Proton Stereotactic Body Radiation Therapy Research Articles

The Status and Challenges for Prostate Stereotactic Body Radiation Therapy Treatments in United States Proton Therapy Centers: An NRG Oncology Practice Survey

PurposeTo report the current practice pattern of the proton stereotactic body radiation therapy (SBRT) for prostate treatments. Materials and MethodsA survey was designed to inquire about the practice of proton SBRT treatment for prostate cancer. The survey was distributed to all 30 proton therapy centers in the United States that participate in the National Clinical Trial Network in February, 2023. The survey focused on usage, patient selection criteria, prescriptions, target contours, dose constraints, treatment plan optimization and evaluation methods, patient-specific QA, and image-guided radiation therapy (IGRT) methods. ResultsWe received responses from 25 centers (83% participation). Only 8 respondent proton centers (32%) reported performing SBRT of the prostate. The remaining 17 centers cited 3 primary reasons for not offering this treatment: no clinical need, lack of volumetric imaging, and/or lack of clinical evidence. Only 1 center cited the reduction in overall reimbursement as a concern for not offering prostate SBRT. Several common practices among the 8 centers offering SBRT for the prostate were noted, such as using Hydrogel spacers, fiducial markers, and magnetic resonance imaging (MRI) for target delineation. Most proton centers (87.5%) utilized pencil beam scanning (PBS) delivery and completed Imaging and Radiation Oncology Core (IROC) phantom credentialing. Treatment planning typically used parallel opposed lateral beams, and consistent parameters for setup and range uncertainties were used for plan optimization and robustness evaluation. Measurements-based patient-specific QA, beam delivery every other day, fiducial contours for IGRT, and total doses of 35 to 40 GyRBE were consistent across all centers. However, there was no consensus on the risk levels for patient selection. ConclusionProstate SBRT is used in about 1/3 of proton centers in the US. There was a significant consistency in practices among proton centers treating with proton SBRT. It is possible that the adoption of proton SBRT may become more common if proton SBRT is more commonly offered in clinical trials.

Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

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.

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.

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.

An Integrated Physical Optimization Framework for Proton Stereotactic Body Radiation Therapy FLASH Treatment Planning Allows Dose, Dose Rate, and Linear Energy Transfer Optimization Using Patient-Specific Ridge Filters

Patient-specific ridge filters provide a passive means to modulate proton energy to obtain a conformal dose. Here we describe a new framework for optimization of filter design and spot maps to meet the unique demands of ultrahigh-dose-rate (FLASH) radiation therapy. We demonstrate an integrated physical optimization Intensity-modulated proton therapy (IMPT) (IPO-IMPT) approach for optimization of dose, dose-averaged dose rate (DADR), and dose-averaged linear energy transfer (LETd). We developed an inverse planning software to design patient-specific ridge filters that spread the Bragg peak from a fixed-energy, 250-MeV beam to a proximal beam-specific planning target volume. The software defines patient-specific ridge filter pin shapes and uses a Monte Carlo calculation engine, based on Geant4, to provide dose and LET influence matrices. Plan optimization, using matRAD, accommodates the IPO-IMPT objective function considering dose, dose rate, and LET simultaneously with minimum monitor unit constraints. The framework enables design of both regularly spaced and sparse-optimized ridge filters, from which some pins are omitted to allow faster delivery and selective LET optimization. To demonstrate the framework, we designed ridge filters for 3 example patients with lung cancer and optimized the plans using IPO-IMPT. The IPO-IMPT framework selectively spared the organs at risk by reducing LET and increasing dose rate, relative to IMPT planning. Sparse-optimized ridge filters were superior to regularly spaced ridge filters in dose rate. Depending on which parameter is prioritized, volume distributions and histograms for dose, DADR, and LETd, using evaluation structures specific to heart, lung, and esophagus, show high levels of FLASH dose-rate coverage and/or reduced LETd, while maintaining dose coverage within the beam specific planning target volume. This proof-of-concept study demonstrates the feasibility of using an IPO-IMPT framework to accomplish proton FLASH stereotactic body proton therapy, accounting for dose, DADR, and LETd simultaneously.

