Target Conformity Research Articles

Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study

Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors. Communicated by Ramaswamy H. Sarma

Clinical iterative model development improves knowledge-based plan quality for high-risk prostate cancer with four integrated dose levels

Background Manual volumetric modulated arc therapy (VMAT) treatment planning for high-risk prostate cancer receiving whole pelvic radiotherapy (WPRT) with four integrated dose levels is complex and time consuming. We have investigated if the radiotherapy planning process and plan quality can be improved using a well-tuned model developed through a commercial system for knowledge-based planning (KBP). Material and methods Treatment plans from 69 patients treated for high-risk prostate cancer with manually planned VMAT were used to develop an initial KBP model (RapidPlan, RP). Prescribed doses were 50, 60, 67.5, and 72.5 Gy in 25 fractions to the pelvic lymph nodes, prostate and seminal vesicles, prostate gland, and prostate tumour(s), respectively. This RP model was in clinical use from July 2019 to February 2020, producing another set of 69 clinically delivered treatment plans for a new patient group, which were used to develop a second RP model. Both models were validated on an independent group of 40 patients. Plan quality was compared by D 98% and the Paddick conformity index for targets, mean dose (D mean) and generalised equivalent uniform dose (gEUD) for bladder, bowel bag and rectum, and number of monitor units (MU). Results Target coverage and conformity was similar between manually created and RP treatment plans. Compared to the manually created treatment plans, the final RP model reduced average D mean and gEUD with 2.7 Gy and 1.3 Gy for bladder, 1.2 Gy and 0.9 Gy for bowel bag, and 2.7 Gy and 0.8 Gy for rectum, respectively (p < .05). For rectum, the interpatient variation (i.e., 95% confidence interval) of DVHs was reduced by 23%. Conclusion KBP improved plan quality and consistency among treatment plans for high-risk prostate cancer. Model tuning using KBP-based clinical plans further improved model outcome.

Radiotherapy for unresectable locally advanced non-small cell lung cancer: a narrative review of the current landscape and future prospects in the era of immunotherapy.

Significant recent advances have occurred in the use of radiation therapy for locally advanced non-small cell lung cancer (LA-NSCLC). In fact, the past few decades have seen both therapeutic gains and setbacks in the evolution of radiotherapy for LA-NSCLC. The PACIFIC trial has heralded a new era of immunotherapy and has raised important questions for future study, such as the future directions of radiation therapy for LA-NSCLC in the era of immunotherapy. Modern radiotherapy techniques such as three-dimensional (3D) conformal radiotherapy and intensity-modulated radiotherapy (IMRT) provide opportunities for improved target conformity and reduced normal-tissue exposure. However, the low-dose radiation volume brought by IMRT and its effects on the immune system deserve particular attention when combing radiotherapy and immunotherapy. Particle radiotherapy offers dosimetric advantages and exhibits great immunoregulatory potential. With the ongoing improvement in particle radiotherapy techniques and knowledge, the combination of immunotherapy and particle radiotherapy has tremendous potential to improve treatment outcomes. Of particular importance are questions on the optimal radiation schedule in the settings of radio-immunotherapy. Strategies for the reduction of the irradiated field such as involved-field irradiation (IFI) and omission of clinical target volume (CTV) hold promise for better preservation of immune function while not compromising locoregional and distant control. In addition, different dose-fractionation regimens can have diverse effects on the immune system. Thus, prospective trials are urgently needed to establish the optimal dose fractionation regimen. Moreover, personalized radiotherapy which allows the tailoring of radiation dose to each individual’s genetic background and immune state is of critical importance in maximizing the benefit of radiation to patients with LA-NSCLC.

Dosimetric comparison of tomotherapy and volumetric-modulated arc therapy for children with neuroblastoma.

