Dosimetric evaluation of intensity modulated photon versus proton reirradiation of head and neck cancer.

BACKGROUND: Reirradiation of head and neck cancer (HNC) became more accessible in the last decade, owing to modern irradiation techniques which offer a reduction in treatment related toxicities. The aim of this paper was to comparatively evaluate the dosimetric aspects derived from intensity modulated photon vs. proton treatment planning in reirradiated HNC patients. METHODS: Six recurrent HNC patients were enrolled in this retrospective study. For each patient two treatment plans were created: one IMRT/VMAT and one IMPT plan. The prescribed dose for the second irradiation was between 50 and 70 Gy RBE. The study comparatively analyzed the CTV coverage, doses to organs at risk (OARs) and low doses received by the healthy tissue (other than OAR). RESULTS: Similar CTV coverage was achieved for photon vs proton plans, with the latter presenting better homogeneity in four cases. Maximum dose to CTV was generally higher for photon plans, with differences ranging from 0.3 to 1.9%. For parotid glands and body, the mean dose was lower for proton plans. A notable reduction of low dose to healthy tissue (other than OARs) could be achieved with protons, with an average of 60% and 64% for D10% and Dmean, respectively. CONCLUSION: The dosimetric comparison between photon and proton reirradiation of HNC showed a great need for treatment individualization, concluding that protons should be considered for reirradiation on an individual basis.

Proton 3D dose measurement with a multi-layer strip ionization chamber (MLSIC) device.

Objective. In current clinical practice for quality assurance (QA), intensity modulated proton therapy (IMPT) fields are verified by measuring planar dose distributions at one or a few selected depths in a phantom. A QA device that measures full 3D dose distributions at high spatiotemporal resolution would be highly beneficial for existing as well as emerging proton therapy techniques such as FLASH radiotherapy. Our objective is to demonstrate feasibility of 3D dose measurement for IMPT fields using a dedicated multi-layer strip ionization chamber (MLSIC) device.Approach.Our developed MLSIC comprises a total of 66 layers of strip ion chamber (IC) plates arranged, alternatively, in thexandydirection. The first two layers each has 128 channels in 2 mm spacing, and the following 64 layers each has 32/33 IC strips in 8 mm spacing which are interconnected every eight channels. A total of 768-channel IC signals are integrated and sampled at a speed of 6 kfps. The MLSIC has a total of 19.2 cm water equivalent thickness and is capable of measurement over a 25 × 25 cm2field size. A reconstruction algorithm is developed to reconstruct 3D dose distribution for each spot at all depths by considering a double-Gaussian-Cauchy-Lorentz model. The 3D dose distribution of each beam is obtained by summing all spots. The performance of our MLSIC is evaluated for a clinical pencil beam scanning (PBS) plan.Main results.The dose distributions for each proton spot can be successfully reconstructed from the ionization current measurement of the strip ICs at different depths, which can be further summed up to a 3D dose distribution for the beam. 3D Gamma Index analysis indicates acceptable agreement between the measured and expected dose distributions from simulation, Zebra and MatriXX.Significance.The dedicated MLSIC is the first pseudo-3D QA device that can measure 3D dose distribution in PBS proton fields spot-by-spot.

Combined optimization of spot positions and weights for better FLASH proton therapy.

Objective.In Intensity Modulated Proton Therapy (IMPT), the weights of individual pencil-beams or spots are optimized to fulfil dosimetric constraints. Theses spots are usually located on a regular lattice and their positions are fixed during optimization. In many cases, the range of spot weights may however be limited, leading sometimes to sub-optimal plan quality. An emblematic use case is the delivery of a plan at ultra-high dose rate (FLASH-RT), for which the spot weights are typically constrained to high values.Approach. To improve further the quality of IMPT FLASH plans, we propose here a novel algorithm to optimize both the spot weights and positions directly based on the objectives defined by the treatment planner.Main results. For all cases considered, optimizing the spot positions lead to an enhanced dosimetric score, while maintaining a high dose rate.Significance. Overall, this approach resulted in a substantial plan quality improvement compared to optimizing only the spot weights, and in a similar execution time.

Real-Time Gated Proton Therapy: Commissioning and Clinical Workflow for the Hitachi System.

