Minimizing normal tissue low dose bath for left breast Volumetric Modulated Arc Therapy (VMAT) using jaw offset.

PURPOSE: With proper beam setup and optimization constraints in the treatment planning system, volumetric modulated arc therapy (VMAT) can improve target dose coverage and conformity while reducing doses to adjacent structures for whole breast radiation therapy. However, the low-dose bath effect on critical structures, especially the heart and the ipsilateral lung, remains a concern. In this study, we present a VMAT technique with the jaw offset VMAT (JO-VMAT) to reduce the leakage and scatter doses to critical structures for whole breast radiation therapy. MATERIALS AND METHODS: The data of 10 left breast cancer patients were retrospectively used for this study. CT images were acquired on a CT scanner (GE, Discovery) with the deep-inspiration breath hold (DIBH) technique. The planning target volumes (PTVs) and the normal structures (the lungs, the heart, and the contralateral breast) were contoured on the DIBH scan. A 3D field-in-field plan (3D-FiF), a tangential VMAT (tVMAT) plan, and a JO-VMAT plan were created with the Eclipse treatment planning system. An arc treatment field with the x-jaw closed across the central axis creates a donut-shaped high-dose distribution and a cylinder-shaped low-dose volume along the central axis of gantry rotation. Applying this setup with proper multi-leaf collimator (MLC) modulation, the optimized plan potentially can provide sufficient target coverage and reduce unnecessary irradiation to critical structures. The JO-VMAT plans involve 5-6 tangential arcs (3 clockwise arcs and 2-3 counterclockwise arcs) with jaw offsets. The plans were optimized with objective functions specified to achieve PTV dose coverage and homogeneity; For organs at risk (OARs), objective functions were specified individually for each patient to accomplish the best achievable treatment plan. For tVMAT plans, optimization constraints were kept the same except that the jaw offset was removed from the initial beam setup. The dose volume histogram (DVH) parameters were generated for dosimetric evaluation of PTV and OARs. RESULTS: The D95% to the PTV was greater than the prescription dose of 42.56 Gy for all the plans. With both VMAT techniques, the PTV conformity index (CI) was statistically improved from 0.62 (3D-FiF) to 0.83 for tVMAT and 0.84 for JO-VMAT plans. The difference in the homogeneity index (HI) was not significant. The Dmax to the heart was reduced from 12.15 Gy for 3D-FiF to 8.26 Gy for tVMAT and 7.20 Gy for JO-VMAT plans. However, a low-dose bath effect was observed with tVMAT plans to all the critical structures including the lungs, the heart, and the contralateral breast. With JO-VMAT, the V5Gy and V2Gy of the heart were reduced by 32.7% and 15.4% compared to 3D-FiF plans. Significantly, the ipsilateral lung showed a reduction in mean dose (4.65-3.44 Gy) and low dose parameters (23.4% reduction for V5Gy and 10.7% reduction for V2Gy) for JO-VMAT plans compared to the 3D-FiF plans. The V2Gy dose to the contralateral lung and breast was minimal with JO-VMAT techniques. CONCLUSION: A JO-VMAT technique was evaluated in this study and compared with 3D-FiF and tVMAT techniques. Our results showed that the JO-VMAT technique can achieve clinically comparable coverage and homogeneity and significantly improve dose conformity within PTV. Additionally, JO-VMAT eliminated the low-dose bath effect at all OARs evaluation metrics including the ipsilateral/contralateral lung, the heart, and the contralateral breast compared to 3D-FiF and tVMAT. This technique is feasible for the whole breast radiation therapy of left breast cancers.

Evaluating intra-fractional tumor motion in lung stereotactic radiotherapy with deep inspiration breath-hold.

