Intensity Modulated Proton Therapy Plans Research Articles

Feasibility and constraints of Bragg peak FLASH proton therapy treatment planning.

FLASH proton therapy (FLASH-PT) requires ultra-high dose rate (≥40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modulated proton therapy (IMPT). Bragg peak FLASH-PT and IMPT treatment plans were generated for bone (n=3), brain (n=3), and lung (n=4) targets using the MIROpt research treatment planning system and the Conformal FLASH library developed by Applications SA from the open-source version of UCLouvain. FLASH-PT beams were simulated using monoenergetic spot-scanned protons traversing through a conformal energy modulator, a range shifter, and an aperture. A dose rate constraint of ≥ 40 Gy/s was included in each FLASH-PT plan optimisation. Space limitations in the FLASH-PT adapted beam nozzle imposed a maximum target width constraint, excluding 4 cases from the study. FLASH-PT plans did not satisfy the imposed target dose constraints (D95% ≥ 95% and D2%≤ 105%) but achieved clinically acceptable doses to organs at risk (OARs). IMPT plans adhered to all target and OAR dose constraints. FLASH-PT plans showed a reduction in both target homogeneity (p < 0.001) and dose conformity (non-significant) compared to IMPT. Without accounting for a sparing effect, IMPT plans were superior in target coverage, dose conformity, target homogeneity, and OAR sparing compared to FLASH-PT. Further research is warranted in treatment planning optimisation and beam delivery for clinical implementation of Bragg peak FLASH-PT.

Dosimetric comparison of advanced radiation techniques for scalp-sparing in low-grade gliomas.

Alopecia causes significant distress for patients and negatively impacts quality of life for low-grade glioma (LGG) patients. We aimed to compare and evaluate variations in dose distribution for scalp-sparing in LGG patients with proton therapy and photon therapy, namely intensity-modulated proton therapy (IMPT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT). This retrospective study utilized adataset comprising imaging data from 22patients with LGG who underwent postoperative radiotherapy. Treatment plans were generated for each patient with scalp-optimized (SO) approaches and scalp-non-optimized (SNO) approaches using proton techniques and photons techniques; all plans adhered to the same dose constraint of delivering atotal radiation dose of 54.04 Gy to the target volume. All treatment plans were subsequently analyzed. All the plans generated in this study met the dose constraints for the target volume and OARs. The SO plans resulted in reduced maximum scalp dose (Dmax), mean scalp dose (Dmean), and volume of the scalp receiving 30 Gy (V30) and 40 Gy (V40) compared with SNO plans in all radiation techniques. Among all radiation techniques, the IMPT plans exhibited superior performance compared to other plans for dose homogeneity as for SO plans. Also, IMPT showed lower values for Dmean and Dmax than all photon radiation techniques. Our study provides evidence that the SO approach is afeasible technique for reducing scalp radiation dose. However, it is imperative to conduct prospective trials to assess the benefits associated with this approach.

Immune system dose with proton vs photon radiotherapy for treatment of locally advanced NSCLC

PurposeEmerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution. MethodsData were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et. al. (PMID: 34944813) and Ladbury et. al’s (PMID: 31175902) models were abstracted. Paired t-tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans. ResultsIMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE versus 4.99 Gy, p<0.001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE versus 7.60 Gy, p<0.002). Modeled 2-year-overall-survival was significantly longer with IMPT than IMRT (median 71% vs. 63%; p = 0.03). ConclusionIMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.

Dosimetric impact of bone marrow sparing for robustly optimized IMPT for locally advanced cervical cancer

Background and purposeTo investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC). Materials and methodsTwenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated. ResultsA total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7–21.6] GyRBE , which reduced to 12.0 [10.0–14.0] GyRBE with maximum BMS. The mean OAR dose [range] increased modestly for 1 GyRBE BMS: 0.2 [0.0 – 0.6] GyRBE for bladder, 0.3 [-0.2 – 0.7] GyRBE for rectum, 0.4 [0.1 – 0.8] GyRBE for small bowel, and 0.2 [-0.2 – 0.4] GyRBE for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 – 6.7] GyRBE for bladder, 5.8 [1.8 – 12.4] GyRBE for rectum, 3.9 [1.6 – 5.9] GyRBE for small bowel, and 2.7 [0.6 – 5.9] GyRBE for sigmoid. ConclusionAchieving 1 GyRBE BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks.

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

BackgroundTo assess the feasibility of CBCT-based adaptive intensity modulated proton therapy (IMPT) using automated planning for treatment of head and neck (HN) cancers.MethodsTwenty 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.ResultsGamma 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.ConclusionsCTs 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.

Generation and evaluation of anatomy-preserving virtual CT for online adaptive proton therapy.