Purpose: To describe the commissioning of real-time gated proton therapy (RGPT) and the establishment of an appropriate clinical workflow for the treatment of patients. Materials and Methods: Hitachi PROBEAT provides pencil beam scanning proton therapy with an advanced onboard imaging system including real-time fluoroscopy. RGPT utilizes a matching score to provide instantaneous system performance feedback and quality control for patient safety. The CIRS Dynamic System combined with a Thorax Phantom or plastic water was utilized to mimic target motion. The OCTAVIUS was utilized to measure end-to-end dosimetric accuracy for a moving target across a range of simulated situations. Using this dosimetric data, the gating threshold was carefully evaluated and selected based on the intended treatment sites and planning techniques. An image-guidance workflow was developed and applied to patient treatment. Results: Dosimetric data demonstrated that proton plan delivery uncertainty could be within 2 mm for a moving target. The dose delivery to a moving target could pass 3%/3 mm gamma analysis following the commissioning process and application of the clinical workflow detailed in this manuscript. A clinical workflow was established and successfully applied to patient treatment utilizing RGPT. Prostate cancer patients with implanted platinum fiducial markers were treated with RGPT. Their target motion and gating signal data were available for intrafraction motion analysis. Conclusion: Real-time gated proton therapy with the Hitachi System has been fully investigated and commissioned for clinical application. RGPT can provide advanced and reliable real-time image guidance to enhance patient safety and inform important treatment planning parameters, such as planning target volume margins and uncertainty parameters for robust plan optimization. RGPT improved the treatment of patients with prostate cancer in situations where intrafraction motion is more than defined tolerance.

Esophageal Cancer Outcomes After Definitive Chemotherapy With Intensity Modulated Proton Therapy.

Purpose: The effectiveness of intensity-modulated proton therapy (IMPT) for esophageal cancer treated with definitive concurrent chemoradiation therapy remains inadequately explored. We investigated long-term outcomes and toxicity experienced by patients who received IMPT as part of definitive esophageal cancer treatment. Patients and Methods: We retrospectively identified and analyzed 34 patients with locally advanced esophageal cancer who received IMPT with concurrent chemotherapy as a definitive treatment regimen at The University of Texas MD Anderson Cancer Center from 2011 to 2021. The median IMPT dose was 50.4 GyRBE in 28 fractions; concurrent chemotherapy consisted of fluorouracil and/or taxane and/or platinum. Survival outcomes were determined by the Kaplan-Meier method, and toxicity was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Results: The median age of all patients was 71.5 years. Most patients had stage III (cT3 cM0) adenocarcinoma of the lower esophagus. At a median follow-up time of 39 months, the 5-year overall survival rate was 41.1%; progression-free survival, 34.6%; local regional recurrence-free survival, 78.1%; and distant metastasis-free survival, 65.0%. Common acute chemoradiation therapy-related toxicities included hematologic toxicity, esophagitis (and late-onset), fatigue, weight loss, and nausea (and late-onset); grade 3 toxicity rates were 26.0% for hematologic, 18.0% for esophagitis and 9.0% for nausea. No patient had grade ≥3 wt loss or radiation pneumonitis, and no patients had pulmonary fibrosis or esophageal fistula. No grade ≥4 events were observed except for hematologic toxicity (lymphopenia) in 2 patients. Conclusion: Long-term survival and toxicity were excellent after IMPT for locally advanced esophageal cancer treated definitively with concurrent chemoradiation therapy. When available, IMPT should be offered to such patients to minimize treatment-related cardiopulmonary toxicity without sacrificing outcomes.

A reference-point-method-based online proton treatment plan re-optimization strategy and a novel solution to planning constraint infeasibility problem.

Objective. Propose a highly automated treatment plan re-optimization strategy suitable for online adaptive proton therapy. The strategy includes a rapid re-optimization method that generates quality replans and a novel solution that efficiently addresses the planning constraint infeasibility issue that can significantly prolong the re-optimization process.Approach. We propose a systematic reference point method (RPM) model that minimizes the l-infinity norm from the initial treatment plan in the daily objective space for online re-optimization. This model minimizes the largest objective value deviation among the objectives of the daily replan from their reference values, leading to a daily replan similar to the initial plan. Whether a set of planning constraints is feasible with respect to the daily anatomy cannot be known before solving the corresponding optimization problem. The conventional trial-and-error-based relaxation process can cost a significant amount of time. To that end, we propose an optimization problem that first estimates the magnitude of daily violation of each planning constraint. Guided by the violation magnitude and clinical importance of the constraints, the constraints are then iteratively converted into objectives based on their priority until the infeasibility issue is solved.Main results.The proposed RPM-based strategy generated replans similar to the offline manual replans within the online time requirement for six head and neck and four breast patients. The average targetD95and relevant organ at risk sparing parameter differences between the RPM replans and clinical offline replans were -0.23, -1.62 Gy for head and neck cases and 0.29, -0.39 Gy for breast cases. The proposed constraint relaxation solution made the RPM problem feasible after one round of relaxation for all four patients who encountered the infeasibility issue.Significance. We proposed a novel RPM-based re-optimization strategy and demonstrated its effectiveness on complex cases, regardless of whether constraint infeasibility is encountered.