Proton SBRT for Isolated Nodal Recurrence in Gynecological Cancers

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) for isolated lymph node recurrence has been shown to have good rates of local control (LC) in gynecological cancers. However there exists the risk of toxicities to nearby organs. This single institution, retrospective outcome and dosimetric analysis assesses treatment response, associated GI and GU toxicities and associated characteristics for improved or worsened outcomes with proton based SBRT, hypothesizing that there will be low rates of toxicities while maintaining beneficial outcomes. <h3>Materials/Methods</h3> Adult patients diagnosed with primary gynecologic malignancy with isolated nodal recurrence treated with proton SBRT from 2006-2021 at a single institution were included. Toxicities were evaluated using RTOG/EORTC and CTCAE grading. Descriptive statistics were used to describe characteristics associated with local recurrence, toxicity, and survival. <h3>Results</h3> Fourteen patients with 21 nodal lesions were treated with 19 courses of proton SBRT. Median age was 64.5 (range: 47-78) years at time of initial cancer diagnosis and median of 66.0 (range: 51- 80) years at initial lymph node recurrence. Patients recurred within an average of 13.00 (range: 0.66- 31.41) months from end of initial treatment. Primary cancer sites included endometrium (n= 9), cervix (n= 2), ovary (n= 2), and vagina (n= 2). SBRT doses ranged from 30- 50 Gy (median 40 Gy) in 5-15 fractions with mean BED (alpha beta 10) of 69.93 (range: 48.00- 100.00) and mean BED (alpha beta 3) of 139.95 (range: 72.00- 216.67). Nodal locations treated included para-aortic (n= 7), pelvis (n= 5), iliacs (n= 4), and distant nodes (n= 3, supraclavicular, perirectal, periadrenal). Three pelvic and iliac lesions recurred locally at a median of 2.9 months (range 1.25-29.23) and 50% of patients developed local or distant recurrence. Local control at 3 months, 6 months, 1 year, and 2 years was 84.6%, 83.3%, 81.8%, and 70.0% respectively. Local recurrence free survival (LRFS) at 1 year and 2 years was 80.0%, 75.0% and overall survival (OS) was 54.5%, 44.4% respectively. Six patients developed grade 1 or 2 GI treatment related toxicity (Grade 1: 3, Grade 2: 3). 2 patients developed grade 1 GU toxicity. There were no GI grade 3-5 toxicities or GU grade 2-5 toxicities. Average Dmax to bladder was 14.42 Gy (median 18.62 Gy), range (0.6- 30.6). Average rectum Dmax was 15.75 Gy (range: 0.1- 34.2), median: 15.8 Gy. Median small bowel D2cc was 27 Gy (range: 10- 50.5) <h3>Conclusion</h3> Patients treated with proton SBRT had excellent rates of LC and LRFS and low rates of GI and GU toxicity. Dosimetric analysis also demonstrates low dose to nearby OARs. Based on these findings, Phase I/II trials evaluating dose escalation using proton techniques to further improve local control of isolated nodal recurrences should be considered.

Comparison of Patient-Reported Quality-of-Life between Spot Scanned Proton Stereotactic Body Radiation Therapy and Conventional Proton Therapy after Radiotherapy for Intermediate-Risk Prostate Cancer: A Single-Center Prospective Registry Experience

<h3>Purpose/Objective(s)</h3> Proton stereotactic body proton therapy (SBPT) for prostate cancer takes advantage of biologic advantages with hypofractionation and the technical advances of spot scanning. We report toxicities and quality-of-life (QOL) in patients treated with SBPT versus conventional proton therapy (CPT) in a single-institution prospective registry. <h3>Materials/Methods</h3> Patients (Pt) with localized intermediate-risk prostate cancer (PC) were treated with proton radiation (RT) from 2016 to 2018 on an IRB approved prospective registry. Treatment included SBPT (≥6 Gy/fx) or CPT (<2 Gy/fx) per physician choice. Expanded Prostate Cancer Index Composite (EPIC), AUASI, SF-12, Promis10, FACIT-COST, and PRO-CTCAE QOL were administered pre-RT, end-of-treatment, 3, 6, 12 months post RT, and then annually. Toxicities were recorded according to CTCAE v5. Fisher's Exact and Kruskal-Wallis tests were utilized to compare pt characteristics between groups. Effect of treatment were analyzed using logistic regression (toxicity), Kaplan-Meier statistics, and repeated measure mixed models (QOL) with all events were baseline adjusted. <h3>Results</h3> 191 pts were included with a median follow-up of 43.2 months (SBPT:39.9, CPT: 44.9). SBPT (38 Gy/5 fxs) was used in 47 pts (24.6%) while CPT used in 144 pts (75.6%) ranged from 75.6-79.2 Gy in 39-44 fx. At baseline, SBPT pts, tended to be younger, higher BMI, lower Gleason score, lower T stage, less likely to have had prior or treatment concurrent ADT, and less likely to have had concurrent urinary medications. There was no significant difference between arms in terms of survival (p=0.22) and development of new primary cancers (p=0.63). At last follow-up, there were 1x failures for SBPT and 4x failure for CPT (p=0.92). Grade 2+ AE were experienced by 12.8% SBPT versus 11.1% CPT (p=0.76). When adjusted for baseline toxicity, neither acute (≤3 months) grade 2+ (p=0.3) nor chronic grade 2+ (p=0.24) AEs were significantly different between the arms. No significant differences occurred between the arms for Promis10 overall (p=0.76), Physical (p=0.75), or Social (p=0.79) domains, PRO-CTCAE (p>0.73), or FACIT-COST (p=0.92). In regard to EPIC domains, SBPT pts fared significantly (all p<0.05) better in: urinary, bowel, urinary function, urinary bother, urinary irritative/obstructive, bowel bother, and Mental SF12. All other domains did not approach statistical significance (all p>0.1). <h3>Conclusion</h3> There was no significant difference in PC patients treated with SBPT versus CPT except for an improvement in prostate specific QOL in SBPT patients. SBPT appears safe and effective, while providing improved QOL over CPT.