Daily CTs generated by CBCT correction are required for daily replanning in online-adaptive proton therapy (APT) to effectively deal with inter-fractional changes. Out of the currently available methods, the suitability of a daily CT generation method for proton dose calculation also depends on the anatomical site. We propose an anatomy-preserving virtual CT (APvCT) method as a hybrid method of CBCT correction, which is especially suitable for large anatomy deformations. The accuracy of the hybrid method was assessed by comparison with the corrected CBCT (cCBCT) and virtual CT (vCT) methods in the context of online APT. Seventy-one daily CBCTs of four prostate cancer patients treated with intensity modulated proton therapy (IMPT) were converted to daily CTs using cCBCT, vCT, and the newly proposed APvCT method. In APvCT, planning CT (pCT) were mapped to CBCT geometry using deformable image registration with boundary conditions on controlling regions of interest (ROIs) created with deep learning segmentation on cCBCT. The relative frequency distribution (RFD) of HU, mass density and stopping power ratio (SPR) values were assessed and compared with the pCT. The ROIs in the APvCT and vCT were compared with cCBCT in terms of Dice similarity coefficient (DSC) and mean distance-to-agreement (mDTA). For each patient, a robustly optimized IMPT plan was created on the pCT and subsequent daily adaptive plans on daily CTs. For dose distribution comparison on the same anatomy, the daily adaptive plans on cCBCT and vCT were recalculated on the corresponding APvCT. The dose distributions were compared in terms of isodose volumes and 3D global gamma-index passing rate (GPR) at γ(2%, 2mm) criterion. For all patients, no noticeable difference in RFDs was observed amongst APvCT, vCT, and pCT except in cCBCT, which showed a noticeable difference. The minimum DSC value was 0.96 and 0.39 for contours in APvCT and vCT respectively. The average value of mDTA for APvCT was 0.01cm for clinical target volume and ≤0.01cm for organs at risk, which increased to 0.18cm and ≤0.52cm for vCT. The mean GPR value was 90.9%, 64.5%, and 67.0% for APvCT versus cCBCT, vCT versus cCBCT, and APvCT versus vCT, respectively. When recalculated on APvCT, the adaptive cCBCT and vCT plans resulted in mean GPRs of 89.5±5.1% and 65.9±19.1%, respectively. The mean DSC values for 80.0%, 90.0%, 95.0%, 98.0%, and 100.0% isodose volumes were 0.97, 0.97, 0.97, 0.95, and 0.91 for recalculated cCBCT plans, and 0.89, 0.88, 0.87, 0.85, and 0.81 for recalculated vCT plans. Hausdorff distance for the 100.0% isodose volume in some cases of recalculated cCBCT plans on APvCT exceeded 1.00cm. APvCT contours showed good agreement with reference contours of cCBCT which indicates anatomy preservation in APvCT. A vCT with erroneous anatomy can result in an incorrect adaptive plan. Further, slightly lower values of GPR between the APvCT and cCBCT-based adaptive plans can be explained by the difference in the cCBCT's SPR RFD from the pCT.

Streamlined pin-ridge-filter design for single-energy proton FLASH planning.

FLASH radiotherapy (FLASH-RT) with ultra-high dose rate has yielded promising results in reducing normal tissue toxicity while maintaining tumor control. Planning with single-energy proton beams modulated by ridge filters (RFs) has been demonstrated feasible for FLASH-RT. This study explored the feasibility of a streamlined pin-shaped RF (pin-RF) design, characterized by coarse resolution and sparsely distributed ridge pins, for single-energy proton FLASH planning. An inverse planning framework integrated within a treatment planning system was established to design streamlined pin RFs for single-energy FLASH planning. The framework involves generating a multi-energy proton beam plan using intensity-modulated proton therapy (IMPT) planning based on downstream energy modulation strategy (IMPT-DS), followed by a nested pencil-beam-direction-based (PBD-based) spot reduction process to iteratively reduce the total number of PBDs and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs and the single-energy beam configurations for IMPT planning with pin-RFs (IMPT-RF). This framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model. The FLASH dose was then compared to the reference dose of a conventional IMPT plan to measure the clinical benefit of the FLASH planning technique. The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity (conformity index of <1.2), with minimal changes in V7Gy and V7.4Gy for the lung (<3%) and small increases in maximum doses (Dmax) for other normal structures (<3.4Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to nearly 33% were observed in Dmax for the normal structures situated in the high-to-moderate-dose regions, while negligible changes were found in Dmax for normal structures in low-dose regions. Positive clinical benefits were seen in comparing the FLASH doses to the reference doses, with notable reductions of 21.4%-33.0% in Dmax for healthy tissues in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for normal tissues were observed, such as increased lung V7Gy and V7.4Gy (up to 17.6%). A streamlined pin-RF design was developed and its effectiveness for single-energy proton FLASH planning was validated, revealing positive clinical benefits for the normal tissues in the high dose regions. The coarsened design of the pin-RF demonstrates potential advantages, including cost efficiency and ease of adjustability, making it a promising option for efficient production.