ImportanceIrradiation treatment for pediatric patients with neuroblastoma represents a major challenge due to the pediatric dose limits for critical structures and the necessity of sufficient dose coverage of the clinical target volume for local control.ObjectiveTo investigate dosimetric differences between tomotherapy (TOMO) and volumetric‐modulated arc therapy (VMAT) as retroperitoneal radiotherapy for children with neuroblastoma.MethodsEight patients who received retroperitoneal radiotherapy for neuroblastoma were selected for comparison of TOMO and VMAT treatment plans. The Dmin, Dmax, Dmean, D95, D2, and D98 of planning target volume (PTV), conformity index (CI), heterogeneity index (HI), and organs at risk (OARs) parameters were compared. Delivery machine unit (MU) and image‐guide radiotherapy solution results were also compared.ResultsAll patients received a cumulative dose of 19.5 Gy to the PTV. VMAT showed higher CI (0.93 ± 0.02), compared with TOMO (0.87 ± 0.03, P < 0.001). Notably, the average PTV HI was significantly better using TOMO (1.05 ± 0.01) than VMAT (1.08 ± 0.02, P = 0.003). Compared with VMAT, the Dmin, D95, and D98 all exhibited increases in TOMO; Dmax variation was less than 1% in TOMO. The D0.1cc for the spinal cord and D2cc for the small intestine were better in TOMO in terms of OARs. However, TOMO had more MUs and required a longer delivery time.InterpretationBoth planning techniques are capable of producing high‐ quality treatment plans. TOMO is superior for PTV coverage, but inferior for CI. TOMO requires extra treatment time; its cost is greater than the cost of VMAT.

Dosimetric evaluation of 6 MV and 18 MV intensity-modulated radiotherapy plans for treatment of carcinoma of the cervix

Introduction: Cervical cancer (Ca Cx) is the fourth most frequent cancer in women with an estimated 57000 new cases in 2018 representing 6.6% of all female cancers. Approximately 90% of deaths from cervical cancer occurred in low- and middle-income countries. Material and Methods: A retrospective radiotherapy treatment planning comparative study conducted at the Department of Radiation Physics, Kidwai Memorial Institute of Oncology, Bangalore during June 2018- March 2019. Result: All the plans were normalized to 100 % at Target mean to achieve a similar target dose for quantitative comparison of DVHs. The results for target coverage, OAR sparing, integral dose, and monitoring units. Conclusions: The tradeoff of using 6 MV and 18 MV for cervix patients depends on many parameters. Since the same PTV coverage was forced for both energies by having the same optimization constraints, there was little difference in target coverage and conformity index for both energies.

Assessment of online adaptive MR-guided stereotactic body radiotherapy of liver cancers.

Online Adaptive Radiotherapy (ART) with daily MR-imaging has the potential to improve dosimetric accuracy by accounting for inter-fractional anatomical changes. This study provides an assessment for the feasibility and potential benefits of online adaptive MRI-Guided Stereotactic Body Radiotherapy (SBRT) for treatment of liver cancer. Ten patients with liver cancer treated with MR-Guided SBRT were included. Prescription doses ranged between 27 and 50Gy in 3-5 fx. All SBRT fractions employed daily MR-guided setup while utilizing cine-MR gating. Organs-at-risk (OARs) included duodenum, bowel, stomach, kidneys and spinal cord. Daily MRIs and contours were utilized to create each adapted plan. Adapted plans used the beam-parameters and optimization-objectives from the initial plan. Planning target volume (PTV) coverage and OAR constraints were used to compare non-adaptive and adaptive plans. PTV coverage for non-adapted treatment plans was below the prescribed coverage for 32/47 fractions (68%), with 11 fractions failing by more than 10%. All 47 adapted fractions met prescribed coverage. OAR constraint violations were also compared for several organs. The duodenum exceeded tolerance for 5/23 non-adapted and 0/23 for adapted fractions. The bowel exceeded tolerance for 5/34 non-adaptive and 1/34 adaptive fractions. The stomach exceeded tolerance for 4/19 non-adapted and 1/19 for adaptive fractions. Accumulated dose volume histograms were also generated for each patient. Online adaptive MR-Guided SBRT of liver cancer using daily re-optimization resulted in better target conformality, coverage and OAR sparing compared with non-adaptive SBRT. Daily adaptive planning may allow for PTV dose escalation without compromising OAR sparing.