PURPOSE: To evaluate the intra-fractional tumor motion in lung stereotactic body radiotherapy (SBRT) with deep inspiration breath-hold (DIBH), and to investigate the adequacy of the current planning target volume (PTV) margins. METHODS: Twenty-eight lung SBRT patients with DIBH were selected in this study. Among the lesions, twenty-three were at right or left lower lobe, two at right middle lobe, and three at right or left upper lobe. Post-treatment gated cone-beam computed tomography (CBCT) was acquired to quantify the intra-fractional tumor shift at each treatment. These obtained shifts were then used to calculate the required PTV margin, which was compared with the current applied margin of 5 mm margin in anterior-posterior (AP) and right-left (RL) directions and 8 mm in superior-inferior (SI) direction. The beam delivery time was prolonged with DIBH. The actual beam delivery time with DIBH (Tbeam_DIBH) was compared with the beam delivery time without DIBH (Tbeam_wo_DIBH) for the corresponding SBRT plan. RESULTS: A total of 113 treatments were analyzed. At six treatments (5.3%), the shifts exceeded the tolerance defined by the current PTV margin. The average shifts were 0.0 ± 1.9 mm, 0.1±1.5 mm, and -0.5 ± 3.7 mm in AP, RL, and SI directions, respectively. The required PTV margins were determined to be 4.5, 3.9, and 7.4 mm in AP, RL, and SI directions, respectively. The average Tbeam_wo_DIBH and Tbeam_DIBH were 2.4 ± 0.4 min and 3.6 ± 1.5 min, respectively. The average treatment slot for lung SBRT with DIBH was 25.3 ± 7.9 min. CONCLUSION: Intra-fractional tumor motion is the predominant source of treatment uncertainties in CBCT-guided lung SBRT with DIBH. The required PTV margin should be determined based on data specific to each institute, considering different techniques and populations. Our data indicate that our current applied PTV margin is adequate, and it is possible to reduce further in the RL direction. The time increase of Tbeam_DIBH, relative to the treatment slot, is not clinically significant.

JP4-039, a Mitochondria-Targeted Nitroxide, Mitigates the Effect of Apoptosis and Inflammatory Cell Migration in the Irradiated Mouse Retina.

We hypothesize that the injection of JP4-039, a mitochondria-targeted nitroxide, prior to irradiation of the mouse retina may decrease apoptosis and reduce neutrophil and macrophage migration into the retina. In our study, we aimed to examine the effects of JP4-039 in the mouse retina using fluorescent microscopy, a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and flow cytometry. Forty-five mice and one eye per mouse were used. In Group 1, fluorescent microscopy was used to determine retinal uptake of 10 µL (0.004 mg/µL) of intravitreally injected BODIPY-labeled JP4-039 at 0, 15, and 60 min after injection. In Group 2, the TUNEL assay was performed to investigate the rate of apoptosis after irradiation in addition to JP4-039 injection, compared to controls. In Group 3, flow cytometry was used to determine the extent of inflammatory cell migration into the retina after irradiation in addition to JP4-039 injection, compared to controls. Maximal retinal uptake of JP4-039 was 15 min after intravitreal injection (p < 0.0001). JP4-039-treated eyes had lower levels of retinal apoptosis (35.8 ± 2.5%) than irradiated controls (49.0 ± 2.7%; p = 0.0066) and demonstrated reduced migration of N1 cells (30.7 ± 11.7% vs. 77.7 ± 5.3% controls; p = 0.004) and M1 cells (76.6 ± 4.2 vs. 88.1 ± 3.7% controls, p = 0.04). Pretreatment with intravitreally injected JP4-039 reduced apoptosis and inflammatory cell migration in the irradiated mouse retina, marking the first confirmed effect of this molecule in retinal tissue. Further studies may allow for safety profiling and potential use for patients with radiation retinopathy.

A detailed process map for clinical workflow of a new biology-guided radiotherapy (BgRT) machine.

PURPOSE: Biology-guided radiotherapy (BgRT) is a new external beam radiation therapy modality combining PET-CT with a linear accelerator that has the potential to track and treat one or more tumors in real-time. The use of PET and radiopharmaceutical tracers introduces new processes that are different from the existing treatment processes. In this study, we have developed a process map for the clinical implementation of a prototype BgRT machine. METHODS: A team of 13 members from various radiation therapy disciplines at our institution participated in developing a prospective process map for a prototype BgRT machine. The methodology provided by the AAPM TG 100 report was followed. In particular, the steps unique to the BgRT workflow, using hypofractionated stereotactic body radiation therapy with fluorodeoxyglucose radiolabeled with fluorine-18 (FDG) to guide beam delivery, were analyzed. RESULTS: The multi-disciplinary team in the department of radiation oncology at our institution developed a prospective process map for the clinical BgRT workflow. By focusing on the appropriate level of detail, 15 major subprocesses, 133 steps, and 248 substeps were identified and the process map was agreed upon as being useful, implementable, and manageable. Seventy-four steps from nine subprocesses, 55.6% of the whole process, were analyzed to be the BgRT unique steps. They originate mainly from: (1) acquiring multiple PET images at the BgRT machine with separate patient visits, (2) creating a unique biological treatment volume for BgRT plan (PTVBgRT ), and (3) BgRT plan optimization and treatment delivery using PET images. CONCLUSION: Using BgRT to irradiate multiple metastases in the same session will impact clinical workflow, thus a graphical process map depicting the new clinical workflow with an appropriate level of detail is critical for efficient, safe, and high-quality care. The prospective process map will guide the successful setup and use of the new BgRT system.

