Pencil Beam Scanning Proton Research Articles

Pencil Beam Scanning Proton Therapy for Adolescents and Young Adults with Head and Neck Sarcomas

PurposeTo assess clinical outcomes of adolescents and young adults (AYAs) with head and neck sarcomas (HNSs) treated with pencil beam scanning proton therapy (PBSPT) and to report quality of life (QoL). Materials and MethodsTwenty-eight AYAs (aged 15 to 39 years) with HNS treated between January 2001 and July 2022 at our institution were included. The median age was 21.6 years. Rhabdomyosarcoma (39.3%), Ewing sarcoma (17.9%), chondrosarcoma (14.3%), and osteosarcoma (14.3%) were the most frequent diagnoses. Three (10.7%) patients were metastatic before PBSPT and 13 (46.4%) patients had a tumor with intracranial extension. The median total radiation dose was 63 GyRBE (range, 45 to 74 GyRBE). Thirteen (46.4%) patients received concomitant chemotherapy. Toxicity was reported according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (US National Institutes of Health, Bethesda, Maryland). Survival was estimated using the Kaplan-Meier method. QoL was assessed using a PEDQOL (Pediatric Quality of Life Questionnaire) questionnaire. Self-reported outcomes were assessed using institutional questionnaires. ResultsWith a median follow-up of 57 months (range, 3.7 to 243 months), 5 patients (17.8%) had local failure (LF) only, 2 (7.1%) experienced distant failure (DF) only, and 2 (7.1%) had LF and DF. The estimated 5-year local control (LC) and distant control (DC) rates were 71.8% and 80.5%, respectively. The median times to LF and DF were 13.4 and 22.2 months, respectively. Four (14.3%) patients died, all but one from their HNS. Estimated 5-year overall survival was 90.7%. Six (21.4%) patients developed nonocular grade ≥3 toxicity, which consisted of otitis media (n = 2), hearing impairment (n = 2), osteoradionecrosis (n = 1), and sinusitis (n = 1). Four (14.3%) patients developed cataracts that required surgery. The 5-year freedom from nonocular grade 3 toxicity was 91.1%. No grade 4 or higher toxicity was observed. Adolescents rated their quality of life before treatment worse than their parents did. ConclusionExcellent outcomes with acceptable late-toxicity rates were observed for AYAs with HNS after PBSPT.

Integration and dosimetric validation of a dynamic collimation system for pencil beam scanning proton therapy

Objective. To integrate a Dynamic Collimation System (DCS) into a pencil beam scanning (PBS) proton therapy system and validate its dosimetric impact. Approach. Uncollimated and collimated treatment fields were developed for clinically relevant targets using an in-house treatment plan optimizer and an experimentally validated Monte Carlo model of the DCS and IBA dedicated nozzle (DN) system. The dose reduction induced by the DCS was quantified by calculating the mean dose in 10- and 30-mm two-dimensional rinds surrounding the target. A select number of plans were then used to experimentally validate the mechanical integration of the DCS and beam scanning controller system through measurements with the MatriXX-PT ionization chamber array and EBT3 film. Absolute doses were verified at the central axis at various depths using the IBA MatriXX-PT and PPC05 ionization chamber. Main results. Simulations demonstrated a maximum mean dose reduction of 12% for the 10 mm rind region and 45% for the 30 mm rind region when utilizing the DCS. Excellent agreement was observed between Monte Carlo simulations, EBT3 film, and MatriXX-PT measurements, with gamma pass rates exceeding 94.9% for all tested plans at the 3%/2 mm criterion. Absolute central axis doses showed an average verification difference of 1.4% between Monte Carlo and MatriXX-PT/PPC05 measurements. Significance. We have successfully dosimetrically validated the delivery of dynamically collimated proton therapy for clinically relevant delivery patterns and dose distributions with the DCS. Monte Carlo simulations were employed to assess dose reductions and treatment planning considerations associated with the DCS.

The Applications and Pitfalls of Cone-Beam Computed Tomography-Based Synthetic Computed Tomography for Adaptive Evaluation in Pencil-Beam Scanning Proton Therapy.

The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation.

The implementation of an image-guided system at a proton therapy center facility.