Optically stimulated luminescence dosimeters for simultaneous measurement of point dose and dose-weighted LET in an adaptive proton therapy workflow.

To demonstrate the suitability of optically stimulated luminescence detectors (OSLDs) for accurate simultaneous measurement of the absolute point dose and dose-weighted linear energy transfer (LETD) in an anthropomorphic phantom for experimental validation of daily adaptive proton therapy. A clinically realistic intensity-modulated proton therapy (IMPT) treatment plan was created based on a CT of an anthropomorphic head-and-neck phantom made of tissue-equivalent material. The IMPT plan was optimized with three fields to deliver a uniform dose to the target volume covering the OSLDs. Different scenarios representing inter-fractional anatomical changes were created by modifying the phantom. An online adaptive proton therapy workflow was used to recover the daily dose distribution and account for the applied geometry changes. To validate the adaptive workflow, measurements were performed by irradiating Al2O3:C OSLDs inside the phantom. In addition to the measurements, retrospective Monte Carlo simulations were performed to compare the absolute dose and dose-averaged LET (LETD) delivered to the OSLDs. The online adaptive proton therapy workflow was shown to recover significant degradation in dose conformity resulting from large anatomical and positioning deviations from the reference plan. The Monte Carlo simulations were in close agreement with the OSLD measurements, with an average relative error of 1.4% for doses and 3.2% for LETD. The use of OSLDs for LET determination allowed for a correction for the ionization quenched response. The OSLDs appear to be an excellent detector for simultaneously assessing dose and LET distributions in proton irradiation of an anthropomorphic phantom. The OSLDs can be cut to almost any size and shape, making them ideal for in-phantom measurements to probe the radiation quality and dose in a predefined region of interest. Although we have presented the results obtained in the experimental validation of an adaptive proton therapy workflow, the same approach can be generalized and used for a variety of clinical innovations and workflow developments that require accurate assessment of point dose and/or average LET.

Validation of Fully Automated Robust Multicriterial Treatment Planning for Head and Neck Cancer IMPT

Our purpose was to compare robust intensity modulated proton therapy (IMPT) plans, automatically generated with wish-list-based multicriterial optimization as implemented in Erasmus-iCycle, with manually created robust clinical IMPT plans for patients with head and neck cancer. Thirty-three patients with head and neck cancer were retrospectively included. All patients were previously treated with a manually created IMPT plan with 7000 cGy dose prescription to the primary tumor (clinical target volume [CTV]7000) and 5425 cGy dose prescription to the bilateral elective volumes (CTV5425). Plans had a 4-beam field configuration and were generated with scenario-based robust optimization (21 scenarios, 3-mm setup error, and ±3% density uncertainty for the CTVs). Three clinical plans were used to configure the Erasmus-iCycle wish-list for automated generation of robust IMPT plans for the other 30 included patients, in line with clinical planning requirements. Automatically and manually generated IMPT plans were compared for (robust) target coverage, organ-at-risk (OAR) doses, and normal tissue complication probabilities (NTCP). No manual fine-tuning of automatically generated plans was performed. For all automatically generated plans, voxel-wise minimum D98% values for the CTVs were within clinical constraints and similar to manual plans. All investigated OAR parameters were favorable in the automatically generated plans (all P < .001). Median reductions in mean dose to OARs went up to 667 cGy for the inferior pharyngeal constrictor muscle, and median reductions in D0.03cm3 in serial OARs ranged up to 1795 cGy for the spinal cord surface. The observed lower mean dose in parallel OARs resulted in statistically significant lower NTCP for xerostomia (grade ≥2: 34.4% vs 38.0%; grade ≥3: 9.0% vs 10.2%) and dysphagia (grade ≥2: 11.8% vs 15.0%; grade ≥3: 1.8% vs 2.8%). Erasmus-iCycle was able to produce IMPT dose distributions fully automatically with similar (robust) target coverage and improved OAR doses and NTCPs compared with clinical manual planning, with negligible hands-on planning workload.

Treatment planning comparison for head and neck cancer between photon, proton, and combined proton–photon therapy – From a fixed beam line to an arc

Background and purposeThis study investigates whether combined proton–photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments. Material and methodsFive HNC patients with a planning CT and multiple (4–7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared. ResultsThe target coverage for CPPT without adaptation is insufficient (average V95%=88.4 %), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5 %) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are −2.7 %/-3.4 %/-5.0 % for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are + 0.8 %/-0.9 %/-4.3 %. ConclusionCPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined.

