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

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

Investigate potential clinical benefits and linear energy transfer sparing utilizing proton arc therapy for hepatocellular carcinoma.

PURPOSE: To investigate the potential clinical benefits and dose-averaged Linear Energy Transfer (LETd) sparing, utilizing proton arc plan for hepatocellular carcinoma (HCC) patients in comparison with Intensity Modulated Proton Therapy (IMPT). METHODS: Ten HCC patients have been retrospectively selected. Two planning groups were created: Proton Arc plans using Monaco ver. 6 and the clinical IMPT plan. Both planning groups used the same robustness parameters. The prescription dose is 67.5 Gy (RBE) in 15 fractions of the Clinical Target Volume (CTV). Robustness evaluations were performed to ensure dose coverage. Normal Tissue Complicated Probability (NTCP) model was utilized to predict the possibility of Radiation-Induced Liver Disease (RILD) and evaluate the potential benefit of proton arc therapy. LETd calculation and evaluation were performed as well. RESULTS: Proton arc plan has shown better dosimetric improvements of most Organ-At-Risks (OARs). More specifically, the liver mean dose has been significantly reduced from 14.7 GyE to 10.62 GyE compared to the IMPT plan. The predicted possibility of RILD has also been significantly reduced for cases with a large and deep liver target where healthy liver tissue sparing is a challenge. Additionally, proton arc therapy could increase the average LETd in the target and reduce LETd in adjacent OARs. CONCLUSIONS: The potential clinical benefit of utilizing proton arc therapy HCC varies depending on the patient-specific geometry. With more freedom, proton arc therapy can offer a better dosimetric plan quality in the challenge cases, which might not be feasible using the current IMPT technique.

Proton Therapy Adaptation of Perisinusoidal and Brain Areas in the Cyclotron Centre Bronowice in Krakow: A Dosimetric Analysis.

Applying a proton beam in radiotherapy enables precise irradiation of the tumor volume, but only for continuous assessment of changes in patient anatomy. Proton beam range uncertainties in the treatment process may originate not only from physical beam properties but also from patient-specific factors such as tumor shrinkage, edema formation and sinus filling, which are not incorporated in tumor volume safety margins. In this paper, we evaluated variations in dose distribution in proton therapy resulting from the differences observed in the control tomographic images and the dosimetric influence of applied adaptive treatment. The data from weekly computed tomography (CT) control scans of 21 patients, which serve as the basis for adaptive radiotherapy, were used for this study. Dosimetric analysis of adaptive proton therapy (APT) was performed on patients with head and neck (H&N) area tumors who were divided into two groups: patients with tumors in the sinus/nasal area and patients with tumors in the brain area. For this analysis, the reference treatment plans were forward-calculated using weekly control CT scans. A comparative evaluation of organ at risk (OAR) dose-volume histogram (DVH) parameters, as well as conformity and homogeneity indices, was conducted between the initial and recalculated dose distributions to assess the necessity of the adaptation process in terms of dosimetric parameters. Changes in PTV volume after replanning were observed in seventeen patient cases, showing a discrepancy of over 1 cm3 in ten cases. In these cases, tumor progression occurred in 30% of patients, while regression was observed in 70%. The statistical analysis indicates that the use of the adaptive planning procedure results in a statistically significant improvement in dose distribution, particularly in the PTV area. The findings led to the conclusion that the adaptive procedure provides significant advantages in terms of dose distribution within the treated volume. However, when considering the entire patient group, APT did not result in a statistically significant dose reduction in OARs (α = 0.05).

Dosimetric advantages of adaptive IMPT vs. Enhanced workload and treatment time - A need for automation.

