Range Uncertainties Research Articles

Dosimetric Evaluation of Beam-specific PTV and Worst-case Optimization Methods for Liver Proton Therapy.

In spot-scanning proton therapy, intra-fractional anatomical changes by organ movement can lead to deterioration in dose distribution due to beam range variation. To explore a more robust treatment planning method, this study evaluated the dosimetric characteristics and robustness of two proton therapy planning methods for liver cancer. Two- or three-field treatment plans were created for 11 patients with hepatocellular carcinoma or metastatic liver cancer using a single-field uniform dose (SFUD) technique. The plans were optimized using either beam-specific planning target volume (BSPTV) or worst-case optimization (WCO). The target coverage for the gross tumor volume (GTV), planning target volume (PTV), and organs at risk (OAR) parameters related to toxicity were calculated from the perturbed dose distributions, considering setup and range uncertainties. Statistical analyses of the BSPTV and WCO plans were performed using the Wilcoxon signed-rank sum test (p<0.05). The calculation times for a single optimization process were also recorded and compared. The robustness of the WCO plans in the worst-case scenario was significantly higher than that of the BSPTV plan in terms of GTV target coverage, prevention of maximum dose increase to the gastrointestinal tract, and the dose received by normal liver regions. However, there were no significant differences in PTV, and the calculation time required to create the WCO plan was considerably longer. In SFUD proton therapy for liver cancer, the WCO plans required a longer optimization time but exhibited superior robustness in GTV coverage and sparing of OARs.

Robust optimization incorporating weekly predicted anatomical CTs in IMPT of nasopharyngeal cancer.

Objective.This study proposes a robust optimization (RO) strategy utilizing virtual CTs (vCTs) predicted by an anatomical model in intensity-modulated proton therapy (IMPT) for nasopharyngeal cancer (NPC).Methods and Materials.For ten NPC patients, vCTs capturing anatomical changes at different treatment weeks were generated using a population average anatomy model. Two RO strategies of a 6 beams IMPT with 3 mm setup uncertainty (SU) and 3% range uncertainty (RU) were compared: conventional robust optimization (cRO) based on a single planning CT (pCT), and anatomical RO incorporating 2 and 3 predicted anatomies (aRO2 and aRO3). The robustness of these plans was assessed by recalculating them on weekly CTs (week 2-7) and extracting the voxel wise-minimum and maximum doses with 1 mm SU and 3% RU (voxmin\voxmax1mm3%).Results.The aRO plans demonstrated improved robustness in high-risk CTV1 and low-risk CTV 2 coverage compared to cRO plans. The weekly evaluation showed a lower plan adaptation rate for aRO3 (40%) vs. cRO (70%). The weekly nominal and voxmax1mm3%doses to OARs, especially spinal cord, are better controlled relative to their baseline doses at week 1 with aRO plans. The accumulated dose analysis showed that CTV1&2 had adequate coverage and serial organs (spinal cord and brainstem) were within their dose tolerances in the voxmin\voxmax1mm3%, respectively.Conclusion.Incorporating predicted weekly CTs from a population based average anatomy model in RO improves week-to-week target dose coverage and reduces false plan adaptations without increasing normal tissue doses. This approach enhances IMPT plan robustness, potentially facilitating reduced SU and further lowering OAR doses.

Cardiac motion in patients with ventricular tachycardia: potential implications for the treatment of patients candidates to stereotactic arrhythmia radio-ablation (STAR)

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has proven to be a valid alternative treatment for refractory ventricular tachycardia (VT) in patients who are unsuitable to undergo standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. There is increased research activity on better understanding the complex and fast motion of the heart and on reducing radiation toxicity. Purpose In the context of an in silico study to evaluate the feasibility of STAR with protons in patients with VT, the initial findings related to cardiac motion on the first 10 patients are here presented. Methods Prior to CA, each patient underwent ECG gated CT scans in expiratory breath-hold, with and without contrast and reconstructed at 30% (systole) and 80% (diastole) of the cardiac R-R cycle. Contouring of the ablation target as a clinical target volume (CTV) for proton treatment planning was performed based on a standard electrophysiological study with 3D eletroanatomical mapping. Two different treatment plans were created: the first with only the diastolic CTV as target (gated treatment), the second including both diastolic and systolic CTVs to create an Internal Target Volume (ITV) in the hypothesis of non-gated treatment. Robust optimization was used to create the Planning Target Volume (PTV). Results The target volumes used for treatment planning are given in Table 1. The median CTV was 10.90 (2.93-36.94) cm3 for diastole and 14.26 (1.73-36.31) cm3 for systole. These volumes are somewhat smaller than those reported in patients treated previously with STAR: this difference may be due to the fact that no respiratory motion was included in the target contour and that the study population includes many patients referred for ventricular ectopic beats without structural heart disease, where the ablation target is expected to be smaller as compared to patients with VT in structural heart disease. Despite a small median difference between the diastolic and systolic CTV of 0.53 (0.03-9.61) cm3, the ITV approach resulted in a median increase in volume compared to the largest of the two CTVs of 29 % (1%-44%). When considering the proton range uncertainty and potential errors in patient positioning (PTV), the target is this time enlarged by a factor 2.9 (1.9-3.9). This data indicates that both cardiac motion and uncertainties in patient positioning before treatment will have a large impact on the treatment volume thus affecting the amount of surrounding tissue exposed to radiation. Conclusion The ablation target contour at systole and diastole are of similar magnitude but their non-overlap results in a large increase in treated volume when radiation delivery is not gated for cardiac motion. Further analysis shall investigate on a case-by-case basis the potential reduction in risk of healthy tissue toxicity with cardiac-gated proton delivery.Table 1