RETRACTED: 68. FRAMELESS, VAULT-FREE RADIOSURGERY: INITIAL CLINICAL EXPERIENCE WITH THE ZAP-X STEREOTACTIC SYSTEM

The Zap-X is a novel self-contained and self-shielded dedicated radiosurgery system developed and manufactured by ZAP Surgical Systems, Inc. of San Carlos, California. Intended for the stereotactic radiosurgery (SRS) treatment of benign and malignant intracranial and cervical spine lesions, this gyroscopically stabilized 3 megavolt (MV) linear accelerator (LINAC) provides a unique radiosurgical alternative for selected patients. Beginning in January 2019, a total of 38 metastatic lesions in 24 patients were treated in our facility. Radiation prescription doses ranged from 1500–1900 cGy (single fraction) to 2500 cGy (five fractions), with treatment volumes ranging from .04 to 15.3 cc. Daily treatment times averaged 45 minutes or less. Target coverage, dose homogeneity, and conformality were comparable to the existing Gamma Knife, CyberKnife and LINAC-based radiosurgery treatment systems in daily use at our facility. As with other frameless radiosurgery platforms, the Zap-X proved particularly useful in situations where either surgery or single-fraction radiosurgery was considered a less desirable treatment option; or when fractionated radiosurgery was thought to be radiobiologically advantageous. All treatments were completed without complication. At two months post-treatment, all lesions showed a complete or partial response to therapy based on MRI scan. None of our patients experienced treatment-related skin reaction, cognitive deficit, fatigue or steroid dependency. Among patients who had previously undergone Gamma Knife treatment, there was a clear preference for frameless radiosurgery. In our experience, the Zap-X delivery system offers a high-precision, patient-friendly and cost-effective alternative to traditional dedicated radiosurgical platforms.

Novel strategy with the automatic non-coplanar volumetric-modulated arc therapy for angiosarcoma of the scalp

BackgroundTotal scalp irradiation presents technical and dosimetric challenges. While reports suggest that HyperArc, a new stereotactic radiosurgery planning technique applied to non-coplanar volumetric-modulated arc therapy (VMAT) technique, is associated with high conformity and rapid dose fall-off, the performance of HyperArc for total scalp irradiation has not been explored. The current study aimed to compare the dosimetric performance of HyperArc plans with those of non-coplanar VMAT plans in angiosarcoma of the scalp.MethodsTen patients with angiosarcoma of the scalp were included in this study. The performance of three different plans administered using TrueBeam Edge were compared: non-coplanar VMAT using flattening filter (FF) beams (VMAT-FF), HyperArc using FF beams (HyperArc-FF), and HyperArc using flattening filter free (FFF) beams (HyperArc-FFF). The dose distribution, dosimetric parameters, and dosimetric accuracy for each of these plans were evaluated.ResultsThe three plans showed no statistically significant differences in target volume coverage, conformity, and homogeneity. The HyperArc-FF and HyperArc-FFF plans provided significantly lower mean brain doses (12.63 ± 3.31 Gy and 12.71 ± 3.40 Gy) than did the VMAT-FF plans (17.11 ± 5.25 Gy). There were almost no differences in sparing the organs at risk between the HyperArc-FF and HyperArc-FFF plans. The HyperArc-FF and HyperArc-FFF plans provided a shorter beam-on time than did the VMAT-FF plan. The 3%/2 mm gamma test pass rates were above 95% for all three plans.ConclusionsOur results suggest that the HyperArc plan can be potentially used for radiation therapy of target regions with large and complicated shapes, such as the scalp, and that there are no advantages of using FFF beams.