A Prospective Observational Study of Proton Stereotactic Body Radiation Therapy and Immunotherapy for Recurrent Metastatic Head and Neck Cancer: Initial Report of MC ROR1771 Survival Analysis and Toxicity

<h3>Purpose/Objective(s)</h3> Patients with recurrent head and neck squamous cell carcinoma (HNSCC) after previous platinum-based chemotherapy have a median survival of 6 months or less. CheckMate 141 demonstrated that nivolumab administration to this patient population led to a median 7.5-month survival vs. 5.1-months with standard therapy, with 36% 1-year overall survival. The effect of radiotherapy on tumor immunogenicity when combined with immunotherapy has been an area of interest in immuno-oncology. However, proton therapy's role in this space is not well understood. MC ROR1771 was designed as a multisite prospective observational study to evaluate the addition of stereotactic body proton therapy (SBPT) to nivolumab in a platinum-refractory population. <h3>Materials/Methods</h3> Patients with metastatic histologically confirmed HNSCC from any primary site were eligible. Two cycles of nivolumab every other week were followed by SBPT to 1-2 target lesion(s). Maintenance nivolumab continued every other week with follow-up for progression and treatment toxicity. Subsequent oligoprogression was treated with stereotactic body radiotherapy or SBPT as indicated. Objective criteria included target lesion response rate, overall survival, progression-free survival, time to distant metastasis, toxicity, and evaluation of potential predictive biomarkers. Survival analysis was conducted using the Kaplan-Meier method in statistical software. The focus of this report was survival and toxicity analyses. <h3>Results</h3> 15 patients enrolled with 13 receiving SBPT, after which one treated patient withdrew. Of the remaining twelve, 3 had laryngeal primary, 1 nasopharyngeal, and 8 oropharyngeal. 4 patients underwent one round of prior chemotherapy before enrollment, 3 patients two rounds, and 5 patients three rounds: 10 received concurrent chemoradiation in first line (5 definitive, 5 adjuvant), with 1 receiving neoadjuvant chemotherapy prior to chemoradiation, and one presenting with metastatic disease. SBPT dosing ranged from 35-50 Gy. From initiation of nivolumab, median overall survival was 12.5 months (1-year overall survival 67%), with median progression free survival of 4.5 months. Two patients presented with baseline grade 3 cancer pain; no ≥grade 3 toxicity specific to nivolumab nor SBPT was reported. One patient is still alive at 40 months from initiation of nivolumab. <h3>Conclusion</h3> In this highly pretreated population, overall and progression-free survival compare favorably with CheckMate 141, suggesting that SBPT co-treatment may be beneficial in this population. No ≥grade 3 toxicity occurred with nivolumab nor SBPT. Biochemical analysis and correlation with delineated local, regional, and distant radiographic response are forthcoming. Further prospective evaluation of combination SBPT and immunotherapy is needed.

Clinical Outcomes Following Proton and Photon Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer.