Pencil Beam Scanning (PBS) proton therapy has similar requirements on patient alignment to within 1mm and 1-degree accuracy as photon radiosurgery. This study describes general workflow, acceptance, and commissioning test procedures and their respective results for an independent robotic arm used for Image Guided Radiotherapy (IGRT) for a Proton Therapy System. The system is equipped with kV-imaging techniques capable of orthogonal and Cone-Beam Computed Tomography (CBCT) imaging modalities mounted on an independent robotic arm gantry attached to the ceiling. The imaging system is capable of 360-degree rotation around patients to produce CBCT and kilovoltage orthogonal images. The imaging hardware is controlled by Ehmet Health XIS software, and MIM Software handles the image fusion and registration to an acceptable accuracy of ≤1-mm shifts for patients' alignment. The system was tested according to the requirements outlined in the American Association of Physicists in Medicine (AAPM) Task Group (TG) 142 and TG 179. The system tests included (1) safety, functionality, and connectivity, (2) mechanical testing, (3) image quality, (4) image registration, and (5) imaging dose. Additional tests included imaging gantry isocentricity with a laser tracker and collision-avoiding system checks. The orthogonal and volumetric imaging are comparable in quality to other commercially available On-Board Imagers (OBI) systems. The resulting spatial resolution values were 1.8-, 0.8-, and 0.5-Line Pairs per Millimeter (lp/mm) for orthogonal, full-fan CBCT, and half-fan CBCT, respectively. The image registration is accurate to within 1mm and 1 degree. The data shows consistent imaging-guided system performance with standard deviations in x, y, and z of 0.7, 0.8, and 0.7mm, respectively. The system provides excellent image quality and performance, which can be used for IGRT. The proven accuracy of the x-ray imaging and positioning system at McLaren Proton Therapy Center (MPTC) is 1mm, making it suitable for proton therapy.

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.

Introducing an Experimental Approach to Predict Spot Scanning Time Parameters for a Superconducting Cyclotron Proton Therapy Machine

Proton pencil beam scanning (PBS) delivery sequence varies a lot among institutions due to the differences in vendors, machine types, and beamline configurations, which impacts PBS interplay effects and treatment delivery time estimation. This study aims to develop an independent experimental approach to predict the spot scanning time parameters for a clinical superconducting cyclotron proton therapy machine. This independent experimental approach employed an open-air parallel-plate detector with a temporal resolution of 0.05ms. A series of spot, energy, and dose rate patterns were designed and delivered, including (1) Spot switching time (SSWT) under different spot spacing for IEC-X, IEC-Y directions and diagonal direction (traveling in both X and Y direction) for three energy layers (110, 170 and 230 MeV); The Wilcoxon test is used to validate the prediction of SSWT along the diagonal direction. (2) Energy layer switching time (ELST) with different descending energy gaps for a fixed initial energy and different initial energies for a fixed descending energy gap. (3) Dose rate (MU/min) are measured for different minimum-MU-per-energy-layer (MMPEL), which are compared with the previous publication. A SSWT jump at 10mm (can be customized) spot spacing is observed because of triggering the machine's "raster mode" threshold. Discontinuous two variable piecewise linear functions were used to fit the SSWT in X/Y for spot spacing and energy. SSWT in X/Y is increasing as spot spacing and energy increase. SSWT in the diagonal direction is determined by the time either in the x-direction or y-direction, whichever takes longer (see Table 1 for one example of validations). ELST is linear depending on descending energy gap. The dose rate dependence on MMPEL is confirmed with previous publications of a similar type of machine. The study provided the first independent quantitative experimental modeling of the beam delivery time parameters without any information from vendors. Such machine-specific delivery sequence models could pave the foundation of precise interplay effect evaluation for clinical decision-making.

Pencil Beam Scanning Proton Stereotactic Body Radiation Therapy (SBRT): A Robust Single Institution Experience

To describe the feasibility of treating a complex and diverse group of patients using pencil beam scanning (PBS) proton stereotactic body radiation therapy (SBRT: 5 or fewer fractions, with a fraction size of at least 5 Gy). Our center treats on average 105-120 PBS proton treatments daily, of which 9.5% of treatment courses are proton SBRT. Statistics of disease sites, treatment planning parameters (target volume, prescriptions, number of fields, SFO vs. MFO), and treatment efficiencies (scheduled time slots, actual treatment time) are presented for 305 consecutive SBRT patients receiving 1507 fractions in the past three years. Thermoplastic masks or Vacuum-lock bags are used to immobilize SBRT patients and index the patients' treatment position. Imaging guidance of orthogonal kV images and volumetric cone-beam CT is routinely used for patient setup. SBRT patients are grouped based on the target locations: pelvis (31%), liver (17%), thoracic (13%), spine (8%), abdominal (8%), brain (7%), non-spine bone (7%), ocular (6%), and head and neck (2%). Only 112 patients (37%) were receiving their 1st RT course, whereas 113 (37%) had one prior in-field RT course, and 80 (26%) had multiple prior in-field RT courses. The median [IQR] target volume was 65.4 [29.3, 168] cc (range: 0.3-2475 cc). 72% of cases were planned with SFO and 28% with MFO. On average, 3.76 fields (range: 2 to 12) were planned for each treatment. 44% of the treatments were planned with three or fewer fields, and 10% received more than five fields, most of which involved repainting for moving targets. Over 97% of treatments were delivered in 5 fractions, with ∼3% delivered in 3 fractions. The median [IQR] prescription per treatment was 8 [7, 10] Gy (range: 5-18 Gy per treatment). 85% (84%) of the SBRT treatments were scheduled (delivered) in a 45-minute or shorter slot, and 6% (7%) of treatments were scheduled (delivered) in over a one-hour slot, most commonly for multiple isocenter treatments. 93% of treatments were delivered within 15 minutes of the planned treatment time or shorter. Deep-inspiration breath-hold (DIBH) was applied to 45% of liver SBRT cases, with the remaining 55% planned on 4D CT with (14%) or without (86%) abdominal compression. DIBH was applied in 13% of lung SBRT cases. The application of other motion mitigation approaches, such as volumetric repainting, was determined by the target motion amplitude and whether the patient could tolerate DIBH. In the most diverse and largest proton SBRT experience delivered in the world over the past 3 years, over 300 patients were treated, demonstrating the feasibility and efficiency of delivering proton SBRT in a very busy center. The planning and treatment parameter statistics reported serve as a helpful reference for the proton community.