INTRODUCTION: In head-and-neck IMPT, trigger-based offline plan adaptation (Offlinetrigger-based) is often used. Our goal was to compare this to four alternative adaptive strategies for dosimetry, workload and treatment time, considering also foreseen further technological advancements, including anticipated automation. MATERIALS AND METHODS: Alternative strategies included weekly offline re-planning (Offlineweekly), daily plan selection from a library (Librarystatic and Libraryprogsressive) and a fast, approximate daily online re-optimization approach (Onlinere-opt). Impact on CTV coverage and NTCPs was assessed by simulations based on repeat-CTs from 15 patients. Full daily re-planning was used as dosimetric benchmark. Increases in workload and treatment time were estimated. RESULTS: Both for coverage and NTCPs, fast Onlinere-opt performed as well as full re-planning. Compared to current practice, Onlinere-opt showed enhanced probabilities for high coverage, and resulted in reductions in grade ≥ II NTCPs of 4.6 ±â€¯1.7 %-point for xerostomia and 4.2 ±â€¯2.3 %-point for dysphagia. Offlineweekly and library strategies did not show coverage enhancements and resulted in smaller NTCP improvements. Further automation can largely limit workload and treatment time increases. With anticipated further automation, adaptation-related workload of Offlineweekly, Librarystatic, Libraryprogressive, and Onlinere-opt was expected to increase by 3, 8, 21, and 66 h for 35 fraction treatment courses compared to Offlinetrigger-based. The corresponding adaptation-related prolonged treatment times were estimated to be 0, 4, 6, and 29 min/fraction. CONCLUSION: Online adaptive strategies could approach dosimetric quality of full re-planning at the cost of additional workload and prolonged treatment time compared to the current offline adaptive strategy. Automation needs to play a key role in making more complex adaptive approaches feasible.

Inter-fraction motion robustness in a prospective phase II trial on dose-escalated proton reirradiation for locally recurrent rectal cancer.

Background and purpose: Intensity modulated proton therapy (IMPT) enables generation of conformal dose plans with organ at risk (OAR) sparing potential. However, pelvic IMPT robustness is challenged by inter-fraction motion caused by constant anatomical variations. In this study, the dosimetric impact of inter-fraction motion on target coverage and dose to OAR was quantified in the prospective phase II study ReRad-II on dose-escalated proton reirradiation for locally recurrent rectal cancer (LRRC). Materials and methods: The inter-fraction motion robustness was assessed for the initial twelve patients enrolled in the ReRad-II study. Patients with resectable LRRC were assessed for neoadjuvant IMPT (55 Gy(RBE)/44Fx) and unresectable recurrences for definitive IMPT (57.5-65 Gy(RBE)/ 46-52Fx). Target coverage and dose to OAR were assessed for robustly optimised three-field IMPT, on 12 plan computerized tomography (CT) scans (pCT) - and 47 repetitive control CT scans (cCTs) during the treatment. The target coverage and doses to OAR were re-calculated on each cCT and the mean dose ratio (pCT/cCT-ratio) and target coverage (V95%) was evaluated. Results: The target coverage was robust with a mean dose pCT/cCT-ratio of 1.00 (+/-1%). The V95% target coverage for every cCT were above the accepted worst-case scenario in the robust evaluation. Considerable variation in bladder-, bowel bag-, and bowel loop volume was observed. The OAR with the largest variation in ratio was the bladder (pCT/cCT-ratio: 1.3 (range: 0.5-4.7). Conclusions: IMPT for dose-escalated reirradiation of LRRC provided anatomically robust target coverage despite OAR changes. Inter-fraction motion resulted in OAR doses varying within clinically acceptable range.

Explore the feasibility of using spot-scanning proton arc therapy for a synchrotron accelerator-based proton therapy system - A simulation study.

OBJECTIVE: The aim of this study was to evaluate the feasibility and plan quality of spot-scanning proton arc therapy (SPArc) using a synchrotron-accelerator-based proton therapy system compared to intensity-modulated proton therapy (IMPT). APPROACH: Five representative disease sites, including head and neck, lung, liver, brain chordoma, and prostate cancers, were retrospectively selected. Both IMPT and SPArc plans are generated with the HITACHI ProBEAT PBS system's minimum MU constraints and physics beam model. The SPArc plans are generated with 2.5° sampling frequency. The static delivery time was simulated based on the previously published synchrotron delivery sequence model, and the dynamic delivery time was simulated using a proton arc gantry mechanical model integrated with the synchrotron delivery sequence. Both dosimetric plan quality and delivery efficiency are evaluated. MAIN RESULTS: A superior plan quality is reached compared with the IMPT plans generated for the same disease site. However, a relatively prolonged static and dynamic delivery time post new challenge, as static time increased by 49.22% and dynamic time 59.10% on average. SIGNIFICANCE: This study presents the first simulation results of delivering the SPArc plans using a synchrotron-accelerated proton therapy system. The result shows its feasibility and limitations, which could guide future development.

Robust IMPT and follow-up toxicity in skull base chordoma and chondrosarcoma-a single-institution clinical experience.