Portal dosimetry correction method for validation of single isocenter VMAT plans for multiple brain metastases.

Portal dosimetry is one option for verification of volumetric-modulated arc therapy (VMAT) planning for multiple brain metastases. However, due to the changing response of the portal imager with photon beam energy, the dose transmitted through closed multileaf collimator (MLC) leaves or narrow MLC gaps may be underestimated by the imager. We present a simple method for correcting for these effects that may be implemented within the Eclipse treatment planning system. We recalculated the predicted portal dose with and without this correction for 20 multiple brain met VMAT plans. Before the correction, 3/20 composite plan fields passed our standard quality assurance (QA) criteria (54/80 individual fields); the average gamma passing rate for the composite plans was 76.9 ± 16.6%, and the average gamma value across the composite plans was 0.67 ± 0.23. After correction, 20/20 composite plan fields passed the QA criteria (80/80 individual fields); the average gamma passing rate for composite plans was 99.2 ± 1.4%, the average gamma value across the composite plans was 0.33 ± 0.90. A measure of plan complexity, the average leaf pair opening could be correlated to the gamma analysis results for the uncorrected plans but not for the corrected plans.

Intestinal Radiation Protection and Mitigation by Second-Generation Probiotic Lactobacillus-reuteri Engineered to Deliver Interleukin-22.

(1) Background: The systemic administration of therapeutic agents to the intestine including cytokines, such as Interleukin-22 (IL-22), is compromised by damage to the microvasculature 24 hrs after total body irradiation (TBI). At that time, there is significant death of intestinal microvascular endothelial cells and destruction of the lamina propria, which limits drug delivery through the circulation, thus reducing the capacity of therapeutics to stabilize the numbers of Lgr5+ intestinal crypt stem cells and their progeny, and improve survival. By its direct action on intestinal stem cells and their villus regeneration capacity, IL-22 is both an ionizing irradiation protector and mitigator. (2) Methods: To improve delivery of IL-22 to the irradiated intestine, we gavaged Lactobacillus-reuteri as a platform for the second-generation probiotic Lactobacillus-reuteri-Interleukin-22 (LR-IL-22). (3) Results: There was effective radiation mitigation by gavage of LR-IL-22 at 24 h after intestinal irradiation. Multiple biomarkers of radiation damage to the intestine, immune system and bone marrow were improved by LR-IL-22 compared to the gavage of control LR or intraperitoneal injection of IL-22 protein. (4) Conclusions: Oral administration of LR-IL-22 is an effective protector and mitigator of intestinal irradiation damage.

Prediction of conical collimator collision for stereotactic radiosurgery.

The purpose of this study is to predict the collision clearance distance of stereotactic cones with treatment setup devices in cone-based stereotactic radiosurgery (SRS). The BrainLAB radiosurgery system with a Frameless Radiosurgery Positioning Array and dedicated couch top was targeted in this study. The positioning array and couch top were scanned with CT simulators, and their outer contours of were detected. The minimum clearance distance was estimated by calculating the Euclidian distances between the surface of the SRS cones and the nearest surface of the outer contours. The coordinate transformation of the outer contour was performed by incorporating the Beam's Eye View at a planned arc range and couch angle. From the minimum clearance distance, the collision-free gantry ranges for each couch angle were sequentially determined. An in-house software was developed to calculate the clearance distance between the cone surface and the outer contours, and thus determine the occurrence of a collision. The software was extensively tested for various combinations of couch and arc angles at multiple isocenter locations for two combinations of cone-couch systems. A total of 50 arcs were used to validate the calculation accuracies of the software for each system. The calculated minimum distances and collision-free angles from the software were verified by physical measurements. The calculated minimum distances were found to agree with the measurements to within 0.3 ± 0.9 mm. The collision-free arc angles from the software also agreed with the measurements to within 1.1 ± 1.1° with a 5-mm safety margin for 20 arcs. In conclusion, the in-house software was able to calculate the minimum clearance distance with <1.0 mm accuracy and to determine the collision-free arc range for the cone-based BrainLab SRS system.

Early clinical experience with varian halcyon V2 linear accelerator: Dual-isocenter IMRT planning and delivery with portal dosimetry for gynecological cancer treatments.