A Potential Cause for Unexplained Radiation Toxicity in Proton Therapy

Rare but devastating neurological tissue injury by proton therapy is poorly understood. One consideration is that the transition from passively scattered to pencil beam scanning (PBS) proton radiotherapy over the past decade has affected dose rate. We analyzed clinical data acquired at two institutions on a correlation of voxel-wise dose rates and injury of brain tissue (institution 1) and the optic apparatus (institution 2). All radiation-induced toxicities were delineated (Brain/optic apparatus) on follow-up MRIs. A method to calculate dose rates for PBS plans has been implemented at two institutions independently. Institution 1 reports beam-by-beam time-averaged maximum dose rates per voxel (VMDR) using a 100 ms time interval. Data from four patients who incurred brain tissue injury was included. Dose rate volume histograms were prepared for the target, a 1 cm outer ring to the target, and the necrotic region itself. Prescription doses ranged from 30.6 to 60 Gy delivering either 1.8 or 2.0 Gy per fraction. Tissue injury was generally observed in the dose fall-off at the edge of the target. Additionally, we performed LET weighted dose calculation, robustness analysis, and Monte Carlo calculations. Institution 2 presents voxel-wise dose delivered above a selected dose rate threshold, considering values between 30 and 180 Gy/min. The analysis was performed for 2 cases with optical apparatus injuries and one matching non-toxicity case. Both injuries were observed in the chiasma. Patients received 50.4, 50.4 and 55.8 Gy (non-toxicity) in 1.8 Gy fractions. D1 for chiasma was 51.1, 47.2 and 54 Gy, respectively. Mean and (max) LET in chiasma were 4.02 (4.72), 2.49 (3.16) and 3.44 (4.56) keV/µm accordingly. Institution 1 finds distinct dose rate hot spots in the contoured injured brain regions. Mean VMDR values across all beams are lower in targets than in the 1 cm outer ring (80 Gy/min and 82.8 Gy/min, respectively) and elevated to 113 Gy/min for necrotic regions. Neither of the additional computations showed significant increase of dose in the affected areas. Institution 2 observes that chiasmas, which developed radiation injuries, were exposed to higher dose levels delivered at elevated dose rates (> 72 Gy/min) than the chiasma that did not show any radiation injury. D95 above 72 Gy/min for the two volumes identified as radiation injury was 0.25 and 0.12 Gy/fx, while D98 to chiasmas minus radiation injury or chiasma without any injury for the matching case was 0.06, 0.03 and 0 Gy/fx respectively. Using unique formulations to assess voxel-wise dose rates to brain and optic chiasm, two independent institutions observed that regions with elevated dose rates correlated with radiographic radiation injury. An extended retrospective study including a larger patient cohort with radiation-induced toxicity and asymptomatic patients is under way to confirm or refute the presented observations.

The Interplay Effect and Mitigations with Cyclotron and Linac Proton Beam Scanning for Lung SBRT