Dose Evaluation in 2-Phase Method for Advanced Esophageal Cancer by Hybrid Irradiation Techniques.

Purpose: In concurrent chemoradiotherapy for advanced esophageal cancer, a 2-phase method consisting of initial irradiation of a wide elective nodal region and boost irradiation of the primary lesion is commonly employed. Although dose escalation to the primary lesion may be required to achieve higher local control rates, the radiation dose to critical organs must not exceed dose constraints. To achieve an optimum balance of dose prescription and dose reduction to surrounding organs, such as the lungs and heart, we compared hybrid dose distributions and investigated the best combination of the following recent irradiation techniques: volumetric modulation arc therapy (VMAT), proton broad-beam irradiation, and intensity-modulated proton beam therapy (IMPT). Materials and Methods: Forty-five patients with advanced esophageal cancer whose primary lesions were located in the middle- or lower-thoracic region were studied. Radiotherapy plans for the initial and boost irradiation in the 2-phase method were calculated using VMAT, proton broad-beam irradiation, and IMPT calculation codes, and the dose-volume histogram indices of the lungs and heart for the accumulated plans were compared. Results: In plans using boost proton irradiation with a prescribed dose of 60 Gy(RBE), all dose-volume histogram indices were significantly below the tolerance limits. Initial and boost irradiation with VMAT resulted in the median dose of V30 Gy(RBE)(heart) of 27.4% and an achievement rate below the tolerance limit of 57.8% (26 cases). In simulations of dose escalation up to 70 Gy(RBE), initial and boost IMPT resulted in the highest achievement rate, satisfying all dose constraints in 95.6% (43 cases). Conclusion: Applying VMAT to both initial and boost irradiation is not recommended because of the increased risk of the cardiac dose exceeding the tolerance limit. IMPT may allow dose escalation of up to 70 Gy(RBE) without radiation risks to the lungs and heart in the treatment of advanced esophageal cancer.

Utilizing collimated aperture with proton pencil beam scanning (PBS) for stereotactic radiotherapy.

PURPOSE: Proton stereotactic radiosurgery (PSRS) has emerged as an innovative proton therapy modality aimed at achieving precise dose delivery with minimal impact on healthy tissues. This study explores the dosimetric outcomes of PSRS in comparison to traditional intensity-modulated proton therapy (IMPT) by focusing on cases with small target volumes. A custom-made aperture system designed for proton therapy, specifically tailored to small target volumes, was developed and implemented for this investigation. METHODS: A prerequisite mechanical validation through an isocentricity test precedes dosimetric assessments, ensuring the seamless integration of mechanical and dosimetry analyses. Five patients were enrolled in the study, including two with choroid melanoma and three with arteriovenous malformations (AVM). Two treatment plans were meticulously executed for each patient, one utilizing a collimated aperture and the other without. Both plans were subjected to robust optimization, maintaining identical beam arrangements and consistent optimization parameters to account for setup errors of 2 mm and range uncertainties of 3.5%. Plan evaluation metrics encompassing the Heterogeneity Index (HI), Paddick Conformity Index (CIPaddick), Gradient Index (GI), and the R50% index to evaluate alterations in low-dose volume distribution. RESULTS: The comparative analysis between PSRS and traditional PBS treatment revealed no significant differences in plan outcomes, with both modalities demonstrating comparable target coverage. However, collimated apertures resulted in discernible improvements in dose conformity, dose fall-off, and reduced low-dose volume. CONCLUSIONS: This study underscores the advantageous impact of the aperture system on proton therapy, particularly in cases involving small target volumes.

Longitudinal Assessment of Quality of Life in Nasopharyngeal Cancer Patients Treated with Intensity-Modulated Proton Therapy and Volumetric Modulated Arc Therapy at Different Time Points.