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Phase-change ultrasound contrast agents for proton range verification: towards an in vivo application

Objective.In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a firstin vivoproof-of-concept of this technology.Approach.First, thein vitrobiocompatibility of radiation-sensitive poly(vinyl alcohol) perfluorobutane nanodroplets was investigated using several colorimetric assays. Then,in vivoultrasound contrast was characterized using acoustic droplet vaporization (ADV) and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of thein vivobiocompatibility was performed using ADV and a combination of physiology monitoring and histology.Main results.Nanodroplets were non-toxic over a wide concentration range (<1 mM). In healthy rats, intravenously injected nanodroplets primarily accumulated in the organs of the reticuloendothelial system, where the lifetime of the generated ultrasound contrast (<30 min) was compatible with a typical radiotherapy fraction (<5 min). Spontaneous droplet vaporization did not result in significant background signals. Online ultrasound imaging of the liver of droplet-injected rats demonstrated an energy-dependent proton response, which can be tuned by varying the nanodroplet concentration. However, caution is warranted when deciding on the exact nanodroplet dose regimen as a mild physiological response (drop in cardiac rate, granuloma formation) was observed after ADV.Significance.These findings underline the potential of phase-change ultrasound contrast agents forin vivoproton range verification and provide the next step towards eventual clinical applications.

Clinical advantages of incorporating predicted weekly anatomy in IMPT optimization with reduced setup error

AbstractBackgroundIn head and neck (H&amp;N) cancer treatment, a conventional setup error (SE) of 3mm is often used in robust optimization (cRO3mm). However, cRO3mm may lead to excessive radiation doses to organs at risk (OARs) and does not purposefully compensate for interfractional anatomy variations.PurposeThis study introduces a method using predicted images from an anatomical model and a reduced 1mm SE uncertainty for robust optimization (aRO1mm), aiming to decrease the dose to OARs without affecting the coverage of the clinical target volume (CTV).MethodsThis retrospective study involved 10 nasopharynx radiotherapy patients. Validation CT scans (vCT) from treatment weeks 1 to 6 were analyzed. A predictive anatomical model, designed to capture the average anatomical changes over time, provided predicted CT images for weeks 1, 3, and 5. We compared three optimization scenarios: (1) aRO1mm, using three predicted images with 1mm setup shift and 3% range uncertainty, (2) cRO3mm, with a robust 3mm setup shift and 3% range uncertainty, and (3) cRO1mm, a robust 1mm setup shift and 3% range uncertainty. The accumulated dose to CTVs and serial organs was evaluated under these uncertainties, while parallel OARs were assessed using the accumulated nominal dose (without errors).ResultsThe accumulated volume receiving 94% of the prescribed dose (V94) for CTVs in cRO3mm exceeded 98%, meeting the clinical goal. For high‐risk CTV, the minimum V94 was 96.44% in aRO1mm and 94.05% in cRO1mm. For low‐risk CTV, these values were 97.68% in aRO1mm and 97.15% in cRO1mm. When comparing aRO1mm to cRO3mm on OARs, aRO1mm reduced normal tissue complication probability (NTCP) for grade 2 xerostomia and dysphagia by averages of 3.67% and 1.54%, respectively.ConclusionaRO1mm lowers the radiation dose to OARs compared to the traditional approach, while maintaining adequate dose coverage on the target area. This method offers an improved strategy for managing uncertainties in radiation therapy planning for H&amp;N cancer, enhancing treatment effectiveness.

Development of a proton CT imaging system using scintillator-based range detection.