To evaluate the impact of different types of pencil beam scanning proton accelerators and spot sizes on interplay effects, mitigations, and plan quality for lung cancer patients treated with SBRT. Twenty lung cancer patients (ten peripheral and ten central tumors) treated in our institution with photon SBRT were selected to represent varying tumor volumes and respiratory motion amplitudes for this retrospective study. The respiratory motion amplitude ranged from 0.1 to 1.0 cm with compression. For each patient, plans were created using: 1) cyclotron-generated proton beams (CPB) (σ: 2.7-7.0 mm); 2) linear accelerator proton beams (LPB) (σ: 2.9-5.5 mm); and 3) linear accelerator proton minibeams (LPMB) (σ: 0.9-3.9 mm). Plans were robustly optimized on the GTV using each individual 4DCT phase. Single-filed optimization (SFO) plans were the first attempt, and if the plan quality did not meet the dosimetric requirement, multi-field optimization (MFO) was used. MFO plans were created for all patients for comparison. For each patient, all plans were normalized to have the same dose to 99% of the GTV. Interplay effects were evaluated for ten scenarios of treatment delivery starting in ten breathing phases using machine generic time models and a constant breathing period of 4 seconds. Volumetric repainting (VR) was performed 2-6 times for each plan. To assess plan quality in the nominal scenario, we compared the conformity index (CI), R50, and the percentage of lung volume receiving 20 Gy (RBE) (V20Gy). CI is defined as the ratio of the 100% isodose volume to the GTV. R50 is defined as the 50% isodose volume divided by the GTV. Dmax and V18Gy of the proximal bronchial tree (PBT) were evaluated for central tumors. Twelve of 20 plans can be optimized sufficiently with SFO. In interplay effect evaluation, the mean V100%RX values of the GTV were 99.42±0.6%, 97.52±3.9%, and 94.49±7.3%for CPB, LPB, and LPMB plans respectively. After VR 2/3/5 times, the V100%RX values were improved (on average) by 0.13%/1.84%/4.63% for CPB/LPB/LPMB plans. The delivery time for VR plans was the lowest for LPB plans, while delivery time for LPMB was on average 1 minute longer than CPB plans. VR showed no effect on lung V20Gy, Dmax and V18Gy of the PBT. SFO plans were more robust against the interplay effect compared with MFO plans for LPB and LPMB. Average CIs of 1.88±0.4, 1.79±0.4, and 1.75±0.4; average R50s of 7.99±4.0, 6.68±3.0, and 5.70±2.6; and average lung V20Gy values of 2.81±1.5, 2.26±1.3, and 1.85±1.1 were obtained for CPB, LPB, and LPMB plans, respectively. Dmax and V18Gy of the PBT decreased with decreasing spot sizes. LPMB, with the smallest spot size, produced superior plan quality. In the absence of VR, proton machines with large spot sizes generated more robust plans against interplay effects. VR improved the plan robustness against interplay effects for modalities with small spot sizes and fast energy changes, preserving the low dose sparing aspect of the LPMB, even when motion is included.

Outcomes of Patients Treated with Re-Irradiation for Recurrent Head and Neck Cancer Using Pencil Beam Scanning Proton Therapy

Re-irradiation (re-RT) for recurrent head and neck cancer (HNC) after prior HNC radiation therapy (RT) is clinically challenging given prior radiation of nearby organs at risk (OARs). We describe clinical outcomes and toxicity of pencil beam scanning proton therapy (PBS-PT) for recurrent HNC. We performed a retrospective analysis of recurrent HNC patients treated at a single institution with PBS-PT. Baseline demographic, disease and treatment characteristics were recorded. Local control (LC), locoregional control (LRC), progression free survival (PFS), distant metastasis free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. UVA was completed using logistic regression, and MVA was performed using a backward elimination model. We also report acute and late grade 3+ toxicity outcomes, graded per CTCAE v5.0. A total of 89 patients treated with PBS-PT for recurrent HNC between 2016 and 2022 were included. Primary sites included oropharynx (30.0%), oral cavity (22.5%), sinonasal cavity (15.7%), larynx (12.4%) and nasopharynx (6.7%). The most common tumor histology was SCC (73.0%). Median time to re-RT was 47 months. Median dose of PBS-PT was 60 Gy (range: 40-72) with 50.6% receiving BID treatment. Median GTV volume was 30cc (range 4.8-1083cc). 24% of patients received concurrent systemic therapy (46% cytotoxic, 4.5% immunotherapy). Median follow-up after PBS-PT was 8 months (range: 0-71), and median OS was 13 months (95% CI: 9.3-16.7). The median PFS and DMFS were 7 months (95% CI 5.0-9.0) and 9 months (95% CI 5.3-12.7) respectively. The 1- and 2-year LC rates were 80.8% (95% CI: 70.8-90.8) and 66.2% (95% CI: 50.7-81.7). The 1- and 2-year DMFS were 41.0% (95% CI: 30.0-52.0) and 26.3% (95% CI: 15.7-36.9). On UVA and MVA, smaller GTV volume was associated with improved OS (HR 1.002, p = .004), DMFS (HR 1.002, p = 0.004) and PFS (HR 1.002, p = 0.014). In addition, shorter time to re-RT was associated with worse LRC (HR 1.003, p = 0.002), and higher KPS was associated with improved PFS (HR 0.57, p = 0.04). There were 31 acute grade 3 toxicity events (21 patients), the most common being odynophagia (9.0%) followed mucositis (5.6%), dehydration and dermatitis (both 4.5%). One patient had grade 4 toxicity, laryngeal edema requiring intubation 40 days after completion of re-RT. One patient had acute grade 5 toxicity, an oropharyngeal bleed 74 days after completion of re-RT. There were 35 late toxicity events (n = 27), the most common being dysphagia (n = 7, 7.9%). One patient suffered late grade 5 osteoradionecrosis, which resulted in sepsis. PBS-PT for recurrent HNC results in effective disease control and favorable toxicity. Patients with smaller GTV volume appear to have improved OS, PFS and DMFS, and may be better candidates. Those with shorter time to re-RT also have worse LRC. However, distant failure (DF) comprises a major failure pattern, and biomarkers to identify patients at risk for DF may improve clinical decision making.

Prospective Feasibility Trial of Vertebral Body Sparing Pencil Beam Scanning Proton Craniospinal Irradiation in Growing Children

Advanced proton therapy techniques now allow for delivery of craniospinal irradiation (CSI) to the entire brain and thecal sac while sparing many of the anterior vertebral bodies from doses expected to inhibit growth, though this technique has not been prospectively studied. The purpose of this trial is to test the feasibility and robustness of vertebral body sparing (VBS) CSI in children with standard image guidance, to assess the dosimetric and toxicity benefits of this approach, and to report early clinical outcomes. Children 3-18 years old requiring CSI treatment were eligible for this IRB approved prospective clinical trial. The CSI clinical target volume (CTV) included the brain, entire thecal sac and neural foramina with no expansion. Select anterior vertebral bodies (AVB) could be included at the physician's discretion. The spinal portion of the CTV was treated with PA beam(s) with robust optimization (+/-3.5% range, 5mm positional uncertainty). Daily image guidance included kV/kV imaging. Cone beam CT (CBCT) was acquired weekly after final positioning and a virtual CT (vCT) was created for quality assurance (QA) analysis. Acute toxicity was prospectively assessed weekly during treatment and 1 month after per CTCAE v5.0. Ten children with a median patient age and CSI dose of 9 years (range 3-16) and 36 Gy (RBE) (range 15-36 Gy (RBE)) were enrolled. Common diagnoses were medulloblastoma (n = 4) and non-germinomatous germ cell tumor (n = 3). Seven patients received prior chemotherapy; 2 patients were treated with palliative intent. Dose statistics for the anterior vertebral body varied according to age, CSI dose and portion of the spine, with the greatest sparing in the lower thoracic and lumbar vertebrae for all patients. Nine patients completed all QA CTs; one patient required a replan due to weight gain. For all remaining patients the treatment was highly robust: CTV V95 reduction at the C-spine, T-spine, and L-spine was 0.0±0.1%, 0.6±1.3%, and 0.8±1.1%, respectively. The highest grade non-hematologic acute toxicity was grade 2 alopecia (n = 9) and grade 2 nausea/vomiting (n = 5). One patient reported transient grade 1 esophagitis during treatment. Hematologic toxicity included >/ = grade 3 lymphopenia in 7 patients, >/ = grade 3 leukopenia in 1 patient, >/ = grade 2 anemia in 6 patients, and >/ = grade 1 thrombocytopenia in 3 patients. Median follow-up is 16.6 months (range 10-36 months). Three patients experience intracranial disease progression: 2 local and 1 distant intracranial failure. There were no failures within the spine. Proton vertebral body sparing CSI targeting the thecal sac only is a highly robust treatment technique and is well tolerated. Weekly CBCT to assess changes in soft tissue posterior to the spine is recommended. Further follow-up is required to assess long-term growth outcomes.

Prospective Evaluation of Patient-Reported Outcomes of Invisible Ink Tattoos for the Delivery of External Beam Radiation Therapy: The PREFER Trial

Invisible ink tattoos allow for setup accuracy while avoiding the cosmetic permanence of visible ink tattoos. The goal of this trial was to evaluate patient-reported preference for the use of invisible ink tattoos in a radiation oncology clinic. In an IRB-approved, prospective, feasibility trial, patients at a single institution receiving pencil beam scanning proton therapy to the thorax, abdomen, or pelvis underwent invisible ink tattoo-based treatment setup. Patient preference surveys comparing visible and invisible ink tattoos were completed prior to simulation (17 questions), immediately following simulation (5 questions), and at the end of treatment (18 questions), with preference scored on a 5-point Likert scale from strongly disagree to strongly agree, and cosmesis scored on a 4-point Likert scale of excellent-good-fair-poor. Differences in distributions were examined using Wilcoxon rank-sum tests, Fisher's exact tests, or chi-square tests, where statistical significance was considered at p<0.05. Of 107 patients screened, 102 were enrolled and 94 completed all surveys. Mean age was 55.0 years, and 58.5% were female. Most patients were white (79.1%) and non-Hispanic (92.6%). Patients most commonly had breast (34.0%), prostate (16.0%), and lung (9.6%) cancer. An average of 5 (range 3-8) invisible ink tattoos were placed per patient. Overall, 75.5% of patients reported that they would prefer to receive invisible tattoos vs. visible tattoos, and 88.3% rated the overall cosmetic outcome of invisible ink tattoo marks as excellent or good. Compared to males, females were more willing to travel farther from their home in order to avoid receiving visible tattoos (45.4% vs. 23.1%, p = 0.035) and would pay additional money to avoid receiving visible tattoos (34.5% vs. 5.1%, p = 0.002). Patients who had previously received any tattoo (cosmetic or visible RT tattoos) were more satisfied with the appearance of their invisible ink tattoos compared to those who had never previously received tattoos (82.9% vs. 61.5%, p = 0.022). Patients receiving definitive intent RT were more satisfied with the appearance of the tattoos compared to those receiving palliative intent RT (67.1% vs. 38.9%, p = 0.011). Patients with at least a college education were less satisfied with the appearance of tattoos compared to those without a college education (67.0% vs. 95.0% p = 0.018). These findings demonstrate stronger avoidance of visible tattoos and patient preference for invisible tattoos. The standard incorporation of invisible ink tattoos for patient setup should be strongly considered.