Dosimetric comparison of linac-based modulated techniques for hippocampal sparing whole brain radiotherapy

Intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques were compared in terms of their dosimetric quality, treatment efficiency, and delivery accuracy for hippocampal sparing prophylactic whole brain radiotherapy. Ten previously treated patients were selected for this study. All plans were prescribed to deliver 30 Gy in 10 fractions to 90% of the target volume. RTOG 0933 recommendations were applied for treatment planning. Plans were compared based on the organ at risk (OAR) sparing, homogeneity and conformity indexes, monitor unit (MU), and beam on time (BOT). Delivery accuracy of the plans was also compared. VMAT plans had better homogeneity index and conformity index than IMRT plans. In terms of hippocampus sparing, VMAT plans were superior to other plans. Since brainstem, optic nerves, and chiasm were in the PTV, their doses were nearly equal to each other for both techniques. So, there were no statistical differences between techniques. Although both eyes were not in the PTV, there was no significant dose difference between techniques. However, due to the posterior gantry angles of IMRT plans, lens doses were lower in IMRT plans than those in VMAT plans. The VMAT technique had lower MU and BOT values than the IMRT technique. In terms of delivery accuracy, VMAT plans were superior than IMRT plans. VMAT plans provide better target volume coverage, homogeneity, conformity, and hippocampus sparing when compared with IMRT plans. VMAT plans are also the best in terms of treatment efficiency since they require a much smaller number of MUs and thus a shorter treatment time than IMRT plans.

Feasibility study for marker-based VMAT plan optimization toward tumor tracking.

This work investigates the incorporation of fiducial marker‐based visibility parameters into the optimization of volumetric modulated arc therapy (VMAT) plans. We propose that via this incorporation, one may produce treatment plans that aid real‐time tumor tracking approaches employing exit imaging of the therapeutic beam (e.g., via EPID), in addition to satisfying purely dosimetric requirements. We investigated the feasibility of this approach for a thorax and prostate site using optimization software (MonArc). For a thorax phantom and a lung patient, three fiducial markers were inserted around the tumor and VMAT plans were created with two partial arcs and prescription dose of 48 Gy (4 fractions). For a prostate patient with three markers in the prostate organ, a VMAT plan was created with two partial arcs and prescription dose 72.8 Gy (28 fractions). We modified MonArc to include marker‐based visibility constraints (“hard”and “soft”). A hard constraint (HC) imposes full visibility for all markers, while a soft constraint (SC) penalizes visibility for specific markers in the beams‐eye‐view. Dose distributions from constrained plans (HC and SC) were compared to the reference nonconstrained (NC) plan using metrics including conformity index (CI), homogeneity index (HI), gradient measure (GM), and dose to 95% of planning target volume (PTV) and organs at risk (OARs). The NC plan produced the best target conformity and the least doses to the OARs for the entire dataset, followed by the SC and HC plans. Using SC plans provided acceptable dosimetric tolerances for both the target and OARs. However, OAR doses may be increased or decreased based on the constrained marker location and number of trackable markers. In conclusion, we demonstrate that visibility constraints can be incorporated into the optimization together with dosimetric objectives to produce treatment plans satisfying both objectives. This approach should ensure greater clinical success when applying real‐time tracking algorithms, using VMAT delivery.

Protein Binding Pocket Optimization for Virtual High-Throughput Screening (vHTS) Drug Discovery.

The virtual high-throughput screening (vHTS) approach has been widely used for large database screening to identify potential lead compounds for drug discovery. Due to its high computational demands, docking that allows receptor flexibility has been a challenging problem for virtual screening. Therefore, the selection of protein target conformations is crucial to produce useful vHTS results. Since only a single protein structure is used to screen large databases in most vHTS studies, the main challenge is to reduce false negative rates in selecting compounds for in vitro tests. False negatives are most likely to occur when using apo structures or homology models of protein targets due to the small volume of the binding pocket formed by incorrect side-chain conformations. Even holo protein structures can exhibit high false negative rates due to ligand-induced fit effects, since the shape of the binding pocket highly depends on its bound ligand. To reduce false negative rates and improve success rates for vHTS in drug discovery, we have developed a new Monte Carlo-based approach that optimizes the binding pocket of protein targets. This newly developed Monte Carlo pocket optimization (MCPO) approach was assessed on several datasets showing promising results. The binding pocket optimization approach could be a useful tool for vHTS-based drug discovery, especially in cases when only apo structures or homology models are available.

