Considerations for intensity modulated total body or total marrow and lymphoid irradiation.

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program.

Impact of respiratory motion on lung dose during total marrow irradiation.

We evaluated the impact of respiratory motion on the lung dose during linac-based intensity-modulated total marrow irradiation (IMTMI) using two different approaches: (1) measurement of doses within the lungs of an anthropomorphic phantom using thermoluminescent detectors (TLDs) and (2) treatment delivery measurements using ArcCHECK where gamma passing rates (GPRs) and the mean lung doses were calculated and compared with and without motion. In the first approach, respiratory motions were simulated using a programmable motion platform by using typical published peak-to-peak motion amplitudes of 5, 8, and 12 mm in the craniocaudal (CC) direction, denoted here as M1, M2, and M3, respectively, with 2 mm in both anteroposterior (AP) and lateral (LAT) directions. TLDs were placed in five selected locations in the lungs of a RANDO phantom. Average TLD measurements obtained with motion were normalized to those obtained with static phantom delivery. The mean dose ratios were 1.01 (0.98-1.03), 1.04 (1.01-1.09), and 1.08 (1.04-1.12) for respiratory motions M1, M2, and M3, respectively. To determine the impact of directional respiratory motion, we repeated the experiment with 5-, 8-, and 12-mm motion in the CC direction only. The differences in average TLD doses were less than 1% when compared with the M1, M2, and M3 motions indicating a minimal impact from CC motion on lung dose during IMTMI. In the second experimental approach, we evaluated extreme respiratory motion 15 mm excursion in only the CC direction. We placed an ArcCHECK device on a commercial motion platform and delivered the clinical IMTMI plans of five patients. We compared, with and without motion, the dose volume histograms (DVHs) and mean lung dose calculated with the ArcCHECK-3DVH tool as well as GPR with 3%, 5%, and 10% dose agreements and a 3-mm constant distance to agreement (DTA). GPR differed by 11.1 ± 2.1%, 3.8 ± 1.5%, and 0.1 ± 0.2% with dose agreement criteria of 3%, 5%, and 10%, respectively. This indicates that respiratory motion impacts dose distribution in small and isolated parts of the lungs. More importantly, the impact of respiratory motion on the mean lung dose, a critical indicator for toxicity in IMTMI, was not statistically significant (p > 0.05) based on the Student's t-test. We conclude that most patients treated with IMTMI will have negligible dose uncertainty due to respiratory motion. This is particularly reassuring as lung toxicity is the main concern for future IMTMI dose escalation studies.

Knowledge-based planning for multi-isocenter VMAT total marrow irradiation.

Purpose: Total marrow irradiation (TMI) involves optimization of extremely large target volumes and requires extensive clinical experience and time for both treatment planning and delivery. Although volumetric modulated arc therapy (VMAT) achieves substantial reduction in treatment delivery time, planning process still presents a challenge due to use of multiple isocenters and multiple overlapping arcs. We developed and evaluated a knowledge-based planning (KBP) model for VMAT-TMI to address these clinical challenges. Methods: Fifty-one patients previously treated in our clinic were selected for the model training, while 22 patients from another clinic were used as a test set. All plans used a 3-isocenter to cover sub-target volumes of head and neck (HN), chest, and pelvis. Chest plan was performed first and then used as the base dose for both the HN and pelvis plans to reduce hot spots around the field junctions. This resulted in a wide range of dose-volume histograms (DVH). To address this, plans without the base-dose plan were optimized and added to the library to train the model. Results: KBP achieved our clinical goals (95% of PTV receives 100% of Rx) in a single day, which used to take 4-6 days of effort without KBP. Statistically significant reductions with KBP were observed in the mean dose values to brain, lungs, oral cavity and lenses. KBP substantially improved 105% dose spillage (14.1% ± 2.4% vs 31.8% ± 3.8%), conformity index (1.51 ± 0.06 vs 1.81 ± 0.12) and homogeneity index (1.25 ± 0.02 vs 1.33 ± 0.03). Conclusions: KBP improved dosimetric performance with uniform quality. It reduced dependence on planner experience and achieved a factor of 5 reduction in planning time to produce quality plans to allow its wide-spread clinical implementation.