Near-Surface Dose Avoidance in Patients with Implant-Based Reconstruction Receiving Post-Mastectomy Proton Irradiation

Dose to the near-surface region may contribute to toxic effects and breast reconstruction complications in patients receiving post-mastectomy irradiation. Here we report the acute and chronic toxic effects in patients with implant-based reconstruction receiving post-mastectomy proton irradiation with prospective near-surface dose avoidance. We reviewed the charts of patients with breast cancer who underwent a mastectomy with implant-based reconstruction and a first course of pencil beam scanning proton irradiation at a single institution from 2017-2022. Patients were evaluated weekly on-treatment, 3- and 12-months post-completion, and then annually. Baseline demographics, treatment details, acute and chronic toxicities (CTCAE v.4), unplanned reconstructive surgery, and implant failure were recorded. Inverse probability weighting was used to generate a balanced cohort receiving post-mastectomy photon irradiation. Logistic regression was used for comparison. Sixteen patients with implant reconstruction at the time of treatment completed proton irradiation with a median follow up of 1.6 years. Nine (56%) underwent direct-to-permanent implant reconstruction and seven (44%) underwent two-stage reconstruction via tissue expander; of these, five (71%) completed permanent implant exchange prior to irradiation. Implant placement was pre-pectoral in twelve (75%). All patients received a dose of 50 Gy in 25 fractions; fifteen (94%) received a sequential boost to the mastectomy scar of a median 10 Gy. Fifteen (94%) used a near-surface contour (bound by the chest wall CTV, the skin surface, and the skin-3mm contour) for plan optimization to avoid dose to the near-surface region with a median value of the mean dose of 46.8 Gy. Acute grade > 2 radiation dermatitis was present in thirteen (81%) patients. Two (13%) experienced moist desquamation and ten (63%) experienced grade > 2 chest wall pain. Three (19%) underwent unplanned reconstructive surgery at a median time of 1.6 years post-treatment: all were capsulectomies due to capsular contracture. One (6%) patient experienced implant failure. A matched cohort of 59 patients who received photon irradiation was identified with a weighted median follow up of 2.5 years. The cohorts were similar with respect to rates of grade ≥2 radiation dermatitis, grade ≥2 chest wall pain, and unplanned reconstructive surgery. Proton irradiation resulted in statistically significant decreases in rates of moist desquamation (OR 0.01, 95% CI 0.0002-0.182) and implant failure (OR 0.01, 95% CI 0.0001-0.997). Post-mastectomy proton irradiation with prospective avoidance of the near-surface region in patients with implant-based reconstruction is feasible and well-tolerated; it results in low rates of unplanned reconstructive surgery and implant failure.

Long Term Clinical Outcome and Quality of Life of Children, Adolescents and Young Adults Treated with Pencil Beam Scanning Proton Therapy for Rhabdomyosarcoma

To assess the long-term clinical outcomes of children, adolescents and young adults (CAYAs) with rhabdomyosarcoma (RMS) treated with pencil beam scanning proton therapy (pbsPT). One hundred twenty-one RMS (embryonal, n = 102; 84.3%) patients treated between January 2000 and December 2020 were included in this analysis. The median age was 4.7 years (range, 0.1-35.3). All patients received systemic chemotherapy according to prospective protocols. The median total dose delivered was 54 Gy (RBE) (range, 41.4-74.0). After a median follow-up time of 85.5 month (range,3.4-240.0), we observed 23 local/regional and 12 distant failures. The estimated 5-year local control (LC) and overall survival (OS) was 81.5% and 80%, respectively. For the subgroups of parameningeal (PM), orbital, urogenital and H&N non-PM the 5-year LC was 74.7%, 92%, 100% and 66.7%. The corresponding figures for OS were 68.8%, 100%, 100%, and 66.7, respectively. The 5-year non-ocular Grade 3 toxicity free survival was 78.9%. At the start of pbsPT children and their caregivers reported QoL significantly worse than the norm group. QoL improved however over the follow up period to normal values in nearly all domains. Median of PEDQOL PROXY reported QoL in Normgroup (children: 4- 18 yrs) and RMS patients (n = 27-42 answers per domain): CONCLUSION: Excellent clinical outcome was observed for CAYAs with RMS treated with pbsPT. Two thirds of treatment failures were local. High-grade late non-ocular toxicity was manageable. QoL improved towards normal scores in nearly all domains after therapy.

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.

Adaptation of a Clinical Proton Pencil Beam Scanning System for FLASH Experiments

To characterize a proton pencil beam scanning system for ultra-high dose rate (UHDR) irradiations and validate it with FLASH preclinical experiments. After modifications to the beamline to maximize the beam current at isocenter in our gantry room, we characterized the UHDR beam in terms of: 1) Size and shape of the beam spot in three configurations; pristine beam, 75 mm water-equivalent-thickness (WET) range shifter (RS), and custom-built 135 mm WET RS mounted 310 mm upstream of the aperture in the snout housing. These configurations were analyzed to determine which one achieved the highest dose rate; 2) Beam transport efficiency and beam output. We compared the signal in the monitor chambers of the proton system with a Faraday cup and plane parallel ionization chamber (PPC05, IBA dosimetry) for beam current at the cyclotron from 7.5 nA to 800 nA; 3) Dose homogeneity, beam penumbra, and dose rate for the fields to be used in preclinical irradiations. All measurements were performed at isocenter, in air or at 1 cm depth in solid water, using the highest energy (about 230 MeV), which corresponded to a nominal range of 32.9 cm in water. We modeled the UHDR beam in our treatment planning system (TPS) to optimize the dose homogeneity and lateral penumbra of the irradiation fields. We performed the preclinical experiments in single fractions of 19 Gy (RBE), 21 Gy (RBE) and 23 Gy (RBE) (RBE = 1.1), targeting the pelvis of C57BL/6 mice and using survival as the endpoint. Each arm included 6-10 mice. The proton beam was used in transmission mode, positioning the center of the mouse pelvis at isocenter, and irradiating the pelvis with a 2x6 cm^2 field. Apertures were placed at 9cm from the isocenter to sharpen the lateral penumbra. The range measurements with a multi-layer ionization chamber were consistent within 1 mm with the nominal range. In UHDR mode, the spot size at the isocenter varied from 4.5 mm for the pristine beam to 9.2 mm for the 135 mm RS. The spot size at isocenter remained constant when the beam intensity varied from 7.5 nA to 800 nA at the cyclotron exit. By employing the configuration with the 135 mm RS and optimizing the fields in the TPS, we achieved a dose rate of 1 Gy (RBE)/s for the conventional regime and 75(RBE) Gy/s for the UHDR regime. The monitor chambers of the proton system were affected by recombination at high dose rates: we observed about 35% higher output for the same number of monitor units delivered at 800 nA vs 7.5 nA. The delivered dose was determined with the PPC05 for each field, as this detector did not show recombination effects. When preclinical irradiations were independently monitored, the delivered dose was typically within 1% of the intended value. In three independent experiments, a dose of 21 Gy (RBE) or higher was associated with an increased survival in the UHDR arm compared to the conventional arm. We adapted a clinical proton system for preclinical irradiations at UHDR. Our results confirm the presence of the FLASH effect.

Investigation of scan path optimization in improving proton pencil beam scanning continuous delivery

Objective. To investigate the impact of scan path optimization on the dose accuracy and beam delivery time (BDT) of proton pencil beam scanning in the dose-driven continuous scanning (DDCS). Approach. A diverse set of six clinical plans, representing various spot patterns and treatment sites, was used to evaluate the effectiveness of scan time optimization and scan length optimization. The DDCS dose discrepancy and BDT with optimized scan paths was compared to the default serpentine scan path. Main results. Both scan time optimization and scan path optimization were able to reduce the DDCS dose discrepancy compared to the default serpentine scan path. All plans, except for the layer repainting lung plan, achieved a 2%/2 mm gamma pass rate of over 99% and less than 1% PTV DVH root mean square error (RMSE) through scan path optimization. In the case of the layer repainting lung plan, when compared to the default serpentine scan path, the 2%/2 mm gamma pass rate showed improvements from 91.3% to 93.1% and 95.8%, while the PTV DVH RMSE decreased from 2.1% to 1.7% and 1.1% for scan time optimization and scan length optimization, respectively. Although scan time optimization resulted in shorter total scan times for all plans compared to the default scan path and scan length optimization tended to have longer total scan times. However, due to the short total scan times and their minimal contribution to the total BDT, the impact of scan path optimization on the total BDT was practically negligible. Significance. Both scan time optimization and scan length optimization proved to be effective in minimizing DDCS dose discrepancy. No definitive winner can be determined between these two optimization approaches. Both scan time and scan length optimization had minimal effect on the total BDT.

Beam mask and sliding window-facilitated deep learning-based accurate and efficient dose prediction for pencil beam scanning proton therapy.