An investigation into the robustness of dynamically collimated proton therapy treatments.

To investigate the dosimetric robustness of dynamically collimated proton therapy (DCPT) treatment plans delivered using a dynamic collimation system (DCS) with respect to random uncertainties in beam spot and collimator position as well as systematic offsets in the DCS mounting alignment. This work also demonstrates a technique that can increase plan robustness while preserving target conformity. Variability in beam spot and collimator positioning can result in changes to a beamlet's dose distribution and incident fluence. The robustness of the DCPT treatment plans was evaluated for three intracranial treatment sites by modeling treatment variability as normally distributed random variables with standard deviations reflecting a clinical system. The simulated treatment plans were then recalculated and compared against their nominal, idealized dose distribution among several trials. It was hypothesized that a plan's robustness to these delivery variables could be reduced by restricting a trimmer's placement toward a beamlet's central axis during collimation. By introducing a minimum trimmer offset of 1.5mm, the variation of the planning target volume (PTV) D95% coverage was reduced to within 2% of the prescribed dose. The treatment plans with trimmers that were placed within 0.5mm of a collimated beamlet's central axis resulted in the greatest healthy tissue sparing but deviations as high as 11.4% to the PTV D95% were observed. The nominal conformity of these treatment plans utilizing the 1.5 mm trimmer offset was also well maintained. For each treatment plan studied, the 90% conformity index remained within 6.25% of the conformity index achieved without a minimum trimmer offset, and the D50% of surrounding healthy tissue increased by no more than 3.1Gy relative to a plan without a trimmer offset. While DCPT can offer a significant reduction in healthy tissue irradiation, the results from this work indicate that special care must be taken to ensure proper PTV coverage amid uncertainties associated with this new treatment modality. A simple approach utilizing a minimum trimmer offset was able to preserve the majority of the target conformity and healthy tissue sparing the DCS technology affords while minimizing the uncertainties in this treatment approach.

Immunotherapies for Aging-Related Neurodegenerative Diseases-Emerging Perspectives and New Targets.

Neurological disorders such as Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and vascular dementia (VCID) have no disease-modifying treatments to date and now constitute a dementia crisis that affects 5 million in the USA and over 50 million worldwide. The most common pathological hallmark of these age-related neurodegenerative diseases is the accumulation of specific proteins, including amyloid beta (Aβ), tau, α-synuclein (α-syn), TAR DNA-binding protein 43 (TDP43), and repeat-associated non-ATG (RAN) peptides, in the intra- and extracellular spaces of selected brain regions. Whereas it remains controversial whether these accumulations are pathogenic or merely a byproduct of disease, the majority of therapeutic research has focused on clearing protein aggregates. Immunotherapies have garnered particular attention for their ability to target specific protein strains and conformations as well as promote clearance. Immunotherapies can also be neuroprotective: by neutralizing extracellular protein aggregates, they reduce spread, synaptic damage, and neuroinflammation. This review will briefly examine the current state of research in immunotherapies against the 3 most commonly targeted proteins for age-related neurodegenerative disease: Aβ, tau, and α-syn. The discussion will then turn to combinatorial strategies that enhance the effects of immunotherapy against aggregating protein, followed by new potential targets of immunotherapy such as aging-related processes.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00853-2) contains supplementary material, which is available to authorized users.

Perturb-Scan-Pull: A Novel Method Facilitating Conformational Transitions in Proteins.