PURPOSE: This retrospective cohort study aims to compare the quality of life (QoL) in patients with nasopharyngeal cancer (NPC) treated with intensity-modulated proton therapy (IMPT) versus volumetric modulated arc therapy (VMAT) at different time points. MATERIALS AND METHODS: We conducted a longitudinal assessment of QoL on 287 newly diagnosed NPC patients (IMPT: 41 and VMAT: 246). We collected outcomes of global QoL, functional QoL, C30 symptoms, and HN35 symptoms from EORTC QLQ-C30 and QLQ-HN35 questionnaires at pre-radiotherapy, during radiotherapy (around 40 Gy), 3 months post radiotherapy, and 12-months post radiotherapy (RT). The generalized estimating equation was utilized to interpret the group effect, originating from inherent group differences; time effect, attributed to RT effects over time; and interaction of the group and time effect. RESULTS: IMPT demonstrated superior mean dose reductions in 12 of the 16 organs at risk compared to VMAT, including a significant (>50%) reduction in the oral cavity and larynx. Both groups exhibited improved scores of global QoL, functional QoL, and C30 symptoms at 12 months post RT compared to the pre-RT status. Regarding global QoL and C30 symptoms, there was no interaction effect of group over time. In contrast, significant interaction effects were observed on functional QoL (p = 0.040) and HN35 symptoms (p = 0.004) during RT, where IMPT created an average of 7.5 points higher functional QoL and 10.7 points lower HN35 symptoms than VMAT. CONCLUSIONS: Compared to VMAT, dose reduction attributed to IMPT could translate into better functional QoL and HN35 symptoms, but the effect is time dependent and exclusively observed during the RT phase.

Optimizing linear energy transfer distribution in intensity-modulated proton therapy using the alternating direction method of multipliers.

Purpose: This study develop a novel linear energy transfer (LET) optimization method for intensity-modulated proton therapy (IMPT) with minimum monitor unit (MMU) constraint using the alternating direction method of multipliers (ADMM). Material and methods: The novel LET optimization method (ADMM-LET) was proposed with (1) the dose objective and the LET objective as the optimization objective and (2) the non-convex MMU threshold as a constraint condition. ADMM was used to solve the optimization problem. In the ADMM-LET framework, the optimization process entails iteratively solving the dose sub-problem and the LET sub-problem, simultaneously ensuring compliance with the MMU constraint. Three representative cases, including brain, liver, and prostate cancer, were utilized to evaluate the performance of the proposed method. The dose and LET distributions from ADMM-LET were compared to those obtained using the published iterative convex relaxation (ICR-LET) method. Results: The results demonstrate the superiority of ADMM-LET over ICR-LET in terms of LET distribution while achieving a comparable dose distribution. More specifically, for the brain case, the maximum LET (unit: keV/µm) at the optic nerve decreased from 5.45 (ICR-LET) to 1.97 (ADMM-LET). For the liver case, the mean LET (unit: keV/µm) at the clinical target volume increased from 4.98 (ICR-LET) to 5.50 (ADMM-LET). For the prostate case, the mean LET (unit: keV/µm) at the rectum decreased from 2.65 (ICR-LET) to 2.14 (ADMM-LET). Conclusion: This study establishes ADMM-LET as a new approach for LET optimization with the MMU constraint in IMPT, offering potential improvements in treatment outcomes and biological effects.

Impact of and interplay between proton arc therapy and range uncertainties in proton therapy for head-and-neck cancer.

Objective. Proton therapy reduces the integral dose to the patient compared to conventional photon treatments. However,in vivoproton range uncertainties remain a considerable hurdle. Range uncertainty reduction benefits depend on clinical practices. During intensity-modulated proton therapy (IMPT), the target is irradiated from only a few directions, but proton arc therapy (PAT), for which the target is irradiated from dozens of angles, may see clinical implementation by the time considerable range uncertainty reductions are achieved. It is therefore crucial to determine the impact of PAT on range uncertainty reduction benefits.Approach. For twenty head-and-neck cancer patients, four different treatment plans were created: an IMPT and a PAT treatment plan assuming current clinical range uncertainties of 3.5% (IMPT3.5%and PAT3.5%), and an IMPT and a PAT treatment plan assuming that range uncertainties can be reduced to 1% (IMPT1%and PAT1%). Plans were evaluated with respect to target coverage and organ-at-risk doses as well as normal tissue complication probabilities (NTCPs) for parotid glands (endpoint: parotid gland flow <25%) and larynx (endpoint: larynx edema).Main results. Implementation of PAT (IMPT3.5%-PAT3.5%) reduced mean NTCPs in the nominal and worst-case scenario by 3.2 percentage points (pp) and 4.2 pp, respectively. Reducing range uncertainties from 3.5% to 1% during use of IMPT (IMPT3.5%-IMPT1%) reduced evaluated NTCPs by 0.9 pp and 2.0 pp. Benefits of range uncertainty reductions subsequently to PAT implementation (PAT3.5%-PAT1%) were 0.2 pp and 1.0 pp, with considerably higher benefits in bilateral compared to unilateral cases.Significance. The mean clinical benefit of implementing PAT was more than twice as high as the benefit of a 3.5%-1% range uncertainty reduction. Range uncertainty reductions are expected to remain beneficial even after PAT implementation, especially in cases with target positions allowing for full leveraging of the higher number of gantry angles during PAT.