Proton Based Stereotactic Radiotherapy for Skull Base Patients: Dosimetric Comparison to 4 Modern Radiation Treatment Modalities

Re-irradiation with ablative doses to a smaller target volume and strict critical structure constraint is a challenge for modern radiation planning and delivery systems. Several advanced radiation treatment techniques can be used for fractionated stereotactic ablative radiosurgery (FSRS) in select patients with unresectable recurrent head and neck tumors. In this study, in order to better understand the dosimetry advantage of each technique, we compare the stereotactic treatment plans of our new small spot size Hitachi proton treatment unit to those of CyberKnife stereotactic radiosurgery (CK), Gamma Knife radiosurgery (GK), volumetric modulated arc therapy (VMAT), and MR Linac radiotherapy (MRL). Ten FSRS skull base patients treated at our institution using VMAT (n = 5) or GK (n = 5) techniques. Intensity-modulated proton therapy (IMPT) plans were created in Raystation using Monte Carlo dose calculation algorithm. VMAT, CK, GK and MRL plans were generated in RayStation, Accuray Precision, Leksell Gamma Plan, and Monaco treatment planning systems, separately. Planning goals were to achieve the best target coverage of prescribed dose without compromising the critical organs at risk dose volume constraints of the clinical treatment plans. Plans were compared based on percent CTV coverage, Paddick conformity index (PCI), gradient index (GI, V50/V100), dose homogeneity index (HI, (D2-D98)/D50), low dose bath volume (LDBV, ratio of total volume irradiated between 20% and 50% prescription dose and the target volume), beam-on-time (BOT), and mean/maximum doses to brainstems. The median target volume was 15.5 cm3 (range 1.0 - 36.23 cm3). The prescription was 45 Gy in 5 fractions for VMAT patients, and 21 - 27 Gy in 3 fractions for GK patients. The comparison of the treatment plans of these 5 delivery modalities was shown in table. All techniques achieved comparable CTV coverage. GI was superior for GK plans and outstanding in CK and IMPT plans. IMPT plans were also outstanding in regard to BOT and PCI. Significantly improved HI, LDBV and brainstem mean doses were achieved in IMPT plans. For adjacent brainstem and other OARs, maximum doses were comparable among all techniques. In these five advanced radiation therapy modalities, proton therapy SBRT showed dosimetric advantage over other modalities to spare nearby OARs without sacrifice of target coverage. Further studies are needed to utilize this clinical benefit and investigate plan robustness.

Dosimetric Comparison of Automated Non-Coplanar Volumetric-Modulated Arc Therapy and Intensity-Modulated Proton Therapy in Angiosarcoma of the Scalp

Angiosarcoma of the scalp (AS) is a rare tumor and has often been treated by total scalp irradiation (TSI). TSI is a challenging technique because of the target close to the organs at risks (OARs), located in the skin surface, and helmet-shape of the target. We performed the dosimetric comparison of automated non-coplanar volumetric-modulated arc therapy (HA) and intensity-modulated proton therapy (IMPT) in TSI for AS. A planning study was performed on 20 patients with AS. The clinical target volume (CTV) 1 and CTV2 were defined as gross tumor volume with margin and entire scalp, respectively. For HA, planning target volume (PTV) 1 and PTV2 were defined as CTV1 and CTV2 with 5-mm margins, respectively. For IMPT, robust optimization was utilized which accounted for a 5-mm setup and a 3.5% range uncertainty and dose was prescribed to CTV1 robust and CTV2 robust. The prescription doses were 70 Gy and 56 Gy in 35 fractions to PTV1 (CTV1 robust) and PTV2 (CTV2 robust), respectively, using the simultaneous integrated boost technique. The HA plan was performed using a 6-MV photon beam machine and a 1-cm thick virtual bolus. The HA plan included three half non-coplanar and one full coplanar arc fields. The HA plan used collimator angles of 15°, 60°, 15°, and 120° in the beam with couch rotations of 0°, 45°, 90°, and 315°, respectively. The IMPT plan was performed using a compact proton beam machine dedicated to pencil beam scanning. The IMPT plan used gantry angles of 70°, 150°, 70°, 150°, and 30° in the beam with couch rotations of 0°, 0°, 180°, 180°, and 270°, respectively. The IMPT plan was optimized assuming a relative biological effectiveness of 1.1. The dose distribution and dosimetric parameters for each plan were evaluated. All plans met the goals within the acceptable range in target volume coverage, conformity, and homogeneity. Table shows the dosimetric parameters of OARs in HA and IMPT plans. The doses receiving 0.1 cc of the volume for hippocampus, optic passway, eye, and lens in the IMPT plan were significantly lower than those in the HA plan. The IMPT plan showed a significant reduction in the percentage of brain volume receiving at least 5 Gy (V5 Gy) compared to the HA plan, while the HA plan showed a significant reduction of V10 Gy - V60 Gy and mean brain dose compared to the IMPT plan. The HA plan provided a shorter beam-on time (184 ± 9 s) than did the IMPT plan (446 ± 49 s). The HA and IMPT plans demonstrated different strengths with respect to OARs sparing.