Conformational transitions in proteins facilitate precise physiological functions. Therefore, it is crucial to understand the mechanisms underlying these processes to modulate protein function. Yet, studying structural and dynamical properties of proteins is notoriously challenging due to the complexity of the underlying potential energy surfaces (PES). We have previously developed the perturbation-response scanning (PRS) method to identify key residues that participate in the communication network responsible for specific conformational transitions. PRS is based on a residue-by-residue scan of the protein to determine the subset of residues/forces which provide the closest conformational change leading to a target conformational state, inasmuch as linear response theory applies to these motions. Here, we develop a novel method to further evaluate if conformational transitions may be triggered on the PES. We aim to study functionally relevant conformational transitions in proteins by using results obtained from PRS and feeding them as inputs to steered molecular dynamics simulations. The success and the transferability of the method are evaluated on three protein systems having different complexities of motion on the PES: calmodulin, adenylate kinase, and bacterial ferric binding protein. We find that the method captures the target conformation, while providing key residues and the optimum paths with relatively low free energy profiles.

A novel and clinically useful dynamic conformal arc (DCA)-based VMAT planning technique for lung SBRT.

PurposeVolumetric modulated arc therapy (VMAT) is gaining popularity for stereotactic treatment of lung lesions for medically inoperable patients. Due to multiple beamlets in delivery of highly modulated VMAT plans, there are dose delivery uncertainties associated with small‐field dosimetry error and interplay effects with small lesions. We describe and compare a clinically useful dynamic conformal arc (DCA)‐based VMAT (d‐VMAT) technique for lung SBRT using flattening filter free (FFF) beams to minimize these effects.Materials and MethodsTen solitary early‐stage I‐II non‐small‐cell lung cancer (NSCLC) patients were treated with a single dose of 30 Gy using 3–6 non‐coplanar VMAT arcs (clinical VMAT) with 6X‐FFF beams in our clinic. These clinically treated plans were re‐optimized using a novel d‐VMAT planning technique. For comparison, d‐VMAT plans were recalculated using DCA with user‐controlled field aperture shape before VMAT optimization. Identical beam geometry, dose calculation algorithm, grid size, and planning objectives were used. The clinical VMAT and d‐VMAT plans were compared via RTOG‐0915 protocol compliances for conformity, gradient indices, and dose to organs at risk (OAR). Additionally, treatment delivery efficiency and accuracy were recorded.ResultsAll plans met RTOG‐0915 requirements. Comparing with clinical VMAT, d‐VMAT plans gave similar target coverage with better target conformity, tighter radiosurgical dose distribution with lower gradient indices, and dose to OAR. Lower total number of monitor units and small beam modulation factor reduced beam‐on time by 1.75 min (P < 0.001), on average (maximum up to 2.52 min). Beam delivery accuracy was improved by 2%, on average (P < 0.05) and maximum up to 6% in some cases for d‐VMAT plans.ConclusionThis simple d‐VMAT technique provided excellent plan quality, reduced intermediate dose‐spillage, and dose to OAR while providing faster treatment delivery by significantly reducing beam‐on time. This novel treatment planning approach will improve patient compliance along with potentially reducing intrafraction motion error. Moreover, with less MLC modulation through the target, d‐VMAT could potentially minimize small‐field dosimetry errors and MLC interplay effects. If available, d‐VMAT planning approach is recommended for future clinical lung SBRT plan optimization.

Impact of different treatment techniques for pediatric Ewing sarcoma of the chest wall: IMRT, 3DCPT, and IMPT with/without beam aperture.