Simple SummaryThe current study reports the clinical outcomes of proton and photon stereotactic body radiation therapy (SBRT) for early-stage lung cancer. Out of 202 patients who met the inclusion criteria, 34 received proton SBRT and 168 received photon SBRT. Patients at high risk of developing post-SBRT radiation pneumonitis tended to receive proton SBRT. Oncologic outcomes and toxicity profiles were comparable between treatment modalities. Proton SBRT could be considered for patients with high risk of radiation pneumonitis.We aimed to report the clinical outcomes following stereotactic body radiation therapy (SBRT) using photon or proton equipment in early-stage lung cancer. We retrospectively reviewed 202 cT1-2N0M0 lung cancer patients who underwent SBRT with 60 Gy in four consecutive fractions between 2010 and 2019 at our institution: 168 photon SBRT and 34 proton SBRT. Patients who underwent proton SBRT had relatively poor baseline lung condition compared to those who underwent photon SBRT. Clinical outcomes were comparable between treatment modalities: 5-year local control (90.8% vs. 83.6%, p = 0.602); progression-free survival (61.6% vs. 57.8%, p = 0.370); overall survival (51.7% vs. 51.9%, p = 0.475); and cause-specific survival (70.3% vs. 62.6%, p = 0.618). There was no statistically significant difference in grade ≥ 2 toxicities: radiation pneumonitis (19.6% vs. 26.4%, p = 0.371); musculoskeletal (13.7% vs. 5.9%, p = 0.264); and skin (3.6% vs. 0.0%, p = 0.604). In the binary logistic regression analysis of grade ≥3 radiation pneumonitis, poor performance status and poor baseline diffusion capacity of lung for carbon monoxide were significant. To summarize, though patients with high risk of developing lung toxicity underwent proton SBRT more frequently, the SBRT techniques resulted in comparable oncologic outcomes with similar toxicity profiles. Proton SBRT could be considered for patients at high risk of radiation pneumonitis.

Dose rate and dose robustness for proton transmission FLASH-RT treatment in lung cancer.

To evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment. An in-house FLASH planning platform was used to optimize 10 lung cancer patients previously consecutively treated with proton stereotactic body radiation therapy (SBRT) to receive 3 and 5 transmission beams (Trx-3fds and Trx-5fds, respectively) to 34 Gy in a single fraction. Perturbation scenarios (n=12) for setup and range uncertainties (5mm and 3.5%) were introduced, and dose-volume histogram and dose-rate-volume histogram bands were generated. Conventional proton SBRT clinical plans were used as a reference. RTOG 0915 dose metrics and 40 Gy/s dose rate coverage (V40Gy/s) were used to assess the dose and dose rate robustness. Trx-5fds yields a comparable iCTV D2% of 105.3%, whereas Trx-3fds resulted in inferior D2% of 111.9% to the clinical SBRT plans with D2% of 105.6% (p<0.05). Both Trx-5fds and Trx-3fds plans had slightly worse dose metrics to organs at risk than SBRT plans. Trx-5fds achieved superior dosimetry robustness for iCTV, esophagus, and spinal cord doses than both Trx-3fds and conventional SBRT plans. There was no significant difference in dose rate robustness for V40Gy/s coverage between Trx-3fds and Trx-5fds. Dose rate distribution has similar distributions to the dose when perturbation exists. Transmission plans yield overall modestly inferior plan quality compared to the conventional proton SBRT plans but provide improved robustness and the potential for a toxicity-sparing FLASH effect. By using more beams (5- versus 3-field), both dose and dose rate robustness for transmission plans can be achieved.

Better preservation of erectile function in localized prostate cancer patients with modern proton therapy: Is it cost-effective?

Stereotactic body radiation therapy (SBRT) has gradually been recognized as favorable curative treatment for localized prostate cancer (PC). However, the high rate of erectile dysfunction (ED) after traditional photon-based SBRT remains an ongoing challenge that greatly impacts the quality of life of PC survivors. Modern proton therapy allows higher conformal SBRT delivery and has the potential to reduce ED occurrence but its cost-effectiveness remains uninvestigated. A Markov decision model was designed to evaluate the cost-effectiveness of proton SBRT versus photon SBRT in reducing irradiation-related ED. Base-case evaluation was performed on a 66-year-old (median age of PC) localized PC patient with normal pretreatment erectile function. Further, stratified analyses were performed for different age groups (50, 55, 60, 65, 70, and 75 years) and threshold analyses were conducted to estimate cost-effective scenarios. A Chinese societal willingness-to-pay (WTP) threshold (37,653 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. For the base case, protons provided an additional 0.152 QALY at an additional cost of $7233.4, and the incremental cost-effectiveness ratio was $47,456.5/QALY. Protons was cost-effective for patients ≤62-year-old at the WTP of China (≤66-year-old at a WTP of $50,000/QALY; ≤73-year-old at a WTP of $100,000/QALY). For patients at median age, once the current proton cost ($18,000) was reduced to ≤$16,505.7 or the patient had a life expectancy ≥88 years, protons were cost-effective at the WTP of China. Upon assumption-based modeling, the results of current study support the use of proton SBRT in younger localized PC patients who are previously potent, for better preservation of erectile function. The findings await further validation using data from future comparative clinical trials.