The accuracy of proton therapy and preclinical proton irradiation experiments is susceptible to proton range uncertainties, which partly stem from the inaccurate conversion between CT numbers and relative stopping power (RSP). Proton computed tomography (PCT) can reduce these uncertainties by directly acquiring RSP maps. This study aims to develop a novel PCT imaging system based on scintillator-based proton range detection for accurate RSP reconstruction. The proposed PCT system consists of a pencil-beam brass collimator with a 1mm aperture, an object stage capable of translation and 360° rotation, a plastic scintillator for dose-to-light conversion, and a complementary metal oxide semiconductor (CMOS) camera for light distribution acquisition. A calibration procedure based on Monte Carlo (MC) simulation was implemented to convert the obtained light ranges into water equivalent ranges. The water equivalent path lengths (WEPLs) of the imaged object were determined by calculating the differences in proton ranges obtained with and without the object in the beam path. To validate the WEPL calculation, measurements of WEPLs for eight tissue-equivalent inserts were conducted. PCT imaging was performed on a custom-designed phantom and a mouse, utilizing both 60 and 360 projections. The filtered back projection (FBP) algorithm was employed to reconstruct the RSP from WEPLs. Image quality was assessed based on the reconstructed RSP maps and compared to reference and simulation-based reconstructions. The differences between the calibrated and reference ranges of 110-150 MeV proton beams were within 0.18mm. The WEPLs of eight tissue-equivalent inserts were measured with accuracies better than 1%. Phantom experiments exhibited good agreement with reference and simulation-based reconstructions, demonstrating average RSP errors of 1.26%, 1.38%, and 0.38% for images reconstructed with 60 projections, 60 projections after penalized weighted least-squares algorithm denoising, and 360 projections, respectively. Mouse experiments provided clear observations of mouse contours and major tissue types. MC simulation estimated an imaging dose of 3.44 cGy for decent RSP reconstruction. The proposed PCT imaging system enables RSP map acquisition with high accuracy and has the potential to improve dose calculation accuracy in proton therapy and preclinical proton irradiation experiments.

TEAM: Triangular-mEsh Adaptive and Multiscale proton spot generation method.

Proton therapy is preferred for its dose conformality to spare normal tissues and organs-at-risk (OAR) via Bragg peaks with negligible exit dose. However, proton dose conformality can be further optimized: (1) the spot placement is based on the structured (e.g., Cartesian) grid, which may not offer conformal shaping to complex tumor targets; (2) the spot sampling pattern is uniform, which may be insufficient at the tumor boundary to provide the sharp dose falloff, and at the same time may be redundant at the tumor interior to provide the uniform dose coverage, for example, due to multiple Coulomb scattering (MCS); and (3) the lateral spot penumbra increases with respect to the depth due to MCS, which blurs the lateral dose falloff. On the other hand, while (1) the deliverable spots are subject to the minimum-monitor-unit (MMU) constraint, and (2) the dose rate is proportional to the MMU threshold, the current spot sampling method is sensitive to the MMU threshold and can fail to provide satisfactory plan quality for a large MMU threshold (i.e., high-dose-rate delivery). This work will develop a novel Triangular-mEsh-based Adaptive and Multiscale (TEAM) proton spot generation method to address these issues for optimizing proton dose conformality and plan delivery efficiency. Compared to the standard clinically-used spot placement method, three key elements of TEAM are as follows: (1) a triangular mesh instead of a structured grid: the triangular mesh is geometrically more conformal to complex target shapes and therefore more efficient and accurate for dose shaping inside and around the target; (2) adaptive sampling instead of uniform sampling: the adaptive sampling consists of relatively dense sampling at the tumor boundary to create the sharp dose falloff, which is more accurate, and coarse sampling at the tumor interior to uniformly cover the target, which is more efficient; and (3) depth-dependent sampling instead of depth-independent sampling: the depth-dependent sampling is used to compensate for MCS, that is, with increasingly dense sampling at the tumor boundary to improve dose shaping accuracy, and increasingly coarse sampling at the tumor interior to improve dose shaping efficiency, as the depth increases. In the TEAM method the spot locations are generated for each energy layer and layer-by-layer in the multiscale fashion; and then the spot weights are derived by solving the IMPT problem of dose-volume planning objectives, MMU constraints, and robustness optimization with respect to range and setup uncertainties. Compared to the standard clinically-used spot placement method UNIFORM, TEAM achieved (1) better plan quality using <60% number of spots of UNIFORM; (2) better robustness to the number of spots; (3) better robustness to a large MMU threshold. Furthermore, TEAM provided better plan quality with fewer spots than other adaptive methods (Cartesian-grid or triangular-mesh). A novel triangular-mesh-based proton spot placement method called TEAM is proposed, and it is demonstrated to improve plan quality, robustness to the number of spots, and robustness to the MMU threshold, compared to the clinically-used spot placement method and other adaptive methods.