RBE Model Based Proton Planning of Stereotactic Body Radiotherapy for Spine Metastasis: A Dosimetric Analysis

Study of proton stereotactic body radiotherapy (SBRT) for spine metastasis is limited, largely due to theorized increased risk of spinal cord injury with higher end of range RBE. Though the 1.1 RBE constant for proton beam is clinically used, data indicate that proton RBE is variable and dependent on technical-, tissue-, and patient-factors. To better understand safety of proton SBRT for spine metastasis, we performed a dosimetric analysis comparing plans delivered by photon robotic technique versus intensity modulated proton therapy (IMPT) and accounting for RBE weighted dose. A total of 9 patients with spine metastasis (3 cervical, 3 thoracic, 3 lumbar) previously treated with a frameless robotic radiosurgery system (Sunnyvale, CA) were identified. Each level contained a case with paraspinal extension, a reirradiation case, and a case with epidural extension (Bilsky grade ≥1c) as such cases in current practice often require planning target volume (PTV) under-coverage in order to meet organ at risk (OAR) dose constraints. Given these challenges, selected cases were clinically treated with 30 Gy in 5 fractions despite an institutional preference of further dose escalation. Comparative IMPT plans were generated using 30 GyE in 5 fractions and 1.1 RBE constant. IMPT plans were then made using 1.1 RBE and 45 GyE in 5 fractions: a prescription dose associated with a 2-yr local control rate of 95% on prior tumor control probability modelling. A treatment planning system was used to separately generate and optimize RBE weighted plans based on Carabe-, McNamara-, or Wedenberg models for prescription doses of 30 GyE and 45 GyE. IMPT plans used robust optimization parameters of ± 3.5% range and 2-mm setup uncertainties. PTV coverage and OAR sparing were compared using Wilcoxon signed-rank tests. PTV coverage (PTV volume receiving prescription dose) was significantly improved with IMPT at 30 GyE / 1.1 RBE (median PTV V30: 93%) compared to CK at 30 Gy (median: 88.5%, p = .02). PTV coverage was similar when comparing CK at 30 Gy with IMPT at 45 GyE / 1.1 RBE (median PTV V45: 90%, p = .23). When comparing maximum spinal cord dose (cord Dmax), there was improved OAR sparing with IMPT at 30 GyE / 1.1 RBE (median: 17.6 GyE, p = .04) and IMPT at 45 GyE / 1.1 RBE (median: 16.1 GyE, p = .04) when respectively compared to CK at 30 Gy (median: 18 Gy). No difference was seen in cord Dmax when comparing CK at 30 Gy to RBE weighted plans at 30 GyE using Carabe- (median: 17.3 GyE, p = .22), McNamara- (median: 17.4 GyE, p = .22), or Wedenberg (median: 17.0 GyE, p = .08) model. Median cord Dmax values for RBE weighted plans at 45 GyE were numerically equivalent. The average increase in variable RBE plans' maximum dose compared to fixed RBE plans was 105.3% +/- 3.5%. We report the first dosimetric analysis of proton SBRT for spine metastasis using variable RBE dose models. IMPT may provide improved target coverage and better sparing of adjacent OARs compared to CK though fixed RBE computation may underestimate maximum dose to adjacent OARs.

Mitigation of Dosimetric Uncertainty in MRI-Based Proton Planning Using Spot-Scanning Proton Arc (SPArc) Technique