PURPOSE: Varian Halcyon linear accelerator version 2 (The Halcyon 2.0) was recently released with new upgraded features. The aim of this study was to report our clinical experience with Halcyon 2.0 for a dual-isocenter intensity-modulated radiation therapy (IMRT) planning and delivery for gynecological cancer patients and examine the feasibility of in vivo portal dosimetry. METHODS: Twelve gynecological cancer patients were treated with extended-field IMRT technique using two isocenters on Halcyon 2.0 to treat pelvis and pelvic/or para-aortic nodes region. The prescription dose was 45 Gy in 25 fractions (fxs) with simultaneous integrated boost (SIB) dose of 55 or 57.5 Gy in 25 fxs to involved nodes. All treatment plans, pretreatment patient-specific QA and treatment delivery records including daily in vivo portal dosimetry were retrospectively reviewed. For in vivo daily portal dosimetry analysis, each fraction was compared to the reference baseline (1st fraction) using gamma analysis criteria of 4 %/4 mm with 90% of total pixels in the portal image planar dose. RESULTS: All 12 extended-field IMRT plans met the planning criteria and delivered as planned (a total of 300 fractions). Conformity Index (CI) for the primary target was achieved with the range of 0.99-1.14. For organs at risks, most were well within the dose volume criteria. Treatment delivery time was from 5.0 to 6.5 min. Interfractional in vivo dose variation exceeded gamma analysis threshold for 8 fractions out of total 300 (2.7%). These eight fractions were found to have a relatively large difference in small bowel filling and SSD change at the isocenter compared to the baseline. CONCLUSION: Halcyon 2.0 is effective to create complex extended-field IMRT plans using two isocenters with efficient delivery. Also Halcyon in vivo dosimetry is feasible for daily treatment monitoring for organ motion, internal or external anatomy, and body weight which could further lead to adaptive radiation therapy.

Comparison of the recommendations of the AAPM TG-51 and TG-51 addendum reference dosimetry protocols.

This work quantified differences between recommendations of the TG-51 and TG-51 addendum reference dosimetry protocols. Reference dosimetry was performed for flattened photon beams with nominal energies of 6, 10, 15, and 23 MV, as well as flattening-filter free (FFF) beam energies of 6 and 10 MV, following the recommendations of both the TG-51 and TG-51 addendum protocols using both a Farmer® ionization chamber and a scanning ionization chamber with calibration coefficients traceable to absorbed dose-to-water (Dw ) standards. Differences in Dw determined by the two protocols were 0.1%-0.3% for beam energies with a flattening filter, and up to 0.2% and 0.8% for FFF beams measured with the scanning and Farmer® ionization chambers, respectively, due to kQ determination, volume-averaging correction, and collimator jaw setting. Combined uncertainty was between 0.91% and 1.2% (k = 1), varying by protocol and detector.

4D VMAT planning and verification technique for dynamic tracking using a direct aperture deformation (DAD) method.

We developed a four-dimensional volumetric modulated arc therapy (4D VMAT) planning technique for moving targets using a direct aperture deformation (DAD) method and investigated its feasibility for clinical use. A 3D VMAT plan was generated on a reference phase of a 4D CT dataset. The plan was composed of a set of control points including the beam angle, MLC apertures and weights. To generate the 4D VMAT plan, these control points were assigned to the closest respiratory phases using the temporal information of the gantry angle and respiratory curve. Then, a DAD algorithm was used to deform the beam apertures at each control point to the corresponding phase to compensate for the tumor motion and shape changes. Plans for a phantom and five lung cases were included in this study to evaluate the proposed technique. Dosimetric comparisons were performed between 4D and 3D VMAT plans. Plan verification was implemented by delivering the 4D VMAT plans on a moving QUASAR™ phantom driven with patient-specific respiratory curves. The phantom study showed that the 4D VMAT plan generated with the DAD method was comparable to the ideal 3D VMAT plan. DVH comparisons indicated that the planning target volume (PTV) coverages and minimum doses were nearly invariant, and no significant difference in lung dosimetry was observed. Patient studies revealed that the GTV coverage was nearly the same; although the PTV coverage dropped from 98.8% to 94.7%, and the mean dose decreased from 64.3 to 63.8 Gy on average. For the verification measurements, the average gamma index pass rate was 98.6% and 96.5% for phantom 3D and 4D VMAT plans with 3%/3 mm criteria. For patient plans, the average gamma pass rate was 96.5% (range 94.5-98.5%) and 95.2% (range 94.1-96.1%) for 3D and 4D VMAT plans. The proposed 4D VMAT planning technique using the DAD method is feasible to incorporate the intra-fraction organ motion and shape change into a 4D VMAT planning. It has great potential to provide high plan quality and delivery efficiency for moving targets.

Failure modes and effects analysis (FMEA) for Gamma Knife radiosurgery.