A fast and robust constraint-based online re-optimization approach for automated online adaptive intensity modulated proton therapy in head and neck cancer.

Objective. In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offlineTBre-planning) schedule, including extensive robustness analyses.Approach. The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offlineTBre-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations.Main results. For 14/67 repeat-CTs, offlineTBre-planning resulted in <50% probability ofD98%≥ 95% of the prescribed dose (Dpres) in one or both CTVs, which never happened with online re-optimization. With offlineTBre-planning, eight repeat-CTs had zero probability of obtainingD98%≥ 95%Dpresfor CTV7000, while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] (p< 10-5for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average.Significance. The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing.

SISS-MCO: large scale sparsity-induced spot selection for fast and fully-automated robust multi-criteria optimisation of proton plans.

Objective.Intensity modulated proton therapy (IMPT) is an emerging treatment modality for cancer. However, treatment planning for IMPT is labour-intensive and time-consuming. We have developed a novel approach for multi-criteria optimisation (MCO) of robust IMPT plans (SISS-MCO) that is fully automated and fast, and we compare it for head and neck, cervix, and prostate tumours to a previously published method for automated robust MCO (IPBR-MCO, van de Water 2013).Approach.In both auto-planning approaches, the applied automated MCO of spot weights was performed with wish-list driven prioritised optimisation (Breedveld 2012). In SISS-MCO, spot weight MCO was applied once for every patient after sparsity-induced spot selection (SISS) for pre-selection of the most relevant spots from a large input set of candidate spots. IPBR-MCO had several iterations of spot re-sampling, each followed by MCO of the weights of the current spots.Main results.Compared to the published IPBR-MCO, the novel SISS-MCO resulted in similar or slightly superior plan quality. Optimisation times were reduced by a factor of 6 i.e. from 287 to 47 min. Numbers of spots and energy layers in the final plans were similar.Significance.The novel SISS-MCO automatically generated high-quality robust IMPT plans. Compared to a published algorithm for automated robust IMPT planning, optimisation times were reduced on average by a factor of 6. Moreover, SISS-MCO is a large scale approach; this enables optimisation of more complex wish-lists, and novel research opportunities in proton therapy.

Cone beam CT-based adaptive intensity modulated proton therapy assessment using automated planning for head-and-neck cancer.

BACKGROUND: To assess the feasibility of CBCT-based adaptive intensity modulated proton therapy (IMPT) using automated planning for treatment of head and neck (HN) cancers. METHODS: Twenty HN cancer patients who received radiotherapy and had pretreatment CBCTs were included in this study. Initial IMPT plans were created using automated planning software for all patients. Synthetic CTs (sCT) were then created by deforming the planning CT (pCT) to the pretreatment CBCTs. To assess dose calculation accuracy on sCTs, repeat CTs (rCTs) were deformed to the pretreatment CBCT obtained on the same day to create deformed rCT (rCTdef), serving as gold standard. The dose recalculated on sCT and on rCTdef were compared by using Gamma analysis. The accuracy of DIR generated contours was also assessed. To explore the potential benefits of adaptive IMPT, two sets of plans were created for each patient, a non-adapted IMPT plan and an adapted IMPT plan calculated on weekly sCT images. The weekly doses for non-adaptive and adaptive IMPT plans were accumulated on the pCT, and the accumulated dosimetric parameters of two sets were compared. RESULTS: Gamma analysis of the dose recalculated on sCT and rCTdef resulted in a passing rate of 97.9% ± 1.7% using 3 mm/3% criteria. With the physician-corrected contours on the sCT, the dose deviation range of using sCT to estimate mean dose for the most organ at risk (OARs) can be reduced to (- 2.37%, 2.19%) as compared to rCTdef, while for V95 of primary or secondary CTVs, the deviation can be controlled within (- 1.09%, 0.29%). Comparison of the accumulated doses from the adaptive planning against the non-adaptive plans reduced mean dose to constrictors (- 1.42 Gy ± 2.79 Gy) and larynx (- 2.58 Gy ± 3.09 Gy). The reductions result in statistically significant reductions in the normal tissue complication probability (NTCP) of larynx edema by 7.52% ± 13.59%. 4.5% of primary CTVs, 4.1% of secondary CTVs, and 26.8% tertiary CTVs didn't meet the V95 > 95% constraint on non-adapted IMPT plans. All adaptive plans were able to meet the coverage constraint. CONCLUSION: sCTs can be a useful tool for accurate proton dose calculation. Adaptive IMPT resulted in better CTV coverage, OAR sparing and lower NTCP for some OARs as compared with non-adaptive IMPT.