Accurate and efficient dose calculation is essential for on-line adaptive planning in proton therapy. Deep learning (DL) has shown promising dose prediction results in photon therapy. However, there is a scarcity of DL-based dose prediction methods specifically designed for proton therapy. Successful dose prediction method for proton therapy should account for more challenging dose prediction problems in pencil beam scanning proton therapy (PBSPT) due to its sensitivity to heterogeneities. To develop a DL-based PBSPT dose prediction workflow with high accuracy and balanced complexity to support on-line adaptive proton therapy clinical decision and subsequent replanning. PBSPT plans of 103 prostate cancer patients (93 for training and the other 10 for independent testing) and 83 lung cancer patients (73 for training and the other 10 for independent testing) previously treated at our institution were included in the study, each with computed tomography scans (CTs), structure sets, and plan doses calculated by the in-house developed Monte-Carlo dose engine (considered as the ground truth in the model training and testing). For the ablation study, we designed three experiments corresponding to the following three methods: (1) Experiment 1, the conventional region of interest (ROI) (composed of targets and organs-at-risk [OARs]) method. (2) Experiment 2, the beam mask (generated by raytracing of proton beams) method to improve proton dose prediction. (3) Experiment 3, the sliding window method for the model to focus on local details to further improve proton dose prediction. A fully connected 3D-Unet was adopted as the backbone. Dose volume histogram (DVH) indices, 3D Gamma passing rates with a criterion of 3%/3mm/10%, and dice coefficients for the structures enclosed by the iso-dose lines between the predicted and the ground truth doses were used as the evaluation metrics. The calculation time for each proton dose prediction was recorded to evaluate the method's efficiency. Compared to the conventional ROI method, the beam mask method improved the agreement of DVH indices for both targets and OARs and the sliding window method further improved the agreement of the DVH indices (for lung cancer, CTV D98 absolute deviation: 0.74 ± 0.18 vs. 0.57 ± 0.21 vs. 0.54 ± 0.15 Gy[RBE], ROI vs. beam mask vs. sliding window methods, respectively). For the 3D Gamma passing rates in the target, OARs, and BODY (outside target and OARs), the beam mask method improved the passing rates in these regions and the sliding window method further improved them (for prostate cancer, targets: 96.93% ± 0.53% vs. 98.88% ± 0.49% vs. 99.97% ± 0.07%, BODY: 86.88% ± 0.74% vs. 93.21% ± 0.56% vs. 95.17% ± 0.59%). A similar trend was also observed for the dice coefficients. This trend was especially remarkable for relatively low prescription isodose lines (for lung cancer, 10% isodose line dice: 0.871 ± 0.027 vs. 0.911 ± 0.023 vs. 0.927 ± 0.017). The dose predictions for all the testing cases were completed within 0.25s. An accurate and efficient deep learning-augmented proton dose prediction framework has been developed for PBSPT, which can predict accurate dose distributions not only inside but also outside ROI efficiently. The framework can potentially further reduce the initial planning and adaptive replanning workload in PBSPT.

Dose delivery reproducibility for PBS proton treatment of breast cancer patients with and without mask immobilization

BackgroundSetup reproducibility of the tissue in the proton beam path is critical in maintaining the planned clinical target volume (CTV) dose coverage and sparing the organs at risk (OAR). In this study, we retrospectively evaluated radiation therapy dose reproducibility for proton pencil beam scanning (PBS) treatment of breast cancer patients with and without mask immobilization.MethodsNinety-four patients treated between January 2019 and September 2022 with at least one verification CT scan (V-CT) in treatment position were included for this study. All patients were set up with arms up using the Orfit AIO patient positioning system, with (69 patients) or without (25 patients) mask immobilization in chin, neck, shoulder, upper arm, and chest areas. Two to three enface or near enface single field uniform dose PBS beams were optimized using a commercial treatment planning system. Prescription doses were 25 to 60 GyRBE in 5 to 45 fractions. Treatment plan doses re-calculated on V-CTs were compared to the corresponding planned doses. Cumulative doses were also calculated for patients with at least 3 V-CTs by deform and weighted sum doses from V-CTs to corresponding P-CTs. CTV D95%, ipsilateral-lung V40%, esophagus D0.01cc, and heart mean dose were evaluated and reported as percentages of prescription doses. Differences were large dose deteriorations (LDD) if: (1) CTV (V-CT/cumulative D95%) – (Planned D95%) < − 5%; or (2) Ipsilateral-lung (V-CT/cumulative V40%) – (Planned V40%) > 5%; or (3) Esophagus (V-CT/cumulative D0.01cc) – (Planned D0.01cc) > 10%; or (4) Heart (V-CT/cumulative mean) – (Planned mean) > 1.5%.ResultsOn average, V-CT/cumulative and planned CTV/OAR dose parameter differences were less than 2.2%/1.7% and 3.4%/3.7% for masked and maskless patients, respectively. The percentages of patients with at least one CTV or OAR V-CT/cumulative dose LDD were 20.3%/25.0% and 72.0%/54.0% for masked and maskless patients, respectively.ConclusionsOn average, masked/maskless setups achieved delivered and planned CTV/OAR dose parameters agreed within 2.2%/3.7% for PBS treatment of breast cancer patients in this study. Maskless patients had higher rate of CTV/OAR LDDs compared to masked patients. Dosimetric differences large enough to raise clinical concerns in either group were able to be addressed with replannings.

Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures.

In radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment. Organ doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider etal. Out-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 μSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 μSv (testes) and 48 μSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs. The complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.