PURPOSE: Gamma Knife radiosurgery is a highly precise and accurate treatment technique for treating brain diseases with low risk of serious error that nevertheless could potentially be reduced. We applied the AAPM Task Group 100 recommended failure modes and effects analysis (FMEA) tool to develop a risk-based quality management program for Gamma Knife radiosurgery. METHODS: A team consisting of medical physicists, radiation oncologists, neurosurgeons, radiation safety officers, nurses, operating room technologists, and schedulers at our institution and an external physicist expert on Gamma Knife was formed for the FMEA study. A process tree and a failure mode table were created for the Gamma Knife radiosurgery procedures using the Leksell Gamma Knife Perfexion and 4C units. Three scores for the probability of occurrence (O), the severity (S), and the probability of no detection for failure mode (D) were assigned to each failure mode by 8 professionals on a scale from 1 to 10. An overall risk priority number (RPN) for each failure mode was then calculated from the averaged O, S, and D scores. The coefficient of variation for each O, S, or D score was also calculated. The failure modes identified were prioritized in terms of both the RPN scores and the severity scores. RESULTS: The established process tree for Gamma Knife radiosurgery consists of 10 subprocesses and 53 steps, including a subprocess for frame placement and 11 steps that are directly related to the frame-based nature of the Gamma Knife radiosurgery. Out of the 86 failure modes identified, 40 Gamma Knife specific failure modes were caused by the potential for inappropriate use of the radiosurgery head frame, the imaging fiducial boxes, the Gamma Knife helmets and plugs, the skull definition tools as well as other features of the GammaPlan treatment planning system. The other 46 failure modes are associated with the registration, imaging, image transfer, contouring processes that are common for all external beam radiation therapy techniques. The failure modes with the highest hazard scores are related to imperfect frame adaptor attachment, bad fiducial box assembly, unsecured plugs/inserts, overlooked target areas, and undetected machine mechanical failure during the morning QA process. CONCLUSIONS: The implementation of the FMEA approach for Gamma Knife radiosurgery enabled deeper understanding of the overall process among all professionals involved in the care of the patient and helped identify potential weaknesses in the overall process. The results of the present study give us a basis for the development of a risk based quality management program for Gamma Knife radiosurgery.

Two-year experience with the commercial Gamma Knife Check software.

The Gamma Knife Check software is an FDA approved second check system for dose calculations in Gamma Knife radiosurgery. The purpose of this study was to evaluate the accuracy and the stability of the commercial software package as a tool for independent dose verification. The Gamma Knife Check software version 8.4 was commissioned for a Leksell Gamma Knife Perfexion and a 4C unit at the University of Pittsburgh Medical Center in May 2012. Independent dose verifications were performed using this software for 319 radiosurgery cases on the Perfexion and 283 radiosurgery cases on the 4C units. The cases on each machine were divided into groups according to their diagnoses, and an averaged absolute percent dose difference for each group was calculated. The percentage dose difference for each treatment target was obtained as the relative difference between the Gamma Knife Check dose and the dose from the tissue maximum ratio algorithm (TMR 10) from the GammaPlan software version 10 at the reference point. For treatment plans with imaging skull definition, results obtained from the Gamma Knife Check software using the measurement-based skull definition method are used for comparison. The collected dose difference data were also analyzed in terms of the distance from the treatment target to the skull, the number of treatment shots used for the target, and the gamma angles of the treatment shots. The averaged percent dose differences between the Gamma Knife Check software and the GammaPlan treatment planning system are 0.3%, 0.89%, 1.24%, 1.09%, 0.83%, 0.55%, 0.33%, and 1.49% for the trigeminal neuralgia, acoustic neuroma, arteriovenous malformation (AVM), meningioma, pituitary adenoma, glioma, functional disorders, and metastasis cases on the Perfexion unit. The corresponding averaged percent dose differences for the 4C unit are 0.33%, 1.2%, 2.78% 1.99%, 1.4%, 1.92%, 0.62%, and 1.51%, respectively. The dose difference is, in general, larger for treatment targets in the peripheral regions of the skull owing to the difference in the numerical methods used for skull shape simulation in the GammaPlan and the Gamma Knife Check software. Larger than 5% dose differences were observed on both machines for certain targets close to patient skull surface and for certain targets in the lower half of the brain on the Perfexion, especially when shots with 70 and/or 110 gamma angles are used. Out of the 1065 treatment targets studied, a 5% cutoff criterion cannot always be met for the dose differences between the studied versions of the Gamma Knife Check software and the planning system for 40 treatment targets.

Dosimetric comparison between cone/Iris-based and InCise MLC-based CyberKnife plans for single and multiple brain metastases.