Validation of dual-energy CT-based composition analysis using fresh animal tissues and composition-optimized tissue equivalent samples

Objective. Proton therapy allows for highly conformal dose deposition, but is sensitive to range uncertainties. Several approaches currently under development measure composition-dependent secondary radiation to monitor the delivered proton range in-vivo. To fully utilize these methods, an estimate of the elemental composition of the patient’s tissue is often needed. Approach. A published dual-energy computed tomography (DECT)-based composition-extraction algorithm was validated against reference compositions obtained with two independent methods. For this purpose, a set of phantoms containing either fresh porcine tissue or tissue-mimicking samples with known, realistic compositions were imaged with a CT scanner at two different energies. Then, the prompt gamma-ray (PG) signal during proton irradiation was measured with a PG detector prototype. The PG workflow used pre-calculated Monte Carlo simulations to obtain an optimized estimate of the sample’s carbon and oxygen contents. The compositions were also assessed with chemical combustion analysis (CCA), and the stopping-power ratio (SPR) was measured with a multi-layer ionization chamber. The DECT images were used to calculate SPR-, density- and elemental composition maps, and to assign voxel-wise compositions from a selection of human tissues. For a more comprehensive set of reference compositions, the original selection was extended by 135 additional tissues, corresponding to spongiosa, high-density bones and low-density tissues. Results. The root-mean-square error for the soft tissue carbon and oxygen content was 8.5 wt% and 9.5 wt% relative to the CCA result and 2.1 wt% and 10.3 wt% relative to the PG result. The phosphorous and calcium content were predicted within 0.4 wt% and 1.1 wt% of the CCA results, respectively. The largest discrepancies were encountered in samples whose composition deviated the most from tabulated compositions or that were more inhomogeneous. Significance. Overall, DECT-based composition estimations of relevant elements were in equal or better agreement with the ground truth than the established SECT-approach and could contribute to in-vivo dose verification measurements.

Coesite-bearing garnet xenocrysts from diatexite in the Nordøyane domain, Western Gneiss Region, Norway: implications for eclogite-melt interaction at ultra-high pressure

Ultra-high-pressure (UHP) metamorphic rocks in the Western Gneiss Region (WGR) of Norway formed in subducted Baltican crust during the Scandian phase of the Caledonian orogeny. In the Nordøyane UHP domain, eclogites locally preserve coesite and microdiamond. Along the north coasts of Haramsøya and Flemsøya, in situ eclogite bodies are surrounded by dioritic “diatexite selvages” containing abundant eclogitic enclaves and xenocrysts. In one location eclogite and diatexite are associated with a quartz diorite dyke that is highly contaminated with eclogitic material. The diatexite matrix and dyke have similar plagioclase + quartz + biotite assemblages with abundant embayed and fragmented garnet and clinopyroxene xenocrysts. Coesite is present in some garnet xenocrysts but has not been found in the adjacent eclogite bodies. Pressure–temperature ( P– T) estimates from in situ eclogites range from 2.2–3.2 GPa and 810–840 °C, spanning the quartz–coesite transition, with P– T estimates from xenocrysts spanning a wider range. Diorites and retrogressed eclogites record amphibolite-facies conditions, ca. 1.0–1.5 GPa and 700–800 °C. The wide range and large uncertainties in P– T estimates reflect high-temperature re-equilibration and a relative lack of P-sensitive assemblages. Differences in texture, composition, and included assemblages indicate that the xenocrysts were not derived from the nearby eclogite bodies. By implication, their dioritic hosts were not locally derived but must have originated from a different, probably deeper, source. The results are integrated with a numerical model for WGR tectonic evolution to assess the sources of the melts and their possible effects on the exhumation of UHP rocks in western Norway.