Feasibility study of multiple-energy Bragg peak proton FLASH on a superconducting gantry with large momentum acceptance.

BACKGROUND: While the Bragg peak proton beam (BP) is capable of superior target conformity and organs-at-risk sparing than the transmission proton beam (TB), its efficacy in FLASH-RT is hindered by both a slow energy switching process and the beam current. A universal range shifter (URS) can pull back the high-energy proton beam while preserving the beam current. Meanwhile, a superconducting gantry with large momentum acceptance (LMA-SC gantry) enables fast energy switching. PURPOSE: This study explores the feasibility of multiple-energy BP FLASH-RT on the LMA-SC gantry. METHOD AND MATERIALS: A simultaneous dose and spot map optimization algorithm was developed for BP FLASH-RT treatment planning to improve the dose delivery efficiency. The URS was designed to be 0-27 cm thick, with 1 cm per step. BP plans using the URS were optimized using single-field optimization (SFO) and multiple-field optimization (MFO) for ten prostate cancer patients and ten lung cancer patients. The plan delivery parameters, dose, and dose rate metrics of BP plans were compared to those of TB plans using the parameters of the LMA-SC gantry. RESULTS: Compared to TB plans, BP plans significantly reduced MUs by 42.7% (P < 0.001) with SFO and 33.3% (P < 0.001) with MFO for prostate cases. For lung cases, the reduction in MUs was 56.8% (P < 0.001) with SFO and 36.4% (P < 0.001) with MFO. BP plans also outperformed TB plans by reducing mean normal tissue doses. BP-SFO plans achieved a reduction of 56.7% (P < 0.001) for prostate cases and 57.7% (P < 0.001) for lung cases, while BP-MFO plans achieved a reduction of 54.2% (P < 0.001) for the prostate case and 40.0% (P < 0.001) for lung cases. For both TB and BP plans, normal tissues in prostate and lung cases received 100.0% FLASH dose rate coverage (>40 Gy/s). CONCLUSIONS: By utilizing the URS and the LMA-SC gantry, it is possible to perform multiple-energy BP FLASH-RT, resulting in better normal tissue sparing, as compared to TB plans.

Incorporating variable RBE in IMPT optimization for ependymoma.

PURPOSE: To study the dosimetric impact of incorporating variable relative biological effectiveness (RBE) of protons in optimizing intensity-modulated proton therapy (IMPT) treatment plans and to compare it with conventional constant RBE optimization and linear energy transfer (LET)-based optimization. METHODS: This study included 10 pediatric ependymoma patients with challenging anatomical features for treatment planning. Four plans were generated for each patient according to different optimization strategies: (1) constant RBE optimization (ConstRBEopt) considering standard-of-care dose requirements; (2) LET optimization (LETopt) using a composite cost function simultaneously optimizing dose-averaged LET (LETd ) and dose; (3) variable RBE optimization (VarRBEopt) using a recent phenomenological RBE model developed by McNamara et al.; and (4) hybrid RBE optimization (hRBEopt) assuming constant RBE for the target and variable RBE for organs at risk. By normalizing each plan to obtain the same target coverage in either constant or variable RBE, we compared dose, LETd , LET-weighted dose, and equivalent uniform dose between the different optimization approaches. RESULTS: We found that the LETopt plans consistently achieved increased LET in tumor targets and similar or decreased LET in critical organs compared to other plans. On average, the VarRBEopt plans achieved lower mean and maximum doses with both constant and variable RBE in the brainstem and spinal cord for all 10 patients. To compensate for the underdosing of targets with 1.1 RBE for the VarRBEopt plans, the hRBEopt plans achieved higher physical dose in targets and reduced mean and especially maximum variable RBE doses compared to the ConstRBEopt and LETopt plans. CONCLUSION: We demonstrated the feasibility of directly incorporating variable RBE models in IMPT optimization. A hybrid RBE optimization strategy showed potential for clinical implementation by maintaining all current dose limits and reducing the incidence of high RBE in critical normal tissues in ependymoma patients.