We performed an evaluation of the CyberKnife InCise MLC by comparing plan qualities for single and multiple brain lesions generated using the first version of InCise MLC, fixed cone, and Iris collimators. We also investigated differences in delivery efficiency among the three collimators. Twenty-four patients with single or multiple brain mets treated previously in our clinic on a CyberKnife M6 using cone/Iris collimators were selected for this study. Treatment plans were generated for all lesions using the InCise MLC. Number of monitor units, delivery time, target coverage, conformity index, and dose falloff were compared between MLC- and clinical cone/Iris-based plans. Statistical analysis was performed using the non-parametric Wilcoxon-Mann-Whitney signed-rank test. The planning accuracy of the MLC-based plans was validated using chamber and film measurements. The InCise MLC-based plans achieved mean dose and target coverage comparable to the cone/Iris-based plans. Although the conformity indices of the MLC-based plans were slightly higher than those of the cone/Iris-based plans, beam delivery time for the MLC-based plans was shorter by 30% ~ 40%. For smaller targets or cases with OARs located close to or abutting target volumes, MLC-based plans provided inferior dose conformity compared to cone/Iris-based plans. The QA results of MLC-based plans were within 5% absolute dose difference with over 90% gamma passing rate using 2%/2 mm gamma criteria. The first version of InCise MLC could be a useful delivery modality, especially for clinical situations for which delivery time is a limiting factor or for multitarget cases.

A method to improve dose gradient for robotic radiosurgery.

For targets with substantial volume, collimators of relatively large size are usually selected to minimize the treatment time in robotic radiosurgery. Their large penumbrae may adversely affect the dose gradient around the target. In this study, we implement and evaluate an inner-shell planning method to increase the dose gradient and reduce dose to normal tissues. Ten patients previously treated with CyberKnife M6 system were randomly selected with the only criterion being that PTV be larger than 2 cm(3). A new plan was generated for each patient in which the PTV was split into two regions: a 5 mm inner shell and a core, and a 7.5 mm Iris collimator was exclusively applied to the shell, with other appropriate collimators applied to the core depending on its size. The optimization objective, functions, and constraints were the same as in the corresponding clinical plan. The results were analyzed for V12 Gy, V9 Gy, V5 Gy, and gradient index (GI). Volume reduction was found for the inner-shell method at all studied dose levels as compared to the clinical plans. The absolute dose-volume reduction ranged from 0.05 cm(3) to 18.5 cm(3) with a mean of 5.6 cm(3) for 12 Gy, from 0.2 cm(3) to 38.1 cm(3) with a mean of 9.8 cm(3) for 9 Gy, and from 1.5 cm(3) to 115.7 cm(3) with a mean of 24.8 cm(3) for 5 Gy, respectively. The GI reduction ranged from 3.2% to 23.6%, with a mean of 12.6%. Paired t-test for GI has a p-value of 0.0014. The range for treatment time increase is from -3 min to 20 min, with a mean of 7.0 min. We conclude that irradiating the PTV periphery exclusively with the 7.5 mm Iris collimator, rather than applying mixed collimators to the whole PTV, can substantially improve the dose gradient, while maintaining good coverage, conformity, and reasonable treatment time.

Gamma Knife radiosurgery with CT image-based dose calculation.

The Leksell GammaPlan software version 10 introduces a CT image-based segmentation tool for automatic skull definition and a convolution dose calculation algorithm for tissue inhomogeneity correction. The purpose of this work was to evaluate the impact of these new approaches on routine clinical Gamma Knife treatment planning. Sixty-five patients who underwent CT image-guided Gamma Knife radiosurgeries at the University of Pittsburgh Medical Center in recent years were retrospectively investigated. The diagnoses for these cases include trigeminal neuralgia, meningioma, acoustic neuroma, AVM, glioma, and benign and metastatic brain tumors. Dose calculations were performed for each patient with the same dose prescriptions and the same shot arrangements using three different approaches: 1) TMR 10 dose calculation with imaging skull definition; 2) convolution dose calculation with imaging skull definition; 3) TMR 10 dose calculation with conventional measurement-based skull definition. For each treatment matrix, the total treatment time, the target coverage index, the selectivity index, the gradient index, and a set of dose statistics parameters were compared between the three calculations. The dose statistics parameters investigated include the prescription isodose volume, the 12 Gy isodose volume, the minimum, maximum and mean doses on the treatment targets, and the critical structures under consideration. The difference between the convolution and the TMR 10 dose calculations for the 104 treatment matrices were found to vary with the patient anatomy, location of the treatment shots, and the tissue inhomogeneities around the treatment target. An average difference of 8.4% was observed for the total treatment times between the convolution and the TMR algorithms. The maximum differences in the treatment times, the prescription isodose volumes, the 12 Gy isodose volumes, the target coverage indices, the selectivity indices, and the gradient indices from the convolution and the TMR 10 calculations are 14.9%, 16.4%, 11.1%, 16.8, 6.9%, and 11.4%, respectively. The maximum differences in the minimum and the mean target doses between the two calculation algorithms are 8.1% and 4.2% of the corresponding prescription doses. The maximum differences in the maximum and the mean doses for the critical structures between the two calculation algorithms are 1.3 Gy and 0.7 Gy. The results from the two skull definition methods with the TMR 10 algorithm agree either within ± 2.5% or 0.3 Gy for the dose values, except for a 4.9% difference in the treatment times for a lower cerebellar lesion. The imaging skull definition method does not affect Gamma Knife dose calculation considerably when compared to the conventional measurement-based skull definition method, except in some extreme cases. Large differences were observed between the TMR 10 and the convolution calculation method for the same dose prescription and the same shot arrangements, indicating that the implementation of the convolution algorithm in routine clinical use might be desirable for optimal dose calculation results.

Evaluation of tumor progression and detection of new tumors during repeat Gamma Knife® stereotactic radiosurgery utilizing the co-registration tool in Leksell Gamma Plan®: technical note.

BACKGROUND: Repeat Gamma Knife stereotactic radiosurgery (GKSR) procedures are becoming common, especially for brain metastases. It is important to identify tumors requiring treatment at repeat GKSR and it can be challenging to distinguish treated tumors, tumor progression and new tumors. Using the image co-registration tool within the Leksell Gamma Plan software, we developed a technique to aid in the identification of tumors needing treatment. OBJECTIVES: The objective was to explore a new co-registration technique to identify tumors requiring treatment at repeat GKSR procedures. METHODS: Ten patients who underwent repeat GKSR for brain metastases were identified. Contrast-enhanced volumetric T1 magnetic resonance images (MRI) from the previous GKSR were co-registered with the new images and the resulting two-color format image was used to evaluate tumor status. RESULTS: Using the co-registered images, tumors were characterized as: resolved, regressed, stable, larger or new. Overall, 13.6% of tumors completely resolved, 26.2% regressed, 13.1% remained stable, while 7.9% progressed. Thirty-nine percent of tumors were new. CONCLUSIONS: The co-registration technique makes clinically relevant changes conspicuous on MRI. It distinguishes between tumors potentially requiring treatment and those that have been treated successfully. It can be used with tumors other than metastases and for evaluating tumor response at follow-up.

Dose differences between the three dose calculation algorithms in Leksell GammaPlan.

The purpose of this study was to evaluate the dose differences introduced by the TMR 10 and the convolution dose calculation algorithms in GammaPlan version 10, as compared to the TMR classic algorithm in the previous versions of GammaPlan. Computed axial tomographic images of a polystyrene phantom and a human head were acquired using a GE LightSpeed VCT scanner. A treatment target with a prescription dose of 20 Gy to 50% isodose line was defined in the phantom or the head CT set. The treatment times for single collimator, single shot placements were calculated using the three dose calculation algorithms in GammaPlan version 10. Four comparative studies were conducted: i) the dose matrix position was varied every 10 mm along the x-, y-, z-axes of the stereotactic coordinate system inside the phantom and the treatment times were compared on each matrix for the three collimators of the Gamma Knife Perfexion and the four collimators of the 4C;ii) the study was repeated for the human head CT dataset; iii) the matrix position was varied every 20 mm in the X and the Y directions on the central slice (Z = 100mm) of the head CT and the shot times were compared on each matrix for the 8 mm collimator of both units; a total of 51 matrix positions were identified for each unit; iv) the above comparison was repeated for the head CT transverse slices with Z = 20, 40, 60, 80, 120, 140, and 160 mm. A total of 271 matrix positions were studied. Based on the comparison of the treatment times needed to deliver 20 Gy at 50% isodose line, the equivalent TMR classic dose of the TMR 10 algorithm is roughly a constant for each collimator of the 4C unit and is 97.5%, 98.5%, 98%, and 100% of the TMR 10 dose for the 18 mm, 14 mm, 8 mm, and the 4 mm collimators, respectively. The numbers for the three collimators of the Perfexion change with the shot positions in the range from 99% to 102% for both the phantom and the head CT. The minimum, maximum, and the mean values of the equivalent TMR classic doses of the convolution algorithm on the 271 voxels of the head CT are 99.5%, 111.5%, 106.5% of the convolution dose for the Perfexion, and 99%, 109%, 104.5% for the 4C unit. We identified a maximum decrease in delivered dose of 11.5% for treatment in the superior frontal/parietal vertex region of the head CT for older calculations lacking inhomogeneity correction to account for the greater percentage of the average beam path occupied by bone. The differences in the inferior temporal lobe and the cerebellum/neck regions are significantly less, owing to the counter-balancing effects of both bone and the air cavity inhomogeneities. The dose differences between the TMR 10 and the TMR classic are within ± 2.5% for a single shot placement on both Perfexion and 4C. Dose prescriptions based on the experiences with the TMR classic may need to be adjusted to accommodate the up to 11.5% difference between the convolution and the TMR classic.

