-3 late rectal bleeding (LRB), G3 LRB, and G2-3 faecal incontinence (FI) for IMRT+IRS and IMRT-IRS. All permutations of CRFs were generated to identify most benefit scenarios (MBS) in which a predicted toxicity reduction of ⩾5% points in ⩾25% of the cohort was present due to IRS implantation. RESULTS: IMRT+IRS revealed a significant reduction in V40Gy (p=0.0357) and V75Gy (p<0.0001) relative to IMRT-IRS. For G2-3 acute GI toxicity and G2-3 LRB, the predicted toxicity rates decreased in 17/26 (65%) and 20/26 (77%) patients, and decision rules were derived for 22/32 (69%) and 12/64 (19%) MBS, respectively. From the decision rules, it follows that diabetes status has no impact on G2-3 acute toxicity, and in absence of pre-RT abdominal surgery, the implantation of an IRS is predicted to show no clinically relevant benefit for G2-3 LRB. CONCLUSIONS: Prostate cancer patients who are expected to benefit most from IRS implantation can be identified prior to IMRT based on their CRFs profile.