A Universal Range Shifter and Range Compensator Can Enable Proton Pencil Beam Scanning Single-Energy Bragg Peak FLASH-RT Treatment Using Current Commercially Available Proton Systems

Transmission beams have been proposed for ultra-high dose (or FLASH) proton planning, limiting the organ sparing potentials of proton therapy. By pulling back the ranges of the highest energy proton beams and compensating proton ranges to adapt to the target distally, the exit dose of proton beams can be eliminated to better protect organs at risk while still preserving FLASH dose rate delivery. An inverse planning tool was developed to optimize intensity modulated proton therapy using a single-energy layer for FLASH radiation therapy planning. The range pull-backs were calculated to stop single-energy proton beams at the distal edge of the target. The spot map and weights of each field were optimized to achieve a sufficient dose rate using proton beam Bragg peaks. A C-shape target in phantom, along with 6 consecutive lung cancer patients previously treated using proton stereotactic body radiation therapy were planned using this novel Bragg Peak method and also transmission technique. Dosimetry characteristics and 3-dimensional dose rate were investigated. The minimum monitor units (MU) for transmission and Bragg peak plans were 400 MU/spot and 1200 MU/spot, respectively, corresponding to spot peak dose rates of 670 GyRBE (relative biological effectiveness) per second and 1950 GyRBE per second. Bragg peak plans yield a generally comparable target uniformity while significantly reducing dose spillage volume from the low to medium dose level. For all the 6 lung cases delivery of 34 GyRBE in 1 fraction, assessing Radiation Therapy Oncology Group 0915 constraints, the lung V7GyRBE volume was reduced by up to 32% (P=.001) for Bragg peak plans. The transmission plans tended to generate 2.4% higher FLASH dose rate coverage (V40GyRBE/s) versus Bragg peak plans over the major organs at risk. However, Bragg peak plans could also reach the FLASH radiation therapy threshold of V40GyRBE/s using a higher MU/spot and sophisticated dose-rate optimization algorithm. This first proof-of-concept study has demonstrated this novel method of combining range pull-back and powerful inverse optimization capable of achieving FLASH dose rate based on currently available machine parameters using a single-energy Bragg peak. Similar target coverage and uniformity can be maintained by Bragg peak FLASH plans while substantially improving the sparing of organs at risk compared with transmission plans.

A Novel Proton Pencil Beam Scanning FLASH RT Delivery Method Enables Optimal OAR Sparing and Ultra-High Dose Rate Delivery: A Comprehensive Dosimetry Study for Lung Tumors.

Simple SummaryThis study attempts to answer a novel and clinically relevant question of the value of Bragg-peak-based FLASH planning for lung tumors. Most existing studies and literature are limited to using transmission proton beams at ultra-high dose rates, resulting in unnecessary irradiation exposure to normal tissues beyond the target volume. By combining a new hardware design (universal range shifter and range compensator) and an inverse planning system, the novel Bragg peak method makes the Bragg-peak-based FLASH planning possible. The treatment planning study and dosimetry comparison between single-energy proton Bragg peak beams and transmission proton beams demonstrated superior performances in OAR sparing and comparable FLASH dose rate of the Bragg peak FLASH. Beam angle optimization can further improve Bragg peak FLASH dosimetry performance while maintaining the similar 3D FLASH dose rate coverage for OARs.Purpose: While transmission proton beams have been demonstrated to achieve ultra-high dose rate FLASH therapy delivery, they are unable to spare normal tissues distal to the target. This study aims to compare FLASH treatment planning using single energy Bragg peak proton beams versus transmission proton beams in lung tumors and to evaluate Bragg peak plan optimization, characterize plan quality, and quantify organ-at-risk (OAR) sparing. Materials and Methods: Both Bragg peak and transmission plans were optimized using an in-house platform for 10 consecutive lung patients previously treated with proton stereotactic body radiation therapy (SBRT). To bring the dose rate up to the FLASH-RT threshold, Bragg peak plans with a minimum MU/spot of 1200 and transmission plans with a minimum MU/spot of 400 were developed. Two common prescriptions, 34 Gy in 1 fraction and 54 Gy in 3 fractions, were studied with the same beam arrangement for both Bragg peak and transmission plans (n = 40 plans). RTOG 0915 dosimetry metrics and dose rate metrics based on different dose rate calculations, including average dose rate (ADR), dose-averaged dose rate (DADR), and dose threshold dose rate (DTDR), were investigated. We then evaluated the effect of beam angular optimization on the Bragg peak plans to explore the potential for superior OAR sparing. Results: Bragg peak plans significantly reduced doses to several OAR dose parameters, including lung V7.4Gy and V7Gy by 32.0% (p < 0.01) and 30.4% (p < 0.01) for 34Gy/fx plans, respectively; and by 40.8% (p < 0.01) and 41.2% (p < 0.01) for 18Gy/fx plans, respectively, compared with transmission plans. Bragg peak plans have ~3% less in DADR and ~10% differences in mean OARs in DTDR and DADR relative to transmission plans due to the larger portion of lower dose regions of Bragg peak plans. With angular optimization, optimized Bragg peak plans can further reduce the lung V7Gy by 20.7% (p < 0.01) and V7.4Gy by 19.7% (p < 0.01) compared with Bragg peak plans without angular optimization while achieving a similar 3D dose rate distribution. Conclusion: The single-energy Bragg peak plans achieve superior dosimetry performances in OARs to transmission plans with comparable dose rate performances for lung cancer FLASH therapy. Beam angle optimization can further improve the OAR dosimetry parameters with similar 3D FLASH dose rate coverage.