PurposeTo evaluate the dosimetric differences between photon intensity‐modulated radiation therapy (IMRT) plans, 3D conformal proton therapy (3DCPT), and intensity‐modulated proton therapy (IMPT) plans and to investigate the dosimetric impact of different beam spot size and beam apertures in IMPT for pediatric Ewing sarcoma of the chest wall.Methods and MaterialsSix proton pediatric patients with Ewing sarcoma in the upper, middle, and lower thoracic spine regions as well as upper lumbar spine region were treated with 3DCPT and retrospectively planned with photon IMRT and IMPT nozzles of different beam spot sizes with/without beam apertures. The plan dose distributions were compared both on target conformity and homogeneity, and on organs‐at‐risk (OARs) sparing using QUANTEC metrics of the lung, heart, liver, and kidney. The total integral doses of healthy tissue of all plans were also evaluated.ResultsTarget conformity and homogeneity indices are generally better for the IMPT plans with beam aperture. Doses to the lung, heart, and liver for all patients are substantially lower with the 3DPT and IMPT plans than those of IMRT plans. In the IMPT plans with large spot without beam aperture, some OAR doses are higher than those of 3DCPT plans. The integral dose of each photon IMRT plan ranged from 2 to 4.3 times of proton plans.ConclusionCompared to IMRT, proton therapy delivers significant lower dose to almost all OARs and much lower healthy tissue integral dose. Compared to 3DCPT, IMPT with small beam spot size or using beam aperture has better dose conformity to the target.

Retrospective quality metrics review of stereotactic radiosurgery plans treating multiple targets using single-isocenter volumetric modulated arc therapy.

PurposeTo characterize key plan quality metrics in multi‐target stereotactic radiosurgery (SRS) plans treated using single‐isocenter volumetric modulated arc therapy (VMAT) in comparison to dynamic conformal arc (DCA) plans treating single target. To investigate the feasibility of quality improvement in VMAT planning based on previous planning knowledge.Materials and methods97 VMAT plans of multi‐target and 156 DCA plans of single‐target treated in 2017 at a single institution were reviewed. A total of 605 targets were treated with these SRS plans. The prescription dose was normalized to 20 Gy in all plans for this analysis. Two plan quality metrics, target conformity index (CI) and normal tissue volume receiving more than 12 Gy (V12Gy), were calculated for each target. The distribution of V12Gy per target was plotted as a function of the target volume. For multi‐target VMAT plans, the number of targets being treated in the same plan and the distance between targets were calculated to evaluate their impact on V12Gy. VMAT plans that had a large deviation of V12Gy from the average level were re‐optimized to determine the possibility of reducing the variation of V12Gy in VMAT planning.ResultsConformity index of multi‐target VMAT plans were lower than that of DCA plans while the mean values of 12 Gy were comparable. The V12Gy for a target in VMAT plan did not show apparent dependence on the total number of targets or the distance between targets. The distribution of V12Gy exhibited a larger variation in VMAT plans compared to DCA plans. Re‐optimization of outlier plans reduced V12 Gy by 33.9% and resulted in the V12Gy distribution in VMAT plans more closely resembling that of DCA plans.ConclusionThe benchmark data on key plan quality metrics were established for single‐isocenter multi‐target SRS planning. It is feasible to use this knowledge to guide VMAT planning and reduce high V12Gy outliers.

The impact of isocentric shifts on delivery accuracy during the irradiation of small cerebral targets-Quantification and possible corrections.

PurposeTo assess the impact of isocenter shifts due to linac gantry and table rotation during cranial stereotactic radiosurgery on D98, target volume coverage (TVC), conformity (CI), and gradient index (GI).MethodsWinston‐Lutz (WL) checks were performed on two Elekta Synergy linacs. A stereotactic quality assurance (QA) plan was applied to the ArcCHECK phantom to assess the impact of isocenter shift corrections on Gamma pass rates. These corrections included gantry sag, distance of collimator and couch axes to the gantry axis, and distance between cone‐beam computed tomography (CBCT) isocenter and treatment beam (MV) isocenter. We applied the shifts via script to the treatment plan in Pinnacle 16.2. In a planning study, isocenter and mechanical rotation axis shifts of 0.25 to 2 mm were applied to stereotactic plans of spherical planning target volumes (PTVs) of various volumes. The shifts determined via WL measurements were applied to 16 patient plans with PTV sizes between 0.22 and 10.4 cm3.ResultsArcCHECK measurements of a stereotactic treatment showed significant increases in Gamma pass rate for all three measurements (up to 3.8 percentage points) after correction of measured isocenter deviations. For spherical targets of 1 cm3, CI was most severely affected by increasing the distance of the CBCT isocenter (1.22 to 1.62). Gradient index increased with an isocenter‐collimator axis distance of 1.5 mm (3.84 vs 4.62). D98 (normalized to reference) dropped to 0.85 (CBCT), 0.92 (table axis), 0.95 (collimator axis), and 0.98 (gantry sag), with similar but smaller changes for larger targets. Applying measured shifts to patient plans lead to relevant drops in D98 and TVC (7%) for targets below 2 cm3 treated on linac 1.ConclusionMechanical deviations during gantry, collimator, and table rotation may adversely affect the treatment of small stereotactic lesions. Adjustments of beam isocenters in the treatment planning system (TPS) can be used to both quantify their impact and for prospective correction of treatment plans.