MRI-based synthetic CT (SCT) images created using generative adversarial network (GAN) have been demonstrated to be feasible for intensity-modulated proton therapy (IMPT) planning. However, dose calculation accuracy can be uncertain in some regions within/near the target of head and neck patients due to the local CT number estimation error or sharp dose fall-off. This study investigated the feasibility of using the SPArc technique to mitigate such dosimetric uncertainty. A GAN using a 3D U-net as the generator and a 6-layer 3D convolutional neural network as the discriminator was trained with T1-weighted MR-CT image pairs from 162 nasopharyngeal carcinoma patients (14 for validation). The generator was used to generate SCT images from MR images for 7 test patients. For each test patient, the CT image was used to create a SPArc plan and an IMPT plan with the same clinical objectives. The SPArc plans (control point frequency sampling, arc trajectory, etc.) were optimized using a previously developed iterative approach. The dose distributions of both SPArc plans and IMPT plans were re-calculated on the SCT images and compared to the one calculated on the CT images. The dosimetric uncertainty was quantified using the gamma index. The 2%/2mm and 3%/3mm passing rates for SPArc plans were (96.9¡À2.7) % and (98.6¡À1.5) %, while the passing rates for IMPT plans were (94.0¡À3.9) % and (96.4+2.9) %. A significant reduction in dosimetric uncertainty was identified for SPArc plans (p ¡Ü0.021). Table 1 shows the passing rates for the 7 test individuals. SPArc can mitigate the uncertainty of dose calculation in MRI-based proton planning. Further research needs to validate these findings on a larger patient cohort. The study paves the road map for using MRI for SPArc planning.

Dosimetric and Clinical Results of a Volumetric-Based Skin-Sparing Planning Technique for Patients Treated to the Breast and Chest Wall with Pencil Beam Scanning Proton Therapy

Given clinical concerns for more brisk acute skin toxicity with proton compared with photon RT due to differences in the energy deposition properties, our institution implemented a novel volumetric skin-sparing planning technique (SSPT) for intensity modulated proton therapy (IMPT) for patients treated to the breast or chest wall (CW). This study evaluates SSPT dosimetry and the hypothesis that a SSPT will reduce acute dermatitis during IMPT to the breast and CW. Prior to the development of a consensus technique, skin dose evaluation in IMPT plans was limited to mitigation of skin hot spots and cropping off the skin surface by 3mm for CW and 5mm for intact breast targets (except indications for deliberate skin dosing). In January 2022 our center added volumetric-based skin sparing objectives in addition to hot-spot evaluation as a SSPT. A skin evaluation structure (skin-eval) was defined as a skin rind of 3 mm for CW and 5 mm for intact breast within 5mm of the CTV, bound by the patient's surface. The SSPT incorporated an objective to limit the volume of skin-eval receiving 95% of the prescription dose or more (V95%Rx) to ideally <50% (goal<60%) while still prioritizing CTV coverage and robustness. We compared target coverage, robustness, and skin-eval dosimetry as well as acute on-treatment skin toxicity in patients treated with and without incorporation of this SSPT. Patients with skin/dermal lymphatic invasion or inflammatory breast cancer were excluded. 84 patients who were planned to receive breast or CW IMPT were included (43 planned without and 41 with the SSPT). There was no difference in percentages of patients treated to the intact breast/CW/immediate CW reconstruction between the groups (37%/23%/40% without and 34%/27%/39% with SSPT, p>0.05). Mean skin-evalV95%Rx was 72% vs. 30%, p<0.0001, for those treated without vs. with a SSPT. Maximum %Rx to the skin volume of 0.03 cc, 0.3cc, and 1cc, was higher in patients treated without compared to those with a SSPT (103.1% vs. 101.5%; 101.3% vs. 100.4%; and 101.8% vs. 99.7% (all p=<0.0001)), respectively. There was a small statistical difference in the mean CTV V97.5%Rx in patients treated without vs. with the SSPT (97.8% vs. 96.5%, p=0.0003). Patients planned utilizing the SSPT demonstrated reduced rates of Grade 1 breast pain at Week 2 (12% vs. 33%, p=0.0424) and Grade 2 and 3 dermatitis at Week 5 (grade 2 38% vs. 42%; grade 3, 0% vs. 11%, p=0.0016). There were numerically more patients requiring a treatment break or not completing full intended prescription (4 vs. 1) in the pre-SSPT cohort. A volumetric-based SSPT appears to reduce the frequency of brisk onset dermatitis and near-end of RT significant dermatitis while still maintaining acceptable target coverage and robustness in patients receiving IMPT to the breast and CW.