BACKGROUND: Chordomas and chondrosarcomas of the skull base are rare, slowly growing malignant bone neoplasms. Despite their radioresistant properties, proton therapy has been successfully used as an adjunct to resection or as a definitive treatment. Herewith, we present our experience with robustly optimized intensity-modulated proton therapy (IMPT) and related toxicities in skull base chordoma and chondrosarcoma patients treated at HollandPTC, Delft, the Netherlands. METHODS: Clinical data, treatment plans, and acute toxicities of patients treated between July 2019 and August 2021 were reviewed. CT and 3.0T MRI scans for treatment planning were performed in supine position in a thermoplastic mold. In total, 21 dose optimization and 28 dose evaluation scenarios were simulated. Acute toxicity was scored weekly before and during the treatment according to the CTCAE v4.0. Median follow-up was 35 months (range 12-36 months). RESULTS: Overall, 9 chordoma and 3 chondrosarcoma patients with 1-3 resections prior to IMPT were included; 4 patients had titanium implants. Brainstem core and surface and spinal cord core and surface were used for nominal plan robust optimization in 11, 10, 8, and 7 patients, respectively. Middle ear inflammation, dry mouth, radiation dermatitis, taste disorder, and/or alopecia of grades 1-3 were noted at the end of treatment among 6 patients without similar complaints at inclusion; symptoms disappeared 3 months following the treatment. CONCLUSION: Robustly optimized IMPT is clinically feasible as a postoperative treatment for skull base chordoma and chondrosarcoma patients. We observed acceptable early toxicities (grade 1-3) that disappeared within the first 3 months after irradiation.

Proton Therapy Reduces the Effective Dose to Immune Cells in Mediastinal Hodgkin Lymphoma Patients.

Purpose: Effective dose to circulating immune cells (EDIC) is associated with survival in lung and esophageal cancer patients. This study aimed to evaluate the benefit of intensity-modulated proton therapy (IMPT) for EDIC reduction compared with volumetric modulated arc therapy (VMAT) in mediastinal Hodgkin lymphoma (mHL) patients. Materials and Methods: Ten consecutive mHL patients treated with involved-site IMPT after frontline chemotherapy were included. The mean dose to the heart, lung, and liver and the integral dose to the body were obtained, and we calculated EDIC based on these variables. The effective dose to circulating immune cells was compared between IMPT and VMAT schedules. Results: The median EDIC was reduced from 1.93 Gy (range: 1.31-3.87) with VMAT to 1.08 Gy (0.53-2.09) with IMPT (P < .01). Integral dose reduction was the main driver of EDIC reduction with IMPT, followed by lung sparing. Conclusion: Intensity-modulated proton therapy significantly reduced EDIC in mHL patients undergoing consolidation involved-site radiation therapy. Integral dose reduction combined with improved lung sparing was the main driver of EDIC reduction with IMPT.

In Silico Comparison of Three Different Beam Arrangements for Intensity-Modulated Proton Therapy for Postoperative Whole Pelvic Irradiation of Prostate Cancer.

Background and purpose: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. The aim of this study was to evaluate three different intensity-modulated proton therapy (IMPT) beam arrangements when treating the prostate bed and pelvis in the postoperative setting. Materials and Methods: Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (IMPT2B) (opposed laterals), three-field (IMPT3B) (opposed laterals inferiorly matched to a posterior-anterior beam superiorly), and four-field (IMPT4B) (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. The prescription was 50 Gy radiobiological equivalent (GyE) to the pelvis and 70 GyE to the prostate bed. Comparisons were made using paired two-sided Wilcoxon signed-rank tests. Results: CTV coverages were met for all IMPT plans, with 99% of CTVs receiving ≥ 100% of prescription doses. All organ at risk (OAR) objectives were met with IMPT3B and IMPT4B plans, while several rectum objectives were exceeded by IMPT2B plans. IMPT4B provided the lowest doses to OARs for the majority of analyzed outcomes, with significantly lower doses than IMPT2B +/- IMPT3B for bladder V30-V50 and mean dose; bowel V15-V45 and mean dose; sigmoid maximum dose; rectum V40-V72.1, maximum dose, and mean dose; femoral head V37-40 and maximum dose; bone V40 and mean dose; penile bulb mean dose; and skin maximum dose. Conclusion: This study is the first to compare proton beam arrangements when treating the prostate bed and pelvis. four-field plans provided better sparing of the bladder, bowel, and rectum than 2- and three-field plans. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer.