A comparison of a moderately hypofractionated IMRT planning technique used in a randomised UK external beam radiotherapy trial with an in-house technique for localised prostate cancer

To compare the radiotherapy technique used in a randomised trial with VMAT and an in-house technique for prostate cancer. Techniques are evolving with volumetric modulated arc therapy (VMAT) commonly used. The CHHiP trial used a 3 PTV forward planned IMRT technique (FP_CH). Our centre has adopted a simpler two PTV technique with locally calculated margins. 25 patients treated with FP_CH to 60Gy in 20 fractions were re-planned with VMAT (VMAT_CH) and a two PTV protocol (VMAT_60/52 and VMAT_60/48). Target coverage, conformity index (CI), homogeneity index (HI), monitor units (MU) and dose to the rectum, bladder, hips and penile bulb were compared. PTV coverage was high for all techniques. VMAT_CH plans had better CI than FP_CH (p≤ 0.05). VMAT_60/52/48 plans had better CI than VMAT_CH. FP_CH had better HI and fewer MU than VMAT (p≤ 0.05). More favourable rectum doses were found for VMAT _CH than FP_CH (V48.6, V52.8, V57, p≤ 0.05) with less difference for bladder (p≥ 0.05). Comparing VMAT_CH to VMAT_60/52/48 showed little differences for the bladder and rectum but VMAT_CH had larger penile bulb doses (V40.8, V48.6, mean, D2, p≤ 0.05). Femoral head doses (V40.8) were similarly low for all techniques (p=≥ 0.05). VMAT produced more conformal plans with smaller rectum doses compared to FP_CH albeit worse HI and more MU. VMAT_60/52 and VMAT_60/48 plans had similar rectal and bladder doses to VMAT_CH but better CI and penile bulb doses which may reduce toxicity.

Feasibility of automatic IMRT planning for cervical cancer based on a database of previously-treated patients

Objective To develop and evaluate an automatic intensity-modulated radiation therapy (IMRT) program for cervical cancer based on a database of overlap volume histogram (OVH) and high-quality cervical IMRT plans for previously-treated patients. Methods A database consisting of high-quality IMRT plans and OVHs from 200 cervical cancer patients was established. OVHs of another 26 cervical cancer patients were converted into gray level images to calculate the image similarity compared with those from the database. The planning optimization function of the patients from the database with the highest image similarity was selected and inherent Pinnacle3 scripts were utilized to automatically generate IMRT plan. Finally, the dosimetric parameters, plan quality and design time were statistically compared between the automatic and manual plans. Results The target coverage, conformity index and homogeneity index did not significantly differ between two plans (all P>0.05). The V40, V45 and mean dose for the rectum in the automatic plans were significantly decreased by 6.1%, 1.3% and 50.7 cGy than those in the manual plans (all P 0.05). The plan design time was shortened by 71% in the automatic plans. Conclusions The automatic IMRT plans based on a database of OVH and high-quality IMRT plans can not only significantly shorten the plan design time, but also reduce the irradiated dose of normal tissues without compromising the target coverage and conformity index. Key words: Cervical neoplasm/intensity-modulated radiation therapy; Overlap volume histogram; Automatic plan