Proton Single-Energy Bragg-Peak FLASH Using Clinical Systems Can Achieve IMPT-Equivalent Plan Quality for Breast and Prostate Cancers

Most current proton FLASH-RT studies focus on transmission proton techniques. In this study, we propose a novel method for achieving FLASH dose rate in hypofractionated proton radiotherapy using the Bragg peak of a single-energy proton beam. The dosimetric characteristics using this novel technique for proton pencil beam scanning (PBS) stereotactic body radiation therapy (SBRT) of prostate and breast cancers were first investigated based on the clinically available cyclotron beam parameters. This novel approach uses the distal tracking technique that enables PBS Bragg-peak of the highest proton energy to adapt to the target distally. Positioning of the Bragg peak at different depths is achieved using a universal range shifter and range compensator. To investigate the feasibility of this approach, we developed an in-house treatment planning platform for intensity-modulated proton therapy (IMPT) delivery and performed dosimetric studies on prostate and breast SBRT cases previously treated with conventional proton PBS technique. FLASH plans were generated using a similar clinical beam arrangement to deliver 40 Gy (RBE) in 5 fractions. Dose metrics were compared between the clinical and FLASH plans. Dose-rate volume histograms (DRVH) were also calculated to investigate the 40 Gy/s coverage (V40 Gy/s) of organs-at-risk (OARs) for FLASH plans. The distal tracking can precisely stop the Bragg peak at the target distal edge, and Bragg peak plans achieved tumor coverage and dose conformality equivalent to IMPT plans. The clinical IMPT plans yielded slightly superior target dose uniformity -CTV Dmax of FLASH plans was 10% higher for prostate and 2% higher for breast. There was no significant difference between the clinical and FLASH plans in dose metrics for major OARs, including rectum, large bowel, heart, and lung. Higher maximal doses to femoral heads (∼2 Gy) and urethra (∼6 Gy) were observed in prostate FLASH plans than in the clinical plans but were still within clinically accepted dose limits. The V40 Gy/s for OARs were >90% for prostate FLASH plans and >76.5% for breast FLASH plans. The proposed single-energy Bragg-peak FLASH technique eliminates exit dose associated with transmission proton FLASH and can still yield comparable plan quality and OAR sparing while preserve sufficient FLASH dose rate coverage for prostate and breast proton SBRT. This study demonstrates the potential application of Bragg peaks for highly conformal FLASH-RT using clinical cyclotron systems to treat prostate and breast cancer patients, which moves towards clinical application.

Five-Fraction Proton Therapy for Chordomas and Chondrosarcomas of the Skull Base: Preliminary Results of a Prospective Series

To describe the first series of patients with clival chordomas and chondrosarcomas treated with extremely hypofractionated proton therapy in a single institution with focus on acute tolerance and dosimetric parameters. A total of 11 consecutive patients with biopsy proven chordomas and chondrosarcomas were prospectively included in a five-fraction proton therapy protocol between June 2022 and January 2023. The inclusion criteria for this protocol were: Age > 18 yo., Karnofsky Performance Status (KPS) ≥ 70%, absence of metastases, no previous radiation courses, clinical target volume (CTV) up to 50 cc and CTV location relative to organs at risk that allowed compliance with the necessary dose restrictions for hypofractionated treatments in 5 fractions, according to the international guidelines. Treatment was delivered with a Proteus®ONE cyclotron using Pencil Beam Scanning (PBS) Intensity-Modulated Proton Therapy (IMPT). Patient setup was performed with CBCT imaging at isocenter and X-Ray obliques, allowing a robust planning with 1 mm setup uncertainty and 3.5% range uncertainty. IMPT plans were obtained with RayStation employing 4 to 6 non-coplanar beams. In 7 patients' apertures were used in 2 of the beams, to reduce lateral penumbra and to optimize dose gradient. A total of 11 patients (7 males and 5 females) with an age range between 29 and 79 yo, were included. 6 patients with classic chordomas and 5 patients with grade I-II chondrosarcomas were treated with a total dose of 37.5 GyRBE and 35 GyRBE, respectively, in 5 daily fractions. All the patients had received previous surgery with complete resection in 2 patients, subtotal resection in 7 patients and partial resection in 2 patients. Most common symptoms at diagnosis were diplopia and headache and baseline median KPS after surgery was 90% (70 - 100%). Median CTV was 30.62 cc (10.56 - 47.47 cc). Median CTV coverage was V95% = D95.5%. Median maximal dose for the brainstem was 26.5 GyRBE (30 - 24.7 GyRBE) and for the optic pathway was 20.7 GyRBE (8.9 - 23.6 GyRBE). Median follow-up was 3 months (8 - 1 months). Acute toxicity during follow-up was mild, with grade I - II headache (64%), grade I asthenia (45%), grade I nausea (27%), grade I dysphagia (18%) and reversible alopecia (45%). Only one patient showed nystagmus and mild loss of strength in left lower limb related with an ischemic brainstem lesion, in a low dose region, not clearly radiation related. 8 patients had a 3-month follow-up MRI with no signs of progression. Five-fraction proton therapy for the treatment of clival chordomas and chondrosarcomas is dosimetrically feasible and well tolerated for selected patients. Proton therapy remains a limited resource, consequently, reducing treatment time can have significant financial and psychosocial implications. Longer follow up is needed to validate these results.