Feasibility and Patient Tolerance of Proton Based Stereotactic Body Radiotherapy

<h3>Purpose/Objective(s)</h3> Proton-based stereotactic body radiotherapy (SBRT) may provide a dosimetric benefit vs photon SBRT in certain cases, seeking to reduce toxicity risks or facilitate reirradiation, though data are limited. We assessed the feasibility and patient tolerance of proton SBRT for palliation and ablation. <h3>Materials/Methods</h3> From Sep. 2019 to Dec. 2020, 58 patients were simulated for proton SBRT to 68 lesions. Acute toxicities were prospectively recorded using CTCAE grading without attribution, and patient-reported outcomes were assessed prior to and at completion of treatment using the MD Anderson Symptom Inventory (MDASI) and EQ-5D5L visual analogue score (VAS). <h3>Results</h3> 52 of 58 patients (90%) received SBRT treatment. Treatment was not initiated in 6 patients due insurance denial (n = 1), change in treatment plan (n = 1), interval disease progression (n = 1), transition to hospice (n = 2), or death (n = 1). Fractionation varied by indication and disease site with a median of 5 fractions and a median fractional dose of 8 Gy. Proton range uncertainty (RU) was ± 3.5% in soft tissue and ± 5% in lung. For bone or immobile lesions, a target equivalent to a standard photon SBRT PTV was defined and optimized with RU. For mobile targets, 4D CT was used to define an ITV for robust optimization, typically with 5 mm positional uncertainty + RU, using a PTV Evaluation for assessment of comparable SBRT plan metrics. Among 27 patients with 4D CT assessment of target motion, 20 (74%) were treated with beam-gated breath hold, 4 (15%) with abdominal compression, and 3 (11%) free breathing. Cone beam CT (CBCT) was used for image guidance at each fraction. Average conformity index was 1.06 and average number of treatment fields per target was 4 (range of 2-8). The median treatment time per fraction was 41 minutes (range 18-171 mins). There was a significant difference in treatment time for patients requiring breath hold (67 vs 47 mins, <i>P</i> = 0.006). Five patients (10%) required adaptive replanning due to set up uncertainties (n = 3) or tumor growth (n = 2). 11 patients (21%) had concurrent systemic therapy. 21 patients (40%) had no observable acute toxicity associated with treatment. Maximum recorded toxicities, related or unrelated to SBRT treatment, were grade 1 in 25 patients (48%), grade 2 (fatigue, depression, anorexia, proctitis) in 5 patients (10%), and grade 3 (dysphagia and hoarseness) in 1 patient (2%). Comparing pretreatment to end of treatment timepoints, there was a significant improvement in the mean VAS (68 to 76, <i>P</i> = 0.027, n = 33), with no significant change in the mean MDASI symptom (1.8, 1.8) or interference (2.2, 2.3) scores. <h3>Conclusion</h3> Proton-based SBRT was feasible and well-tolerated with no decrement in patient reported outcomes and a mean 8 point improvement in VAS at the conclusion of SBRT. Further follow-up is necessary for tumor control and late effects analysis.