Dose estimation using in-beam positron emission tomography: Demonstration for 11C and 15O ion beams

Ion therapy has been well established for many decades owing to sharp depth-dose gradient and high cell-killing capability of ions. However, monitoring of the incident ions is needed to reduce ion range uncertainty for effective tumor treatment. Positron-emitting ion beams, known as radioactive ion (RI) beams, can be used as the optimal clinical approach for simultaneously treating and monitoring the incident ions using positron emission tomography (PET) imaging. The low intensity of RI beams, which previously was the main difficulty of their clinical use, was recently addressed by the development of accelerator technology. Since the quantity of interest in ion therapy is the dose and a direct comparison of planned and delivered doses is highly desirable, we focused on predicting the depth dose from PET images for RI beams in this work for the first time. We developed a method for predicting the depth dose of polyenergetic ion beams of 11C and 15O from PET images of these ion beams. The depth dose in water was measured for mono- and polyenergetic ion beams. The monoenergetic ion beams had a momentum acceptance (MA) of ±0.25%, while the polyenergetic beams had an MA of ±2.5%. PET imaging was performed during and shortly after irradiation of a polymethylmethacrylate (PMMA) phantom with mono- and polyenergetic radioactive ion beams. The energy distribution of each polyenergetic ion beam was obtained from the measured momentum distribution of that beam. A set of depth dose and PET profiles in PMMA was constructed for several monoenergetic ion beams using measured data of a monoenergetic ion beam and the range-energy relation. To estimate the depth dose for each polyenergetic beam, a linear combination of weighted PET profiles of monoenergetic beams was iteratively fitted to the measured PET profile of the polyenergetic beam, and the resulting weights were combined with the corresponding monoenergetic depth doses to predict the depth dose distribution. Significance. The depth doses of the polyenergetic ion beams were predicted with mean relative errors of 2.20% and 1.95% for 11C and 15O ion beams, respectively. These errors represent the mean value of the differences between the predicted and measured values, normalized to the maximum measured value. The predicted distal fall-off positions at 80% of the Bragg peak were within 0.13 mm of the measured values for both ion beams. The applicability of the method was demonstrated for a head phantom irradiated with 11C ion beams using Monte Carlo simulation and the predicted distal fall-off positions at 80% of the Bragg peak was within 0.08 mm of the simulated values.

Patient-specific deep learning for 3D protoacoustic image reconstruction and dose verification in proton therapy.

Protoacoustic (PA) imaging has the potential to provide real-time 3D dose verification of proton therapy. However, PA images are susceptible to severe distortion due to limited angle acquisition. Our previous studies showed the potential of using deep learning to enhance PA images. As the model was trained using a limited number of patients' data, its efficacy was limited when applied to individualpatients. In this study, we developed a patient-specific deep learning method for protoacoustic imaging to improve the reconstruction quality of protoacoustic imaging and the accuracy of dose verification for individualpatients. Our method consists of two stages: in the first stage, a group model is trained from a diverse training set containing all patients, where a novel deep learning network is employed to directly reconstruct the initial pressure maps from the radiofrequency (RF) signals; in the second stage, we apply transfer learning on the pre-trained group model using patient-specific dataset derived from a novel data augmentation method to tune it into a patient-specific model. Raw PA signals were simulated based on computed tomography (CT) images and the pressure map derived from the planned dose. The reconstructed PA images were evaluated against the ground truth by using the root mean squared errors (RMSE), structural similarity index measure (SSIM) and gamma index on 10 specific prostate cancer patients. The significance level was evaluated by t-test with the p-value threshold of 0.05 compared with the results from the groupmodel. The patient-specific model achieved an average RMSE of 0.014 ( ), and an average SSIM of 0.981 ( ), out-performing the group model. Qualitative results also demonstrated that our patient-specific approach acquired better imaging quality with more details reconstructed when comparing with the group model. Dose verification achieved an average RMSE of 0.011 ( ), and an average SSIM of 0.995 ( ). Gamma index evaluation demonstrated a high agreement (97.4% [ ] and 97.9% [ ] for 1%/3 and 1%/5mm) between the predicted and the ground truth dose maps. Our approach approximately took 6 s to reconstruct PA images for each patient, demonstrating its feasibility for online 3D dose verification for prostate protontherapy. Our method demonstrated the feasibility of achieving 3D high-precision PA-based dose verification using patient-specific deep-learning approaches, which can potentially be used to guide the treatment to mitigate the impact of range uncertainty and improve the precision. Further studies are needed to validate the clinical impact of thetechnique.

A novel fast robust optimization algorithm for intensity-modulated proton therapy with minimum monitor unit constraint.