Genetically Engineered Probiotic Limosilactobacillus reuteri Releasing IL-22 (LR-IL-22) Modifies the Tumor Microenvironment, Enabling Irradiation in Ovarian Cancer.

Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We recently established the role of Limosilactobacillus reuteri in releasing IL-22 (LR-IL-22) as an effective radiation mitigator, and we have now assessed its effect in an ovarian cancer mouse model. We hypothesized that an LR-IL-22 gavage would enable intestinal radioprotection by modifying the tumor microenvironment and, subsequently, improving overall survival in female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer. Herein, we report that the LR-IL-22 gavage not only improved overall survival in mice when combined with a PD-L1 inhibitor by inducing differential gene expression in irradiated stem cells but also induced PD-L1 protein expression in ovarian cancer cells and mobilized CD8+ T cells in whole abdomen irradiated mice. The addition of LR-IL-22 to a combined treatment modality with fractionated whole abdomen radiation (WAI) and systemic chemotherapy and immunotherapy regimens can facilitate a safe and effective protocol to reduce tumor burden, increase survival, and improve the quality of life of a locally advanced ovarian cancer patient.

Edema-induced changes in tumor cell surviving fraction and tumor control probability in 131Cs permanent prostate brachytherapy implant patients.

The study is designed to investigate the effect of edema on the delivered dose, tumor cell surviving fraction (SF), and tumor control probability (TCP) in the patients of prostate cancer who underwent (131)Cs permanent seed implantation. The dose reduction, the SF, and the TCP for edematous prostate implants were calculated for 31 patients who underwent real-time (131)Cs permanent seed implantation for edema half-lives (EHL), ranging from 4 days to 34 days and for edema magnitudes (M0) varying from 5% to 60% of the actual prostate volume. A dose reduction in (131)Cs implants varied from 1.1% (for EHL = 4 days and M(0) = 5%) to 32.3% (for EHL = 34 days and M(0) = 60%). These are higher than the dose reduction in 125I implants, which vary from 0.3% (for EHL = 4 days and M(0) = 5%) to 17.5% (for EHL = 34 days and M(0) = 60%). As EHL increased from 4 days to 34 days and edema magnitude increased from 5% to 60%, the natural logarithmic value of SF increased by 4.57 and the TCP decreased by 0.80. Edema induced increase in the SF and decrease in the TCP in (131)Cs seed implants, is significantly more pronounced in a combination of higher edema magnitude and larger edema half-lives than for less edema magnitude and lower edema half-lives, as compared for M(0) = 60% and EHL = 34, and M(0) = 5% and EHL = 4 days.

Dosimetric effect of respiratory motion on volumetric-modulated arc therapy-based lung SBRT treatment delivered by TrueBeam machine with flattening filter-free beam.

The purpose of this study is to investigate the interplay effect between dynamic MLC movement and tumor respiratory motion in volumetric-modulated arc therapy (VMAT)-based lung SBRT treatment delivered by the flattening filter-free (FFF) beam of a Varian TrueBeam machine. Six lung cancer patients with tumor motions ranging between 0.5-1.6 cm were recruited in this study. All patients underwent 4D-CT scan with audiocoaching. A two-arc VMAT plan was retrospectively generated using Varian's Eclipse planning system for each patient. To explicitly describe the interplay effect, the contributions of each control point in the original static VMAT plans to each respiratory phase were calculated, and then ten new VMAT plans corresponding to different respiratory phases were generated and imported back into Eclipse planning system to calculate the radiation dose based on the CT images of related respiratory phase. An in-house 4D dose calculation program with deformable registration capacity was used to calculate the accumulative 4D dose distribution of the targets. For all patients, the PTV coverage dropped significantly with increased respiratory motion amplitude. However, V100 and D90 of the GTV and GTV + 5 mm, which mimic the target with setup error of less than 5 mm, were either unchanged or slightly increased up to 1.2%, and the variations of their minimum doses were less than 3.2%. Our results indicated that for VMAT-based lung SBRT treatment delivered by FFF beam of TrueBeam machine, the impact of interplay effects on target coverage is insignificant, as long as a sufficient margin was given.