Comparison of passive-scattered and intensity-modulated proton beam therapy of craniospinal irradiation with proton beams for pediatric and young adult patients with brain tumors.

PURPOSE: To investigate the dose stability of craniospinal irradiation based on irradiation method of proton beam therapy (PBT). METHODS AND MATERIALS: Twenty-four pediatric and young adult brain tumor patients (age: 1-24 years) were examined. Treatment method was passive-scattered PBT (PSPT) in 8 patients and intensity-modulated PBT (IMPT) in 16 patients. The whole vertebral body (WVB) technique was used in 13 patients whose ages were younger than 10, and vertebral body sparing (VBS) technique was used for the remaining 11 patients aged 10 and above. Dose stability of planning target volume (PTV) against set-up error was investigated. RESULTS: The minimum dose (Dmin) of IMPT was higher than that of PSPT (p = 0.01). Inhomogeneity index (INH) of IMPT was lower than that of PSPT (p = 0.004). When the irradiation field of the cervical spinal cord level (C level) was shifted, the maximum dose (Dmax) was lower in IMPT, and mean dose (Dmean) was higher than PSPT as movement became greater to the cranial-caudal direction (p = 0.000-0.043). Dmin was higher and INH was lower in IMPT in all directions (p = 0.000-0.034). When the irradiation field of the lumber spinal cord level (L level) was shifted, Dmax was lower in IMPT as movement became greater to the cranial direction (p = 0.000-0.028). Dmin was higher and INH was lower in IMPT in all directions (p = 0.000-0.022). CONCLUSIONS: The PTV doses of IMPT and PSPT are robust and stable in both anterior-posterior and lateral directions at both C level and L level, but IMPT is more robust and stable than PSPT for cranial-caudal movements. TRIAL REGISTRY: Clinical Trial Registration number: No. 04-03.

Comparative Effectiveness of Intensity-Modulated Proton Therapy Versus Intensity-Modulated Radiotherapy for Patients With Inoperable Esophageal Squamous Cell Carcinoma Undergoing Curative-Intent Concurrent Chemoradiotherapy.

INTRODUCTION: This study compared outcomes in patients with inoperable esophageal squamous cell carcinoma (ESCC) undergoing curative-intent concurrent chemoradiotherapy (CCRT) with intensity-modulated radiotherapy (IMRT) versus intensity-modulated proton therapy (IMPT). METHODS: The study encompassed a retrospective cohort analysis of patients with inoperable ESCC who underwent curative-intent CCRT from January 1, 2015, to December 31, 2020, with data sourced from the Taiwan Cancer Registry Database. In this study, both IMRT and IMPT delivered a total equivalent effective dose of approximately 5040 cGy in 28 fractions, accompanied by platinum-based chemotherapy administered as per established protocols. Multivariate Cox regression analyses were performed to assess oncologic outcomes, and statistical analyses were conducted, including inverse probability of treatment-weighted and Fine and Gray method for competing risks. RESULTS: The observed risks of ESCC-specific and all-cause mortality were lower in patients treated with IMPT compared with those treated with IMRT, with adjusted hazard ratios (aHRs) of 0.62 (95% confidence interval [CI]: 0.58-0.70) and 0.72 (95% CI: 0.66-0.80), respectively. IMPT also reduced grade 2 radiation-induced side effects, such as pneumonitis, fatigue, and major adverse cardiovascular events, with aHRs (95% CI) of 0.76 (0.66-0.82), 0.10 (0.07-0.14), and 0.70 (0.67-0.73), respectively. However, IMPT was associated with an increased risk of grade 2 radiation dermatitis, with aHR (95% CI) of 1.48 (1.36-1.60). No substantial differences were found in the incidence of radiation esophagitis between IMPT and IMRT when adjusting for covariates. CONCLUSION: IMPT seems to be associated with superiority over IMRT in managing patients with inoperable ESCC undergoing curative-intent CCRT, suggesting improved survival outcomes and reduced toxicity. These findings have significant implications for the treatment of ESCC, particularly when surgery is not an option.

Dose comparison of robustly optimized intensity modulated proton therapy (IMPT) vs IMRT and VMAT photon plans for testicular seminoma.