Intensity-modulated proton therapy (IMPT) optimizes spot intensities and position, providing better conformability. However, the successful application of IMPT is dependent upon addressing the challenges posed by range and setup uncertainties. In order to address the uncertainties in IMPT, robust optimization is essential. This study aims to develop a novel fast algorithm for robust optimization of IMPT with minimum monitor unit (MU) constraint. The study formulates a robust optimization problem and proposes a novel, fast algorithm based on the alternating direction method of multipliers (ADMM) framework. This algorithm enables distributed computation and parallel processing. Ten clinical cases were used as test scenarios to evaluate the performance of the proposed approach. The robust optimization method (RBO-NEW) was compared with plans that only consider nominal optimization using CTV (NMO-CTV) without handling uncertainties and PTV (NMO-PTV) to handle the uncertainties, as well as with conventional robust-optimized plans (RBO-CONV). Dosimetric metrics, including D95, homogeneity index, and Dmean, were used to evaluate the dose distribution quality. The area under the root-mean-square dose (RMSD)-volume histogram curves (AUC) and dose-volume histogram (DVH) bands were used to evaluate the robustness of the treatment plan. Optimization time cost was also assessed to measure computationalefficiency. The results demonstrated that the RBO plans exhibited better plan quality and robustness than the NMO plans, with RBO-NEW showing superior computational efficiency and plan quality compared to RBO-CONV. Specifically, statistical analysis results indicated that RBO-NEW was able to reduce the computational time from to s ( ) and reduce the mean organ-at-risk (OAR) dose from % of the prescription dose to % of the prescription dose ( ) compared toRBO-CONV. This study introduces a novel fast robust optimization algorithm for IMPT treatment planning with minimum MU constraint. Such an algorithm is not only able to enhance the plan's robustness and computational efficiency without compromising OAR sparing but also able to improve treatment plan quality andreliability.

Benefit of range uncertainty reduction in robust optimisation for proton therapy of brain, head-and-neck and breast cancer patients

Background and PurposeThe primary cause of range uncertainty in proton therapy is inaccuracy in estimating the stopping-power ratio from computed tomography. This study examined the impact on dose-volume metrics by reducing range uncertainty in robust optimisation for a diverse patient cohort and determined the level of range uncertainty that resulted in a relevant reduction in doses to organs-at-risk (OARs). Materials and MethodsThe effect of reducing range uncertainty on OAR doses was evaluated by robustly optimising six proton plans with varying range uncertainty levels (ranging from 3.5% in the original plan to 1.0%), keeping setup uncertainty fixed. All plans used the initial clinical treatment plan’s beam directions and optimisation objectives and were optimised until a clinically acceptable plan was achieved across all setup and range scenarios. The effect of reduced range uncertainty on dose-volume metrics for OARs near the target was evaluated. This study included 30 brain cancer patients, as well as five head-and-neck and five breast cancer patients, investigating the relevance of reducing range uncertainty when different setup uncertainties were used. ResultsLowering range uncertainty slightly reduced the nominal dose to surrounding tissue. For body volume receiving 80% of the prescribed dose, reducing range uncertainty from 3.5% to 2.0% resulted in a median decrease of 4 cm3 for the brain, 17 cm3 for head-and-neck, and 27 cm3 for breast cancer patients. ConclusionsReducing range uncertainty in robust optimisation showed a reduction in dose to OARs. The clinical relevance depends on the affected organs and the clinical dose constraints.

Dosimetric comparison of IMPT vs VMAT for multiple lung lesions: an NTCP model-based decision-making strategy

To compare the dosimetric differences in volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in stereotactic body radiation therapy (SBRT) of multiple lung lesions and determine a normal tissue complication probability (NTCP) model-based decision strategy that determines which treatment modality the patient will use. A total of 41 patients were retrospectively selected for this study. The number of patients with 1-6 lesions was 5, 16, 7, 6, 3, and 4, respectively. A prescription dose of 70 GyRBE in 10 fractions was given to each lesion. SBRT plans were generated using VMAT and IMPT. All the IMPT plans used robustness optimization with ± 3.5% range uncertainties and 5 mm setup uncertainties. Dosimetric metrics and the predicted NTCP value of radiation pneumonitis (RP), esophagitis, and pericarditis were analyzed to evaluate the potential clinical benefits between different planning groups. In addition, a threshold for the ratio of PTV to lungs (%) to determine whether a patient would benefit highly from IMPT was determined using receiver operating characteristic curves. All plans reached target coverage (V70GyRBE ≥ 95%). Compared with VMAT, IMPT resulted in a significantly lower dose of most thoracic normal tissues. For the 1-2, 3-4 and 5-6 lesion groups, the lung V5 was 29.90 ± 9.44%, 58.33 ± 13.35%, and 81.02 ± 5.91% for VMAT and 11.34 ± 3.11% (p < 0.001), 21.45 ± 3.80% (p < 0.001), and 32.48 ± 4.90% (p < 0.001) for IMPT, respectively. The lung V20 was 12.07 ± 4.94%, 25.57 ± 6.54%, and 43.99 ± 11.83% for VMAT and 6.76 ± 1.80% (p < 0.001), 13.14 ± 2.27% (p < 0.01), and 19.62 ± 3.48% (p < 0.01) for IMPT. The Dmean of the total lung was 7.65 ± 2.47 GyRBE, 14.78 ± 2.75 GyRBE, and 21.64 ± 4.07 GyRBE for VMAT and 3.69 ± 1.04 GyRBE (p < 0.001), 7.13 ± 1.41 GyRBE (p < 0.001), and 10.69 ± 1.81 GyRBE (p < 0.001) for IMPT. Additionally, in the VMAT group, the maximum NTCP value of radiation pneumonitis was 73.91%, whereas it was significantly lower in the IMPT group at 10.73%. The accuracy of our NTCP model-based decision model, which combines the number of lesions and PTV/Lungs (%), was 97.6%. The study demonstrated that the IMPT SBRT for multiple lung lesions had satisfactory dosimetry results, even when the number of lesions reached 6. The NTCP model-based decision strategy presented in our study could serve as an effective tool in clinical practice, aiding in the selection of the optimal treatment modality between VMAT and IMPT.