Investigation of the Relationship between Aperture Use for Treating Small and Shallow Brain Lesions in Proton Therapy with Different Spot Size Variations in Three Proton Therapy Systems

To compare plan quality among standard vs. aperture-based Intensity-Modulated Proton Therapy (IMPT) using cyclotron-generated proton beams (CPB), linear accelerator proton beams (LPB), and linear accelerator proton minibeams (LPMB) for multiple brain metastases. Fifty-five brain lesions from twenty patients were planned with three different spot size ranges using CPBs (σ: 2.7-7.0 mm) and compared against LPBs (σ: 2.9-5.5 mm), and LPMBs (σ: 0.9-3.9 mm). Apertures with a diameter of 0.3 cm were applied to beams irradiating all tumors < 1 cm3 in volume and any tumor < 2.5 cm depth in the patient and compared against the same patient plans containing no apertures. All plans were optimized with the multi-field optimization (MFO) technique using the Monte Carlo algorithm. Dose coverage to each lesion for each proton plan was set to 99% of the GTV receiving the prescription (Rx) dose for all plans. Robustness with ±2 mm setup uncertainty and ±2% range uncertainty was included in robust evaluation using V100%Rx > 95% of the GTV. Conformity index (CI) and gradient index (GI) were used to analyze the effect of apertures vs. no apertures (standard) for each IMPT plan type. CI was defined as the volume of the 100% isodose line divided by the volume of the GTV + 2 mm expansion to account for robust planning. The Wilcoxon signed rank test was utilized to determine the statistical significance of dosimetric results compared between aperture-based and standard IMPT plans. When apertures were implemented in the treatment planning for all shallow and small brain lesions, shallow brain tumors showed the most prominent improvement in conformity and gradient index. A 6.7% difference in average conformity was calculated for standard vs. aperture-based plans for LPMBs, followed by a 5.3% improvement for CPBs. Improvement in gradient index for standard vs. aperture-based plans was significant for both shallow and deeper tumors for CPB and LPB plan types, as shown in Table 1 below. CPB and LPB plan gradient indices were statistically significant for comparing aperture-based vs. standard IMPT plans. We successfully quantified plan quality and evaluated results for aperture- vs. standard IMPT plans using CPBs, LPBs, and LPMBs for brain metastases. Plan quality improves the greatest with apertures applied to beams irradiating shallow tumors. Apertures may not be necessary for small, deeper tumors with IMPT.

Intensity-Modulated Proton Therapy (IMPT) Offered Advantageous Dosimetry Compared to Volumetric Arc Therapy (VMAT) or Helical Tomotherapy (HT) in Patients with Synchronous Bilateral Breast Cancer

Radiotherapy of synchronous bilateral breast cancer poses some technical challenges with regards to dose coverage and sparing of organs at risk (OAR). In this study, we aimed to evaluate dosimetric characteristics of 3 different techniques, IMPT vs photon (VMAT and HT). We hypothesized that IMPT would result in lower doses to organs at risk, as compared to the other 2 techniques. A total of 10 patients with synchronous bilateral breast cancer who were treated with VMAT at our institution were retrospectively analyzed. Clinical target volume (CTV) included chest wall and regional nodes (supraclavicular fossa and internal mammary chain) and prescription dose was 40.05 Gy in 15 daily fractions. HT and IMPT plans were generated for each patient. Dose-volume statistics, including planning target volume (PTV) coverage and dose to OAR: lungs, heart, thyroid, spinal cord, brachial plexus and esophagus, were compared between modalities using a paired T-test. Mean age of patients was 61 years (43-84). Majority of the patients (80%) were ER+ PR+ and HER2-. 40% of patients underwent breast reconstruction following surgery. All 3 techniques provided adequate target volume distribution and OAR sparing. Compared to VMAT and HT plans, IMPT had better heart and lung sparing effects, resulting in lower mean and V25 Gy heart dose; mean, V20 Gy and V5 Gy lung dose (p<0.0001). There was no significant difference in VMAT and HT plans for mean heart and lung dose. VMAT plans showed significantly lower V25 Gy heart dose on average (p = 0.04). V5 Gy lung dose was slightly lower in HT compared to VMAT plans, approaching statistical significance (p = 0.08). PTV coverage was adequate for all 3 techniques. All techniques fulfilled cord, esophagus, thyroid and brachial plexus constraints. IMPT plans showed significantly better OAR sparing compared to photon techniques. All 3 techniques met OAR constraints, and resulted in adequate target volume coverage. As IMPT is significantly more costly than VMAT or HT techniques, appropriate patient selection is important to deliver treatment in the most resource-effective manner for patients who would derive the most benefit, for example those with young age or existing heart or lung comorbidities.