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.

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.

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.

The Diagnostic Value of MR Imaging in Determining the Lymph Node Status of Patients with Non-Small Cell Lung Cancer: A Meta-Analysis.

Purpose To summarize existing evidence of thoracic magnetic resonance (MR) imaging in determining the nodal status of non-small cell lung cancer (NSCLC) with the aim of elucidating its diagnostic value on a per-patient basis (eg, in treatment decision making) and a per-node basis (eg, in target volume delineation for radiation therapy), with results of cytologic and/or histologic examination as the reference standard. Materials and Methods A systematic literature search for original diagnostic studies was performed in PubMed, Web of Science, Embase, and MEDLINE. The methodologic quality of each study was evaluated by using the Quality Assessment of Diagnostic Accuracy Studies 2, or QUADAS-2, tool. Hierarchic summary receiver operating characteristic curves were generated to estimate the diagnostic performance of MR imaging. Subgroup analyses, expressed as relative diagnostic odds ratios (DORs) (rDORs), were performed to evaluate whether publication year, methodologic quality, and/or method of evaluation (qualitative [ie, lesion size and/or morphology] vs quantitative [eg, apparent diffusion coefficients in diffusion-weighted images]) affected diagnostic performance. Results Twelve of 2551 initially identified studies were included in this meta-analysis (1122 patients; 4302 lymph nodes). On a per-patient basis, the pooled estimates of MR imaging for sensitivity, specificity, and DOR were 0.87 (95% confidence interval [CI]: 0.78, 0.92), 0.88 (95% CI: 0.77, 0.94), and 48.1 (95% CI: 23.4, 98.9), respectively. On a per-node basis, the respective measures were 0.88 (95% CI: 0.78, 0.94), 0.95 (95% CI: 0.87, 0.98), and 129.5 (95% CI: 49.3, 340.0). Subgroup analyses suggested greater diagnostic performance of quantitative evaluation on both a per-patient and per-node basis (rDOR = 2.76 [95% CI: 0.83, 9.10], P = .09 and rDOR = 7.25 [95% CI: 1.75, 30.09], P = .01, respectively). Conclusion This meta-analysis demonstrated high diagnostic performance of MR imaging in staging hilar and mediastinal lymph nodes in NSCLC on both a per-patient and per-node basis. (©) RSNA, 2016 Online supplemental material is available for this article.

Technical feasibility of integrating 7 T anatomical MRI in image-guided radiotherapy of glioblastoma: a preparatory study.

OBJECTIVES: The use of 7 Tesla (T) magnetic resonance imaging (MRI) has recently shown great potential for high-resolution soft-tissue neuroimaging and visualization of microvascularization in glioblastoma (GBM). We have designed a clinical trial to explore the value of 7 T MRI in radiation treatment of GBM. For this aim we performed a preparatory study to investigate the technical feasibility of incorporating 7 T MR images into the neurosurgical navigation and radiotherapy treatment planning (RTP) systems via qualitative and quantitative assessment of the image quality. MATERIALS AND METHODS: The MR images were acquired with a Siemens Magnetom 7 T whole-body scanner and a Nova Medical 32-channel head coil. The 7 T MRI pulse sequences included magnetization-prepared two rapid acquisition gradient echoes (MP2RAGE), T2-SPACE, SPACE-FLAIR and gradient echo sequences (GRE). A pilot study with three healthy volunteers and an anthropomorphic 3D phantom was used to assess image quality and geometrical image accuracy. RESULTS: The MRI scans were well tolerated by the volunteers. Susceptibility artefacts were observed in both the cortex and subcortical white matter at close proximity to air-tissue interfaces. Regional loss of signal and contrast could be minimized by the use of dielectric pads. Image transfer and processing did not degrade image quality. The system-related spatial uncertainty of geometrical distortion-corrected MP2RAGE pulse sequences was ≤2 mm. CONCLUSION: Integration of high-quality and geometrically-reliable 7 T MR images into neurosurgical navigation and RTP software is technically feasible and safe.

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.

Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD). METHODS: We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis. RESULTS: Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases). CONCLUSIONS: In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.

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.

Can FDG-PET assist in radiotherapy target volume definition of metastatic lymph nodes in head-and-neck cancer?

BACKGROUND AND PURPOSE: The role of FDG-PET in radiotherapy target volume definition of the neck was evaluated by comparing eight methods of FDG-PET segmentation to the current CT-based practice of lymph node assessment in head-and-neck cancer patients. MATERIALS AND METHODS: Seventy-eight head-and-neck cancer patients underwent coregistered CT- and FDG-PET scans. Lymph nodes were classified as "enlarged" if the shortest axial diameter on CT was 10mm, and as "marginally enlarged" if it was 7-10mm. Subsequently, lymph nodes were assessed on FDG-PET applying eight segmentation methods: visual interpretation (PET(VIS)), applying fixed thresholds at a standardized uptake value (SUV) of 2.5 and at 40% and 50% of the maximum signal intensity of the primary tumor (PET(SUV), PET(40%), PET(50%)) and applying a variable threshold based on the signal-to-background ratio (PET(SBR)). Finally, PET(40%N), PET(50%N) and PET(SBRN) were acquired using the signal of the lymph node as the threshold reference. RESULTS: Of 108 nodes classified as "enlarged" on CT, 75% were also identified by PET(VIS), 59% by PET(40%), 43% by PET(50%) and 43% by PET(SBR). Of 100 nodes classified as "marginally enlarged", only a minority were visualized by FDG-PET. The respective numbers were 26%, 10%, 7% and 8% for PET(VIS), PET(40%), PET(50%) and PET(SBR). PET(40%N), PET(50%N) and PET(SBRN), respectively, identified 66%, 82% and 96% of the PET(VIS)-positive nodes. CONCLUSIONS: Many lymph nodes that are enlarged and considered metastatic by standard CT-based criteria appear to be negative on FDG-PET scan. Alternately, a small proportion of marginally enlarged nodes are positive on FDG-PET scan. However, the results are largely dependent on the PET segmentation tool used, and until proper validation FDG-PET is not recommended for target volume definition of metastatic lymph nodes in routine practice.

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.

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.

Convex reformulation of biologically-based multi-criteria intensity-modulated radiation therapy optimization including fractionation effects.

Finding fluence maps for intensity-modulated radiation therapy (IMRT) can be formulated as a multi-criteria optimization problem for which Pareto optimal treatment plans exist. To account for the dose-per-fraction effect of fractionated IMRT, it is desirable to exploit radiobiological treatment plan evaluation criteria based on the linear-quadratic (LQ) cell survival model as a means to balance the radiation benefits and risks in terms of biologic response. Unfortunately, the LQ-model-based radiobiological criteria are nonconvex functions, which make the optimization problem hard to solve. We apply the framework proposed by Romeijn et al (2004 Phys. Med. Biol. 49 1991-2013) to find transformations of LQ-model-based radiobiological functions and establish conditions under which transformed functions result in equivalent convex criteria that do not change the set of Pareto optimal treatment plans. The functions analysed are: the LQ-Poisson-based model for tumour control probability (TCP) with and without inter-patient heterogeneity in radiation sensitivity, the LQ-Poisson-based relative seriality s-model for normal tissue complication probability (NTCP), the equivalent uniform dose (EUD) under the LQ-Poisson model and the fractionation-corrected Probit-based model for NTCP according to Lyman, Kutcher and Burman. These functions differ from those analysed before in that they cannot be decomposed into elementary EUD or generalized-EUD functions. In addition, we show that applying increasing and concave transformations to the convexified functions is beneficial for the piecewise approximation of the Pareto efficient frontier.

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.

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.

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.

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.