Quantifying the Dosimetric Impact of Proton Range Uncertainties on RBE-Weighted Dose Distributions in Intensity-Modulated Proton Therapy for Bilateral Head and Neck Cancer.

In current clinical practice, intensity-modulated proton therapy (IMPT) head and neck cancer (HNC) plans are generated using a constant relative biological effectiveness (cRBE) of 1.1. The primary goal of this study was to explore the dosimetric impact of proton range uncertainties on RBE-weighted dose (RWD) distributions using a variable RBE (vRBE) model in the context of bilateral HNC IMPT plans. The current study included the computed tomography (CT) datasets of ten bilateral HNC patients who had undergone photon therapy. Each patient's plan was generated using three IMPT beams to deliver doses to the CTV_High and CTV_Low for doses of 70 Gy(RBE) and 54 Gy(RBE), respectively, in 35 fractions through a simultaneous integrated boost (SIB) technique. Each nominal plan calculated with a cRBE of 1.1 was subjected to the range uncertainties of ±3%. The McNamara vRBE model was used for RWD calculations. For each patient, the differences in dosimetric metrices between the RWD and nominal dose distributions were compared. The constrictor muscles, oral cavity, parotids, larynx, thyroid, and esophagus showed average differences in mean dose (Dmean) values up to 6.91 Gy(RBE), indicating the impact of proton range uncertainties on RWD distributions. Similarly, the brachial plexus, brain, brainstem, spinal cord, and mandible showed varying degrees of the average differences in maximum dose (Dmax) values (2.78-10.75 Gy(RBE)). The Dmean and Dmax to the CTV from RWD distributions were within ±2% of the dosimetric results in nominal plans. The consistent trend of higher mean and maximum doses to the OARs with the McNamara vRBE model compared to cRBE model highlighted the need for consideration of proton range uncertainties while evaluating OAR doses in bilateral HNC IMPT plans.

Clinical Implementation and Dosimetric Evaluation of a Robust Proton Lattice Planning Strategy Using Primary and Robust Complementary Beams

Pencil-beam scanning proton therapy has been considered a potential modality for the 3D form of spatially fractionated radiation therapy called lattice therapy. However, few practical solutions have been introduced in the clinic. Existing limitations include degradation in plan quality and robustness when using single-field versus multifield lattice plans, respectively. We propose a practical and robust proton lattice (RPL) planning method using multifield and evaluate its dosimetric characteristics compared to clinically acceptable photon lattice plans. Seven cases previously treated with photon lattice therapy were used to evaluate a novel RPL planning technique using 2-orthogonal beams: a primary beam (PB) and a robust complementary beam (RCB) that deliver 67% and 33%, respectively, of the prescribed dose to vertices inside the gross target volume (GTV). Only RCB is robustly optimized for setup and range uncertainties. The number and volume of vertices, peak-to-valley dose ratios (PVDRs), and volume of low dose to GTV of proton and photon plans were compared. The RPL technique was then used in the treatment of 2 patients and their dosimetric parameters were reported. The RPL strategy was able to achieve the clinical planning goals. Compared to previously treated photon plans, the average number of vertices increased by 30%, the average vertex volume by 49% (18.2 ± 25.9 cc vs 12.2 ± 14.5 cc, P = .21), and higher PVDR (10.5 ± 4.8 vs 2.5 ± 0.9, P < .005) was achieved. In addition, RPL plans show more conformal dose with less low dose to GTV (V30%, 60.9% ± 7.2% vs 81.6% ± 13.9% and V10%, 88.3% ± 4.5% vs 98.6% ± 3.6% [P < .01]). The RPL plan for 2 treated patients showed PVDRs of 4.61 and 14.85 with vertices-to-GTV ratios of 1.52% and 1.30%, respectively. A novel RPL planning strategy using a pair of orthogonal beams was developed and successfully translated to the clinic. The proposed method can generate better quality plans, a higher number of vertices, and higher PVDRs than currently used photon lattice plans.