SBRT for the Treatment of Isolated Local Recurrence of Resected Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Following curative resection for pancreatic ductal adenocarcinoma (PDAC), there are high rates of local recurrence. The optimal treatment of patients with isolated local recurrence (ILR) – recurrence in the abdomen without distant metastases – is not known. This study evaluated stereotactic body radiation therapy (SBRT) as a treatment option for ILR. <h3>Materials/Methods</h3> A multi-institutional retrospective analysis was performed on patients with ILR of PDAC following oncologic surgical resection treated with SBRT. Patient demographics, tumor and prior treatment characteristics, details of recurrence, SBRT treatment design and dosimetry, and patient follow-up and toxicity data were recorded from the medical record. Progression and overall survival estimates were calculated using cumulative incidence and Kaplan-Meier models, respectively. <h3>Results</h3> Between January 2010 and December 2020, 34 patients (17 males and 17 females, median age 69 years) were treated at five institutions in the United States. At the time of initial resection, most patients had T3 tumors (71%) and involved lymph nodes (71%). 31 of 34 (91%) patients underwent a Whipple procedure and 3 (9%) had a distal pancreatectomy. The R0 resection rate was 68%. 29% and 85% received neoadjuvant or adjuvant chemotherapy, respectively; and 12% and 27% had prior neoadjuvant or adjuvant radiation courses around the time of initial surgical resection. Median time to ILR was 18.7mos. The most common location of recurrence was in the pancreatic remnant or near the superior mesenteric artery. All patients underwent 5-fraction photon (28 patients) or proton (6 patients) SBRT to a median dose of 3500cGy (range 3000-4000cGy) with a median BED of 5950cGy (α/β = 10). Median follow-up after SBRT was 3.05 years. The 1-year and 2-year cumulative incidence of cancer progression were 72% (95% CI 56-93%) and 92% (95% CI 76-100%). Distant metastasis was the most common site of first recurrence (15 of 23 recurrences, 65%). 6 patients (25%) had local failure as site of first recurrence. Prior radiation was not associated with increased risk of progression after SBRT (HR 1.31 95% CI 0.56-3.07, <i>P</i> = 0.54). 1-year and 2-year overall survival was 64% (95% CI 49-84%) and 40% (95% CI 25-64%), with a median survival of 1.2 years from time of SBRT. Four patients (12%) developed grade 3 toxicities within one year after completion of SBRT. There were no grade 4-5 toxicities. <h3>Conclusion</h3> For treatment of PDAC ILR after surgical resection, SBRT was well tolerated and offered high rates of local tumor control with low treatment-related toxicity.

Uniform versus non-uniform dose prescription for proton stereotactic body radiotherapy of liver tumors investigated by extensive motion-including treatment simulations

Compared to x-ray-based stereotactic body radiotherapy (SBRT) of liver cancer, proton SBRT may reduce the normal liver tissue dose. For an optimal trade-off between target and liver dose, a non-uniform dose prescription is often applied in x-ray SBRT, but lacks investigation for proton SBRT. Also, proton SBRT is prone to breathing-induced motion-uncertainties causing target mishit or dose alterations by interplay with the proton delivery. This study investigated non-uniform and uniform dose prescription in proton-based liver SBRT, including effects of rigid target motion observed during planning-4DCT and treatment. The study was based on 42 x-ray SBRT fractions delivered to 14 patients under electromagnetic motion-monitoring. For each patient, a non-uniform and uniform proton plan were made. The uniform plan was renormalized to be iso-toxic with the non-uniform plan using a NTCP model for radiation-induced liver disease. The motion data were used in treatment simulations to estimate the delivered target dose with rigid motion. Treatment simulations were performed with and without a repainting scheme designed to mitigate interplay effects. Including rigid motion, the achieved CTV mean dose after three fractions delivered without repainting was on average (±SD) 24.8 ± 8.4% higher and the D98% was 16.2 ± 11.3% higher for non-uniform plans than for uniform plans. The interplay-induced increase in D2% relative to the static plans was reduced from 3.2 ± 4.1% without repainting to −0.5 ± 1.7% with repainting for non-uniform plans and from 1.5 ± 2.0% to 0.1 ± 1.3% for uniform plans. Considerable differences were observed between estimated CTV doses based on 4DCT motion and intra-treatment motion. In conclusion, non-uniform dose prescription in proton SBRT may provide considerably higher tumor doses than uniform prescription for the same complication risk. Due to motion variability, target doses estimated from 4DCT motion may not accurately reflect the delivered dose. Future studies including modelling of deformations and associated range uncertainties are warranted to confirm the findings.

Proton stereotactic body radiation therapy for liver metastases-results of 5-year experience for 81 hepatic lesions.

To report on our institutional experience using Proton stereotactic body radiation therapy (SBRT) for patients with liver metastases. All patients with liver metastases treated with Proton SBRT between September 2012 and December 2017 were retrospectively analyzed. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method calculated from the time of completion of Proton SBRT. LC was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Forty-six patients with 81 lesions were treated with Proton SBRT. The median age was 65.5 years old (range, 33-86 years) and the median follow up was 15 months (range, 1-54 months). The median size of the gross tumor volume (GTV) was 2.5 cm (range, 0.7-8.9 cm). Two or more lesions were treated in 56.5% of patients, with one patient receiving treatment to a total of five lesions. There were 37 lesions treated with a biologically effective dose (BED) ≤60, 9 lesions with a BED of 61-80, 22 lesions with a BED of 81-100, and 13 lesions with a BED >100. The 1-year and 2-year LC for all lesions was 92.5% (95% CI, 82.7% to 96.8%). The grade 1 and grade 2 toxicity rates were 37% and 6.5%, respectively. There were no grade 3 or higher toxicities and no cases of radiation-induced liver disease (RILD). Proton SBRT for the treatment of liver metastases has promising LC rates with the ability to safely treat multiple liver metastases. Accrual continues for our phase II trial treating liver metastases with Proton SBRT to 60 GyE (Gray equivalent) in 3 fractions.