BACKGROUND: Patients with stage II seminoma have traditionally been treated with photons to the retroperitoneal and iliac space, which leads to a substantial dose bath to abdominal and pelvic organs at risk (OAR). As these patients are young and with excellent prognosis, reducing dose to OAR and thereby the risk of secondary cancer is of utmost importance. We compared IMPT to opposing IMRT fields and VMAT, assessing dose to OAR and both overall and organ-specific secondary cancer risk. MATERIAL AND METHODS: A comparative treatment planning study was conducted on planning CT-scans from ten patients with stage II seminoma, treated with photons to a 'dog-leg' field with doses ranging from 20 to 25 Gy and a 10 Gy sequential boost to the metastatic lymph node(s). Photon plans were either 3-4 field IMRT (Eclipse) or 1-2 arc VMAT (Pinnacle). Proton plans used robust (5 mm; 3.5%) IMPT (Eclipse), multi field optimization with 3 posterior fields supplemented by 2 anterior fields at the level of the iliac vessels. Thirty plans were generated. Mean doses to OARs were compared for IMRT vs IMPT and VMAT vs IMPT. The risk of secondary cancer was calculated according to the model described by Schneider, using excess absolute risk (EAR, per 10,000 persons per year) for body outline, stomach, duodenum, pancreas, bowel, bladder and spinal cord. RESULTS: Mean doses to all OARs were significantly lower with IMPT except similar kidney (IMRT) and spinal cord (VMAT) doses. The relative EAR for body outline was 0.59 for IMPT/IMRT (p < .05) and 0.33 for IMPT/VMAT (p < .05). Organ specific secondary cancer risk was also lower for IMPT except for pancreas and duodenum. CONCLUSION: Proton therapy reduced radiation dose to OAR compared to both IMRT and VMAT plans, and potentially reduce the risk of secondary cancer both overall and for most OAR.

An orthogonal matching pursuit optimization method for solving minimum-monitor-unit problems: Applications to proton IMPT, ARC and FLASH.

BACKGROUND: The intensities (i.e., number of protons in monitor unit [MU]) of deliverable proton spots need to be either zero or meet a minimum-MU (MMU) threshold, which is a nonconvex problem. Since the dose rate is proportionally associated with the MMU threshold, higher-dose-rate proton radiation therapy (RT) (e.g., efficient intensity modulated proton therapy (IMPT) and ARC proton therapy, and high-dose-rate-induced FLASH effect needs to solve the MMU problem with larger MMU threshold, which however makes the nonconvex problem more difficult to solve. PURPOSE: This work will develop a more effective optimization method based on orthogonal matching pursuit (OMP) for solving the MMU problem with large MMU thresholds, compared to state-of-the-art methods, such as alternating direction method of multipliers (ADMM), proximal gradient descent method (PGD), or stochastic coordinate descent method (SCD). METHODS: The new method consists of two essential components. First, the iterative convex relaxation (ICR) method is used to determine the active sets for dose-volume planning constraints and decouple the MMU constraint from the rest. Second, a modified OMP optimization algorithm is used to handle the MMU constraint: the non-zero spots are greedily selected via OMP to form the solution set to be optimized, and then a convex constrained subproblem is formed and can be conveniently solved to optimize the spot weights restricted to this solution set via OMP. During this iterative process, the new non-zero spots localized via OMP will be adaptively added to or removed from the optimization objective. RESULTS: The new method via OMP is validated in comparison with ADMM, PGD and SCD for high-dose-rate IMPT, ARC, and FLASH problems of large MMU thresholds, and the results suggest that OMP substantially improved the plan quality from PGD, ADMM and SCD in terms of both target dose conformality (e.g., quantified by max target dose and conformity index) and normal tissue sparing (e.g., mean and max dose). For example, in the brain case, the max target dose for IMPT/ARC/FLASH was 368.0%/358.3%/283.4% respectively for PGD, 154.4%/179.8%/150.0% for ADMM, 134.5%/130.4%/123.0% for SCD, while it was <120% in all scenarios for OMP; compared to PGD/ADMM/SCD, OMP improved the conformity index from 0.42/0.52/0.33 to 0.65 for IMPT and 0.46/0.60/0.61 to 0.83 for ARC. CONCLUSIONS: A new OMP-based optimization algorithm is developed to solve the MMU problems with large MMU thresholds, and validated using examples of IMPT, ARC, and FLASH with substantially improved plan quality from ADMM, PGD, and SCD.