Local Recurrence Following Total Marrow Radiation: Implications for Clinical Target Delineation.

Total marrow radiation is an emerging treatment modality used in patients undergoing stem cell transplantation. We present a rare case of a patient undergoing total marrow irradiation with concurrent ablative stem cell transplantation with local failures in two out-of-field areas that were not included in the clinical target volume A 31-year-old female patient initially presented with abdominal pain secondary to chronic myelogenous leukemia. She underwent dasatinib treatment for years, but subsequently developed recurrence and underwent consolidation systemic chemotherapy followed by allogeneic stem cell transplantation with adjuvant total marrow irradiation. Several months later, she noticed increased left jaw swelling and dysphagia with associated right ankle swelling. Biopsy of the right ankle and left mandible were consistent with recurrent myeloid sarcoma. This case report suggests that inclusion of the mandible and lower extremities may be necessary when performing total marrow radiation.

Frame-based radiosurgery of multiple metastases using single-isocenter volumetric modulated arc therapy technique.

Single-isocenter volumetric modulated arc therapy (VMAT) technique can provide stereotactic radiosurgery (SRS) treatment with improved delivery efficiency for treating multiple metastases. Nevertheless, planning is time consuming and verification of frame-based SRS setup, especially at noncoplanar angles, can be challenging. We report on a single-isocenter VMAT technique with a special focus on improving treatment workflow and delivery verification to exploit the minimized patient motion of the frame-based SRS. We developed protocols for preplanning and verification for VMAT and evaluated them for ten patient cases. Preplans based on MRI were used to generate comparable treatment plans using CT taken on the day of treatment after frame placement. Target positioning accuracy was evaluated by stereoscopic in-room kV imaging. Dosimetric accuracy of the noncoplanar plan delivery was validated using measurement-guided 3D dose reconstruction as well as film-based end-to-end test with a Rando phantom. Average absolute differences of homogeneity indices, conformity indices, and V12Gy between MR preplans and CT-based plans were within 5%. In-room imaging positioning accuracy of 0.4 mm was verified to be independent of the distance to the isocenter. For treatment verification, average local and global passing rates of the 3D gamma (1 mm, 3%) were 86% and 99%, respectively. D99 values were matched within 5% for individual target structures (>0.5 cc). Additional film analysis confirmed dosimetric accuracy for small targets that had large verification errors in the 3D dose reconstruction. Our results suggest that the advantages of frame-based SRS and noncoplanar single-isocenter VMAT technique can be combined for efficient and accurate treatment of patients with multiple metastases.

A preplanning method for stereotactic radiosurgery to improve treatment workflow.

Frame-based stereotactic radiosurgery (SRS) requires fixation of an invasive head ring to ensure accurate targeting. Minimizing waiting time with a fixed head ring is important for patient comfort and satisfaction. We report a practical preplanning solution for the Brainlab iPlan treatment planning system that reduces waiting time by expediting the planning process on treatment day. A water-filled anthropomorphic head phantom was used to acquire a surrogate CT image set for preplanning and fused with patient's MRI, which was obtained before the day of treatment. Once an acceptable preplan was obtained, it was saved as a plan template and the phantom image set was removed from the Brainlab database to prevent any confusion and mix-up of image sets. On the treatment day, the patient's CT and MRI were fused, and the customized beam settings of the preplan template were then applied and optimized. Up to 10-fold of reduction in treatment plan time was demonstrated by bench testing with multiple planners and a variety of cases. Loading the plan template and fine-tuning the preconfigured beam settings took only a small fraction of the preplan time to restore the conformity and dose falloff comparable to those of the preplan. For instance, preplan time was 2 hr for a two-isocenter case, whereas, it took less than 20 min for a less experienced planner to plan it on the day of treat-ment using the preplan method. The SRS preplanning technique implemented in this study for the Brainlab iPlan treatment planning system offers an opportunity to explore possible beam configurations thoroughly, optimize planning parameters, resolve gantry angle clearance issues, and communicate and address challenges with physicians before the treatment day. Preplanning has been proven to improve plan quality and to improve efficiency in our clinic, especially for multiple-isocenter and dosimetrically challenging cases.

Increased dose near the skin due to electromagnetic surface beacon transponder.

The purpose of this study was to evaluate the increased dose near the skin from an electromagnetic surface beacon transponder, which is used for localization and tracking organ motion. The bolus effect due to the copper coil surface beacon was evaluated with radiographic film measurements and Monte Carlo simulations. Various beam incidence angles were evaluated for both 6 MV and 18 MV experimentally. We performed simulations using a general-purpose Monte Carlo code MCNPX (Monte Carlo N-Particle) to supplement the experimental data. We modeled the surface beacon geometry using the actual mass of the glass vial and copper coil placed in its L-shaped polyethylene terephthalate tubing casing. Film dosimetry measured factors of 2.2 and 3.0 enhancement in the surface dose for normally incident 6 MV and 18 MV beams, respectively. Although surface dose further increased with incidence angle, the relative contribution from the bolus effect was reduced at the oblique incidence. The enhancement factors were 1.5 and 1.8 for 6 MV and 18 MV, respectively, at an incidence angle of 60°. Monte Carlo simulation confirmed the experimental results and indicated that the epidermal skin dose can reach approximately 50% of the dose at dmax at normal incidence. The overall effect could be acceptable considering the skin dose enhancement is confined to a small area (~ 1 cm2), and can be further reduced by using an opposite beam technique. Further clinical studies are justified in order to study the dosimetric benefit versus possible cosmetic effects of the surface beacon. One such clinical situation would be intact breast radiation therapy, especially large-breasted women.

Multiparametric imaging of tumor oxygenation, redox status, and anatomical structure using Overhauser-enhanced MRI-prepolarized MRI system.

An integrated Overhauser-enhanced MRI-Prepolarized MRI system was developed to obtain radiobiological information that could be accurately coregistered with diagnostic quality anatomic images. EPR and NMR images were acquired through the double resonance technique and field cycling of the main magnetic field from 5 mT to 0.5 T. Dedicated EPR and NMR coils were devised to minimize radiofrequency power deposition with high signal-to-noise ratio. Trityl and nitroxide radicals were used to characterize oxygen and redox sensitivities of multispin echo Overhauser-enhanced MRI. Oxygen resolution of 3 mmHg was obtained from 2 mM deoxygenated trityl phantoms. Trityl radicals were stable in reducing environments and did not alter the redox-sensitive decaying rate of the nitroxide signals. Nitroxide radicals had a compounding effect for the trityl oximetry. Tumor oxygenation and redox status were acquired with anatomical images by injecting trityl and nitroxide probes subsequently in murine tumors. The Overhauser-enhanced MRI-Prepolarized MRI system is ready for quantitative longitudinal imaging studies of tumor hypoxia and redox status as radiotherapy prognostic factors.

Where it's at really matters: in situ in vivo vascular endothelial growth factor spatially correlates with electron paramagnetic resonance pO2 images in tumors of living mice.

PURPOSE: Tumor microenvironments show remarkable tumor pO(2) heterogeneity, as seen in prior EPR pO(2) images (EPROI). pO(2) correlation with hypoxia response proteins is frustrated by large rapid pO(2) changes with position. PROCEDURES: To overcome this limitation, biopsies stereotactically located in the EPROI were used to explore the relationship between vascular endothelial growth factor A (VEGF) concentrations in living mouse tumors and the local EPROI pO(2). RESULTS: Quantitative ELISA VEGF concentrations correlated (p = 0.0068 to 0.019) with mean pO(2), median pO(2), and the fraction of voxels in the biopsy volume with pO(2) less than 3, 6, and 10 Torr. CONCLUSIONS: This validates EPROI hypoxic fractions at the molecular level and provides a new paradigm for the assessment of the relationship, in vivo, between hypoxia and hypoxia response proteins. When translated to human subjects, this will enhance understanding of human tumor pathophysiology and cancer response to therapy.

MRI guidance for accelerated partial breast irradiation in prone position: imaging protocol design and evaluation.

PURPOSE: To design and evaluate a magnetic resonance imaging (MRI) protocol to be incorporated in the simulation process for external beam accelerated partial breast irradiation. METHODS AND MATERIALS: An imaging protocol was developed based on an existing breast MRI technique with the patient in the prone position on a dedicated coil. Pulse sequences were customized to exploit T1 and T2 contrast mechanisms characteristic of lumpectomy cavities. A three-dimensional image warping algorithm was included to correct for geometric distortions related to nonlinearity of spatially encoding gradients. Respiratory motion, image distortions, and susceptibility artifacts of 3.5-mm titanium surgical clips were examined. Magnetic resonance images of volunteers were acquired repeatedly to analyze residual setup deviations resulting from breast tissue deformation. RESULTS: The customized sequences generated high-resolution magnetic resonance images emphasizing lumpectomy cavity morphology. Respiratory motion was negligible with the subject in the prone position. The gradient-induced nonlinearity was reduced to less than 1 mm in a region 15 cm away from the isocenter of the magnet. Signal-void regions of surgical clips were 4 mm and 8 mm for spin echo and gradient echo images, respectively. Typical residual repositioning errors resulting from breast deformation were estimated to be 3 mm or less. CONCLUSIONS: MRI guidance for accelerated partial breast irradiation with the patient in the prone position with adequate contrast, spatial fidelity, and resolution is possible.

Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.

PURPOSE: To compare bone marrow-sparing intensity-modulated pelvic radiotherapy (BMS-IMRT) with conventional (four-field box and anteroposterior-posteroanterior [AP-PA]) techniques in the treatment of cervical cancer. METHODS AND MATERIALS: The data from 7 cervical cancer patients treated with concurrent chemotherapy and IMRT without BMS were analyzed and compared with data using four-field box and AP-PA techniques. All plans were normalized to cover the planning target volume with the 99% isodose line. The clinical target volume consisted of the pelvic and presacral lymph nodes, uterus and cervix, upper vagina, and parametrial tissue. Normal tissues included bowel, bladder, and pelvic bone marrow (PBM), which comprised the lumbosacral spine and ilium and the ischium, pubis, and proximal femora (lower pelvis bone marrow). Dose-volume histograms for the planning target volume and normal tissues were compared for BMS-IMRT vs. four-field box and AP-PA plans. RESULTS: BMS-IMRT was superior to the four-field box technique in reducing the dose to the PBM, small bowel, rectum, and bladder. Compared with AP-PA plans, BMS-IMRT reduced the PBM volume receiving a dose >16.4 Gy. BMS-IMRT reduced the volume of ilium, lower pelvis bone marrow, and bowel receiving a dose >27.7, >18.7, and >21.1 Gy, respectively, but increased dose below these thresholds compared with the AP-PA plans. BMS-IMRT reduced the volume of lumbosacral spine bone marrow, rectum, small bowel, and bladder at all dose levels in all 7 patients. CONCLUSION: BMS-IMRT reduced irradiation of PBM compared with the four-field box technique. Compared with the AP-PA technique, BMS-IMRT reduced lumbosacral spine bone marrow irradiation and reduced the volume of PBM irradiated to high doses. Therefore BMS-IMRT might reduce acute hematologic toxicity compared with conventional techniques.

Electron paramagnetic resonance oxygen image hypoxic fraction plus radiation dose strongly correlates with tumor cure in FSa fibrosarcomas.

PURPOSE: Tumor hypoxia has long been known to produce resistance to radiation. In this study, electron paramagnetic resonance (EPR) oxygen imaging was investigated for its power to predict the success of tumor control according to tumor oxygenation level and radiation dose. METHODS AND MATERIALS: A total of 34 EPR oxygen images were obtained from the legs of C3H mice bearing 0.5-cm(3) FSa fibrosarcomas under both normal (air breathing) and clamped tumor conditions. Under the same conditions as those during which the images were obtained, the tumors were irradiated to a variety of doses near the FSa dose at which 50% of tumors were cured. Tumor tissue was distinguished from normal tissue using co-registration of the EPR oxygen images with spin-echo magnetic resonance imaging of the tumor and/or stereotactic localization. The tumor voxel statistics in the EPR oxygen image included the mean and median partial pressure of oxygen and the fraction of tumor voxels below the specified partial pressure of oxygen values of 3, 6, and 10 mm Hg. Bivariate logistic regression analysis using the radiation dose and each of the EPR oxygen image statistics to determine which best separated treatment failure from success. RESULTS: The measurements of the dose at which 50% of tumors were cured were similar to those found in published data for this syngeneic tumor. Bivariate analysis of 34 tumors demonstrated that tumor cure correlated with dose (p = 0.004) and with a <10 mm Hg hypoxic fraction (p = 0.023). CONCLUSION: Our results have shown that, together, radiation dose and EPR image hypoxic fraction separate the population of FSa fibrosarcomas that are cured from those that fail, thus predicting curability.

Very-low-frequency electron paramagnetic resonance (EPR) imaging of nitroxide-loaded cells.

Recent advances in electron paramagnetic resonance (EPR) imaging have made it possible to image, in real time in vivo, cells that have been labeled with nitroxide spin probes. We previously reported that cells can be loaded to high (millimolar) intracellular concentrations with (2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-ylmethyl)amine-N,N-diacetic acid by incubation with the corresponding acetoxymethyl (AM) ester. Furthermore, the intracellular lifetime (t(1/e)) of this nitroxide is 114 min-sufficiently long to permit in vivo imaging studies. In the present study, at a gradient of approximately 50 mT/m, we acquire and compare EPR images of a three-tube phantom, filled with either a 200-microM solution of the nitroxide, or a suspension of cells preincubated with the nitroxide AM ester. In both cases, 3-mm resolution images can be acquired with excellent signal-to-noise ratios (SNRs). These findings indicate that cells well-loaded with nitroxide are readily imageable by EPR imaging, and that in vivo tracking studies utilizing such cells should be feasible.

Comparison of local and global angular interpolation applied to spectral-spatial EPR image reconstruction.

Spectral-spatial images reconstructed from a small number of projections suffer from streak artifacts that are seen as noise, particularly in the spectral dimension. Interpolation in projection space can reduce artifacts in the reconstructed images. The reduction of background artifacts improves lineshape fitting. In this work, we compared the performances of angular interpolation implemented using linear, cubic B-spline, and sinc methods. Line width maps were extracted from 4-D EPR images of phantoms using spectral fitting to evaluate each interpolation method and its robustness to noise. Results from experiment and simulation showed that the cubic B-spline, angular interpolation was preferable to either sinc or linear interpolation methods.

Simulation of 4D spectral-spatial EPR images.

Electron paramagnetic resonance imaging (EPRI) can be modeled by the forward projection of a 4D synthetic spectral-spatial phantom. We developed a simulation tool for EPRI and carried out a quantitative comparison between simulation and experiment, focusing on the signal and noise characteristics. The signal height in the simulation was compared to that in the experimental projections at gradients of different magnitudes and directions. We investigated the noise power spectrum of an EPR imager and incorporated it into the simulation. The signal and noise modeling of the simulation achieved the same performance as the EPR imager. Using this simulation, various sampling schemes were tried to find an optimized parameter set under the customized noise model of this EPR imager.