Robustness of intensity modulated proton treatment of esophageal cancer for anatomical changes and breathing motion

Background and purposeIn this study, we assessed the robustness of intensity modulated proton therapy (IMPT) in esophageal cancer for anatomical variations during treatment. MethodsThe first sixty esophageal cancer patients, treated clinically with chemoradiotherapy were included. The treatment planning strategy was based on an internal target volume (ITV) approach, where the ITV was created from the clinical target volumes (CTVs) delineated on all phases of a 4DCT. For optimization, a 3 mm isotropic margin was added to the ITV, combined with robust optimization using 5 mm setup and 3 % range uncertainty. Each patient received weekly repeat CTs (reCTs). Robust plan re-evaluation on all reCTs, and a robust dose summation was performed. To assess the factors influencing ITV coverage, a multivariate linear regression analysis was performed. Additionally, clinical adaptations were evaluated. ResultsThe target coverage was adequate (ITV V94%>98 % on the robust voxel-wise minimum dose) on most reCTs (91 %), and on the summed dose in 92 % of patients. Significant predictors for ITV coverage in the multivariate analysis were diaphragm baseline shift and water equivalent depth (WED) of the ITV in the beam direction. Underdosage of the ITV mainly occurred in week 1 and 4, leading to treatment adaptation of eight patients, all on the first reCT. ConclusionOur IMPT treatment of esophageal cancer is robust for anatomical variations. Adaptation appears to be most effective in the first week of treatment. Diaphragm baseline shifts and WED are predictive factors for ITV underdosage, and should be incorporated in an adaptation protocol.

RADT-06. ENCOURAGING OUTCOMES AFTER CRANIO-SPINAL IRRADIATION (CSI) WITH MODERN IMAGE GUIDED INTENSITY MODULATED PROTON THERAPY (IMPT) (IMPT-CSI) IN CHILDREN AND YOUNG ADULTS (AYA)- AN INSTITUTION EXPERIENCE

Abstract BACKGROUND Outcomes of IMPT-CSI in children and adolescent-young adults (AYA) treated at our institute over a period of 5 years was analyzed MATERIALS AND METHODS 92 children/AYA were treated by IMPT-CSI. PTV definition of the spine for skeletally immature patients was modified to only the vertebral body without isotropic margins. All plans were multifield optimized for 5 mm robustness (cranio-caudal) &amp; 2.5% range uncertainty. The treatment set-up was confirmed by both orthogonal radiograph and CBCT. Toxicity was graded as per RTOG criteria. RESULTS Median CSI dose of 35GyE in 21 fractions was given to cohort with 74% males, median age of 7 years (2-39 years), consisting of Medulloblastoma (58%), other Embryonal tumours (20%), recurrent Ependymoma (10%), GCT (10%) and others (2%) with 18% being reirradiation and under sedation in 25%. Concurrent chemotherapy was given in 40%. The median V98% for clinical target volumes and V95% for PTVs of the brain, spine and craniospinal were &amp;gt;97%. Isodose 95% covered the cribriform plate completely and optic nerves keeping Dmax to the lens &amp;lt;3.9 GyRBE, critical OARs (mean of the cohort- Cochlea Dmax 28GyE, midline mucosa 23.2GyE, Esophagus 23.2GyE and gonads (testes and ovaries- 0GyE and 0.4GyE). The online set-up verification showed translational and rotational deviation within 2 mm and 0.5 in 94% and 97% of the cases. Radiation dermatitis was Grade 2-40%; Gr3-10%. Neutropenia was Grade 3 in 30%; few needed G-CSF. Less than 10% developed &amp;gt;grade 3 significant weight loss/ anorexia/ mucositis. At median F/U 20 months (6–60m), 12 patients have progressed with PFS of 78% &amp; OS of 87%, best in GCT and worst in Ependymoma (recurrent), 100% vs. 55% (p&amp;lt;0.014) CONCLUSION Outcomes of IMPT-CSI in children and young adults, showed very encouraging dosimetry, toxicity profile and long-term survival.

Dosimetric and NTCP advantages of robust proton therapy over robust VMAT for Stage III NSCLC in the immunotherapy era

AimsTo assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. Material and methods10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. ResultsBoth PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004).ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). ConclusionsPBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected.