Danny Lee

Goal: This study evaluates the feasibility and outcome of a personalized MRI-based liver SBRT treatment planning platform with the SPION contrast agent Ferumoxytol^® (Sandoz Inc.; Princeton, NJ, USA) to maintain a superior real-time visualization of liver tumors and volumes of functional hepatic parenchyma for radiotherapy planning throughout multi-fractionated liver SBRT with online plan adaptations on an Elekta Unity 1.5 T MR-Linac (Elekta; Stockholm, Sweden). Materials and Methods: Patients underwent SPION-enhanced MRI on the Elekta Unity MR-Linac for improved tumor and functional hepatic parenchyma visualization. An automated contouring algorithm was applied for the delineation and subsequent guided avoidance of functional liver parenchyma volumes (FLVs) on the SPION-enhanced MR-Linac. Radiation dose constraints were adapted exclusively to FLV. Local control, toxicity, and survival were assessed with at least 6-month radiographic follow-up. Pre- and post-transplant outcomes were analyzed in the subset of patients with HCC and hepatic cirrhosis who completed SBRT as a bridge to liver transplant. Model of End-Stage Liver Disease (MELD-Na) was used to score hepatic function before and after SBRT. Results: With a median follow-up of 23 months (range: 3–40 months), 23 HCC patients (26 lesions treated) and 9 patients (14 lesions treated) with hepatic metastases received SBRT (mean dose: 48 Gy, range: 36–54 Gy) in 1–5 fractions. Nearly all patients in this study had pe-existing liver conditions, including hepatic cirrhosis (23), prior TACE (7), prior SBRT (18), or history of hepatic resection (2). Compared to the non-contrast images, SPIONs improved tumor visibility on post-SPION images on the background of negatively enhancing functionally active hepatic parenchyma. Prolonged SPION-contrast retention within hepatic parenchyma enabled per-fraction treatment adaptation throughout the entire multi-fraction treatment course. FLV loss (53%, p < 0.0001) was observed in cirrhotic patients, but functional and anatomic liver volumes remained consistent in non-cirrhotic patients. Mean dose to FLV was maintained within the liver threshold tolerance to radiation in all patients after the optimization of Step-and-Shoot Intensity-Modulated Radiotherapy (SS-IMRT) on the SPION-enhanced MRI-Linac. No radiation-induced liver disease was observed within 6 months post-SBRT, and the MELD-Na score in cirrhotic patients was not significantly elevated at 3-month intervals after SBRT completion. Conclusions: SPION Ferumoxytol^® administered intravenously as an alternative MRI contrast agent on the day of SBRT planning produces a long-lasting contrast effect between tumors and functional hepatic parenchyma for precision targeting and guided avoidance during the entire course of liver SBRT, enabling fast and accurate online plan adaptation on the 1.5 T Elekta Unity MR-Linac. This approach demonstrates a safe and effective bridging therapy for patients with hepatic cirrhosis, leading to low toxicity and favorable transplant outcomes.

Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme^®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant.

A 1.5T MRI combined with a linear accelerator (Unity^®, Elekta; Stockholm, Sweden) is a device that shows promise in MRI-guided stereotactic body radiation treatment (SBRT). Previous studies utilized the manufacturer’s pre-set MRI sequences (i.e., T2 Weighted (T2W)), which limited the visualization of pancreatic and intra-abdominal tumors and organs at risk (OAR). Here, a T1 Weighted (T1W) sequence was utilized to improve the visualization of tumors and OAR for online adapted-to-position (ATP) and adapted-to-shape (ATS) during MRI-guided SBRT. Twenty-six patients, 19 with pancreatic and 7 with intra-abdominal cancers, underwent CT and MRI simulations for SBRT planning before being treated with multi-fractionated MRI-guided SBRT. The boundary of tumors and OAR was more clearly seen on T1W image sets, resulting in fast and accurate contouring during online ATP/ATS planning. Plan quality in 26 patients was dependent on OAR proximity to the target tumor and achieved 96 ± 5% and 92 ± 9% in gross tumor volume D_90% and planning target volume D_90%. We utilized T1W imaging (about 120 s) to shorten imaging time by 67% compared to T2W imaging (about 360 s) and improve tumor visualization, minimizing target/OAR delineation uncertainty and the treatment margin for sparing OAR. The average time-consumption of MRI-guided SBRT for the first 21 patients was 55 ± 15 min for ATP and 79 ± 20 min for ATS.

The use of super-paramagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent (SPION-CA) can safely label hepatic macrophages and be localized within hepatic parenchyma for T2*- and R2*-MRI of the liver. To date, no study has utilized the R2*-MRI with SPIONs for quantifying liver heterogeneity to characterize functional liver parenchyma (FLP) and hepatic tumors. This study investigates whether SPIONs enhance liver heterogeneity for an auto-contouring tool to identify the voxel-wise functional liver parenchyma volume (FLPV). This was the first study to directly evaluate the impact of SPIONs on the FLPV in R2*-MRI for 12 liver cancer patients. By using SPIONs, liver heterogeneity was improved across pre- and post-SPION MRI sessions. On average, 60% of the liver [range 40–78%] was identified as the FLPV in our auto-contouring tool with a pre-determined threshold of the mean R2* of the tumor and liver. This method performed well in 10 out of 12 liver cancer patients; the remaining 2 needed a longer echo time. These results demonstrate that our contouring tool with SPIONs can facilitate the heterogeneous R2* of the liver to automatically characterize FLP. This is a desirable technique for achieving more accurate FLPV contouring during liver radiation treatment planning.

PurposeTo implement an independent 3D dose verification system with RayStation (RaySearch, Stockholm, Sweden) for online adaptive radiotherapy on Elekta Unity MR-Linac (MRL). MethodsPlan quality of simple-single-field and intensity-modulated radiotherapy (IMRT) plans were investigated in a comparison of (1) Monte-Carlo calculated data using MRL Monaco with high magnetic field (1.5 T) and (2) Collapsed-Cone calculated data using RayStation. The dose quality of RayStation plans, compared to corresponding Monaco plans, was (1) visually inspected in percentage depth-dose curves, inline and crossline profiles, and (2) quantified in 3D gamma-passing-rates. Processing time was measured to evaluate the practical efficacy of our system using 5 prostate IMRT plans.ResultsCompared to Monaco simple-single-field plans as ground truth, RayStation simple-single-field plans achieved an average 95.7% and 98.5% in 2%/2mm and 3%/3mm of 3D gamma criteria, respectively. Gantry angle dependency in simple-single-field plans was <2% in both 2%/2mm and 3%/3mm, and field size dependency was <5% in 2%/2mm and <2% in 3%/3mm. Compared to Monaco IMRT plans, RayStation IMRT plans achieved an average 95.1% (3%/3mm). The entire processing time of the independent 3D dose verification system was an average approximately 200 s. ConclusionsThis was the study to implement an independent 3D dose verification process using RayStation with an in-house 3D gamma analysis software. This led to an average 95% plan quality in 3%/3mm gamma criteria and added an average 200 s throughout the entire verification processes. These results demonstrate that this approach can be applicable and efficient for online quality assurance for MRL online adaptive radiotherapy planning.

The use of trajectory log files for routine patient quality assurance is gaining acceptance. Such use requires the validation of the trajectory log itself. However, the accurate localization of a multileaf collimator (MLC) leaf while it is in motion remains a challenging task. We propose an efficient phantom‐less technique using the EPID to verify the dynamic MLC positions with high accuracy. Measurements were made on four Varian TrueBeams equipped with M120 MLCs. Two machines were equipped with the S1000 EPID; two were equipped with the S1200 EPID. All EPIDs were geometrically corrected prior to measurements. Dosimetry mode EPID measurements were captured by a frame grabber card directly linked to the linac. All leaf position measurements were corrected both temporally and geometrically. The readout latency of each panel, as a function of pixel row, was determined using a 40 × 1.0 cm² sliding window (SW) field moving at 2.5 cm/s orthogonal to the row readout direction. The latency of each panel type was determined by averaging the results of two panels of the same type. Geometric correction was achieved by computing leaf positions with respect to the projected isocenter position as a function of gantry angle. This was determined by averaging the central axis position of fields at two collimator positions of 90° and 270°. The radiological to physical leaf end position was determined by comparison of the measured gap with that determined using a feeler gauge. The radiological to physical leaf position difference was found to be 0.1 mm. With geometric and latency correction, the proposed method was found to be improve the ability to detect dynamic MLC positions from 1.0 to 0.2 mm for all leaves. Latency and panel residual geometric error correction improve EPID‐based MLC position measurement. These improvements provide for the first time a trajectory log QA procedure.

Introduction: 4D‐MRI, compared to 4D‐CT, provides better soft‐tissue contrast for target delineation. However, motion artefacts are often observed due to residual breathing variations. This study is to present a retrospective 4D‐MRI reconstruction method based on 2D diaphragm profiles to improve the quality of 4D‐MR images in the presence of significant breathing variations.Methods: The proposed 4D‐MRI reconstruction method utilized diaphragm profiles (2D cine images on a single sagittal plan at the peak diaphragm) in conjunction with 4D‐MR scans (2D‐cine images on multiple pre‐determined coronal planes along the anterior‐posterior direction over a volume of interest). The diaphragm profile images were exploited to sort the 4D‐MR scans by matching respiratory amplitude of diaphragm on the 4D‐MR scans to the diaphragm profiles. To evaluate reconstructed 4D‐MR images (ten 3D‐MR images), sagittal images on ten 3D‐MR images under free breathing (FB) and respiratory guidance (GB) were compared with diaphragm profile images (reference) from 13 healthy volunteers.Results: Forty‐four 4D‐MR scan datasets were successfully reconstructed without distinct respiratory‐related motion artefacts even with the presence of breathing variation. The differences in diaphragm profiles between the reference and corresponding reconstructed images in the mean of root mean square were similar between FB (3.5 mm) and GB (3.0 mm), confirming that the 4D‐MRI reconstruction method was effective even with significant breathing variation.Conclusions: The diaphragm profiles were utilized to reconstruct 4D‐MR images with spatial reliability and a fixed scan time under FB and GB. Our method can provide reliable 4D information of thoracic and abdominal regions for MRI‐guided radiotherapy.