Object dependent sweep width reduction with spectral-spatial EPR imaging.

For spectral-spatial EPR imaging, prior knowledge about the spatial support of an imaged object can be exploited in two ways. We can shrink the spatial field of view (FOV) to closely wrap the object in a sphere or reduce the sweep width in a projection dependent fashion. Use of a smaller spatial FOV with the same number of samples enhances spatial resolution by reducing voxel volume at the expense of signal-to-noise and a consequent degraded line-width resolution. We have developed another approach to define sweep width that prunes away the portions of the projection sweep with no signal. This reduces data acquisition time for the continuous wave (CW) EPR image proportional to the sweep width reduction. This method also avoids voxel volume reduction. Using the reduced-sweep method, we decreased the data acquisition time by 20% maintaining spatial and linewidth resolution.

Spatially uniform sampling in 4-D EPR spectral-spatial imaging.

Four-dimensional EPR imaging involves a computationally intensive inversion of the sampled Radon transform. Conventionally, N-dimensional reconstructions have been carried out with N-1 stages of 2-D backprojection to exploit a dimension-dependent reduction in execution time. The huge data size of 4-D EPR imaging demands the use of a 3-stage reconstruction each consisting of 2-D backprojections. This gives three orders of magnitude reduction in computation relative to a single stage 4-D filtered backprojection. The multi-stage reconstruction, however, requires a uniform angular sampling that yields an inefficient distribution of gradient directions. We introduce a solution that involves acquisition of projections uniformly distributed in solid angle and reconstructs in three 2-D stages with the spatial uniform solid angle data set converted to uniform linear angular projections using 2-D interpolation. Images were taken from the two sampling schemes to compare the spatial resolution and the line width resolution. The degradation in the image quality due to the additional interpolation was small, and we achieved approximately 30% reduction in data acquisition time.

Scaling of EPR spectral-spatial images with size of sample: images of a sample greater than 5 cm in linear dimension.

The authors have obtained spectral-spatial EPR images of a phantom significantly larger than those previously obtained. Images of a homogeneous phantom 4.2 cm in diameter and 6.5 cm in length with B1 equivalent to that used for smaller samples give a similar linewidth resolution both with linewidth population distributions of width 0.1 microT. Spatial resolution appeared to have modest degradation. Images of the large homogeneous phantom provide maps of the magnetic field of a partially shimmed magnet.

Electron paramagnetic resonance oxygen images correlate spatially and quantitatively with Oxylite oxygen measurements.

Tumor oxygenation predicts cancer therapy response and malignant phenotype. This has spawned a number of oxymetries. Comparison of different oxymetries is crucial for the validation and understanding of these techniques. Electron paramagnetic resonance (EPR) imaging is a novel technique for providing quantitative high-resolution images of tumor and tissue oxygenation. This work compares sequences of tumor pO2 values from EPR oxygen images with sequences of oxygen measurements made along a track with an Oxylite oxygen probe. Four-dimensional (three spatial and one spectral) EPR oxygen images used spectroscopic imaging techniques to measure the width of a spectral line in each image voxel from a trityl spin probe (OX063, Amersham Health R&D) in the tissues and tumor of mice after spin probe injection. A simple calibration allows direct, quantitative translation of each line width to an oxygen concentration. These four-dimensional EPR images, obtained in 45 minutes from FSa fibrosarcomas grown in the legs of C3H mice, have a spatial resolution of approximately 1 mm and oxygen resolution of approximately 3 Torr. The position of the Oxylite track was measured within a 2-mm accuracy using a custom stereotactic positioning device. A total of nine images that involve 17 tracks were obtained. Of these, most showed good correlation between the Oxylite measured pO2 and a track located in the tumor within the uncertainties of the Oxylite localizability. The correlation was good both in terms of spatial distribution pattern and pO2 magnitude. The strong correlation of the two modalities corroborates EPR imaging as a useful tool for the study of tumor oxygenation.