Lung Stereotactic Body Radiotherapy (SBRT) Using Spot-Scanning Proton Arc (SPArc) Therapy: A Feasibility Study.

PurposeWe developed a 4D interplay effect model to quantitatively evaluate breathing-induced interplay effects and assess the feasibility of utilizing spot-scanning proton arc (SPArc) therapy for hypo-fractionated lung stereotactic body radiotherapy (SBRT). The model was then validated by retrospective application to clinical cases.Materials and MethodsA digital lung 4DCT phantoms was used to mimic targets in diameter of 3cm with breathing motion amplitudes: 5, 10, 15, and 20 mm, respectively. Two planning groups based on robust optimization were generated: (1) Two-field Intensity Modulated Proton Therapy (IMPT) plans and (2) SPArc plans via a partial arc. 5,000 cGy relative biological effectiveness (RBE) was prescribed to the internal target volume (ITV) in five fractions. To quantitatively assess the breathing induced interplay effect, the 4D dynamic dose was calculated by synchronizing the breathing pattern with the simulated proton machine delivery sequence, including IMPT, Volumetric repainting (IMPTvolumetric), iso-layered repainting (IMPTlayer) and SPArc. Ten lung patients’ 4DCT previously treated with VMAT SBRT, were used to validate the digital lung tumor model. Normal tissue complicated probability (NTCP) of chestwall toxicity was calculated.ResultTarget dose were degraded as the tumor motion amplitude increased. The 4D interplay effect phantom model indicated that motion mitigation effectiveness using SPArc was about five times of IMPTvolumetric or IMPTlayer using maximum MU/spot as 0.5 MU at 20 mm motion amplitude. The retrospective study showed that SPArc has an advantage in normal tissue sparing. The probability of chestwall’s toxicity were significantly improved from 40.2 ± 29.0% (VMAT) (p = 0.01) and 16.3 ± 12.0% (IMPT) (p = 0.01) to 10.1 ± 5.4% (SPArc). SPArc could play a significant role in the interplay effect mitigation with breathing-induced motion more than 20 mm, where the target D99 of 4D dynamic dose for patient #10 was improved from 4,514 ± 138 cGy [RBE] (IMPT) vs. 4,755 ± 129 cGy [RBE] (SPArc) (p = 0.01).ConclusionSPArc effectively mitigated the interplay effect for proton lung SBRT compared to IMPT with repainting and was associated with normal tissue sparing. This technology may make delivery of proton SBRT more technically feasible and less complex with fewer concerns over underdosing the target compared to other proton therapy techniques.

Delivery Uncertainty Estimation Using Daily Breath-Hold Cone-Beam CTs For Liver Proton Stereotactic Body Radiotherapy

To estimate for proton stereotactic body radiotherapy (SBRT) plan delivery uncertainty with daily cone-beam CT (CBCT) imaging for liver patients under breath-hold with active breath coordinator (ABC). Images from 11 liver patients previously treated with photon SBRT with ABC at our institution are used for this study. The prescribed dose for the proton SBRT plan is 75 Gy (RBE) in 5 fractions. There is a total of 11 patients with 113 setup CBCT images collected during the patient’s previous photon SBRT treatment. The planning CT and all CBCT images are imported into Raystation 9A. A CT relative linear stopping power (RLSP) curve is calibrated for CBCT and used for proton dose calculation. A four beams proton SBRT plan is optimized with the single field optimization (SFO) technique. All 113 CBCT images are registered to planning CT with bony anatomy (rib cage and vertebrae) or liver to evaluate the delivery uncertainty. The delivery dose is estimated from the proton dose calculation on each CBCT image with the same proton plan. The dose coverages for targets are evaluated for: gross tumor volume (GTV), gtv_multABC_2mmRad_5mmSI, and ptv_5mmRad_7mmSI. Liver positions under DIBH with ABC are not consistent under bony alignment as measured. The inter-fractional and intra-fractional variation of DIBH for liver are analyzed. Proton plan delivery uncertainty can dramatically reduce under well liver alignment (up to 5% prescription dose). Daily CBCT images could be potentially used to estimate proton plan delivery uncertainty for liver patients.