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

BACKGROUND: Intensity-modulated proton therapy (IMPT) optimizes spot intensities and position, providing better conformability. However, the successful application of IMPT is dependent upon addressing the challenges posed by range and setup uncertainties. In order to address the uncertainties in IMPT, robust optimization is essential. PURPOSE: This study aims to develop a novel fast algorithm for robust optimization of IMPT with minimum monitor unit (MU) constraint. METHODS AND MATERIALS: The study formulates a robust optimization problem and proposes a novel, fast algorithm based on the alternating direction method of multipliers (ADMM) framework. This algorithm enables distributed computation and parallel processing. Ten clinical cases were used as test scenarios to evaluate the performance of the proposed approach. The robust optimization method (RBO-NEW) was compared with plans that only consider nominal optimization using CTV (NMO-CTV) without handling uncertainties and PTV (NMO-PTV) to handle the uncertainties, as well as with conventional robust-optimized plans (RBO-CONV). Dosimetric metrics, including D95, homogeneity index, and Dmean, were used to evaluate the dose distribution quality. The area under the root-mean-square dose (RMSD)-volume histogram curves (AUC) and dose-volume histogram (DVH) bands were used to evaluate the robustness of the treatment plan. Optimization time cost was also assessed to measure computational efficiency. RESULTS: The results demonstrated that the RBO plans exhibited better plan quality and robustness than the NMO plans, with RBO-NEW showing superior computational efficiency and plan quality compared to RBO-CONV. Specifically, statistical analysis results indicated that RBO-NEW was able to reduce the computational time from 389.70 ± 207.40 $389.70\pm 207.40$ to 228.60 ± 123.67 $228.60\pm 123.67$ s ( p < 0.01 $p<0.01$ ) and reduce the mean organ-at-risk (OAR) dose from 9.38 ± 12.80 $9.38\pm 12.80$ % of the prescription dose to 9.07 ± 12.39 $9.07\pm 12.39$ % of the prescription dose ( p < 0.05 $p<0.05$ ) compared to RBO-CONV. CONCLUSION: This study introduces a novel fast robust optimization algorithm for IMPT treatment planning with minimum MU constraint. Such an algorithm is not only able to enhance the plan's robustness and computational efficiency without compromising OAR sparing but also able to improve treatment plan quality and reliability.

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

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

Proton therapy reduces the effective dose to immune cells in breast cancer patients.

BACKGROUND: The effective dose to circulating immune cells (EDIC) is associated with survival in lung and esophageal cancer patients. This study aimed to evaluate the benefit of intensity-modulated proton therapy (IMPT) for EDIC reduction as compared to volumetric modulated arc therapy (VMAT) in patients with locally advanced breast cancer (BC). MATERIALS AND METHODS: Ten BC patients treated with locoregional VMAT after breast-conserving surgery were included. Mean dose to the heart (MHD), lungs (MLD), and liver (MlD), as well as the integral dose to the body (ITD), were retrieved, and we calculated EDIC as 0.12â€¯× MLD + 0.08â€¯× MHD + 0.15â€¯× 0.85â€¯× âˆš(n/45)â€¯× MlD + (0.45 + 0.35â€¯× 0.85â€¯× âˆš(n/45))â€¯× ITD/(62â€¯× 103), where n is the number of fractions. EDIC was compared between VMAT and IMPT plans. RESULTS: Median EDIC was reduced from 3.37 Gy (range: 2.53-5.99) with VMAT to 2.13 Gy (1.31-3.77) with IMPT (p < 0.01). For left-sided BC patients, EDIC was reduced from 3.15 Gy (2.53-3.78) with VMAT to 1.65 Gy (1.31-3.77) with IMPT (p < 0.01). For right-sided BC patients, EDIC was reduced from 5.60 Gy (5.06-5.99) with VMAT to 3.38 Gy (3.10-3.77) with IMPT (p < 0.01). Right-sided BC patients had a higher EDIC irrespective of the technique. Integral dose reduction was the main driver of EDIC reduction with IMPT and was associated with lung sparing for left-sided BC patients or liver sparing for right-sided BC patients. CONCLUSION: IMPT significantly reduced EDIC in BC patients undergoing locoregional adjuvant radiotherapy. Integral total dose reduction, associated with improved lung sparing in left-sided BC patients or liver sparing in right-sided BC patients, mainly drove EDIC reduction with IMPT. The emergence of dynamic models taking into account the circulatory kinetics of immune cells may improve the accuracy of the estimate of the dose received by the immune system compared to calculation of the EDIC, which is based solely on static dosimetric data.

Post-irradiation dysbiosis in patients with nasopharyngeal carcinoma having received radiotherapy - A pilot study.

OBJECTIVE: To compare the changes in the sinonasal mucosa microbiome in patients with nasopharyngeal carcinoma (NPC) before and after radiotherapy (RT), and to explore the pathogenesis of post-irradiation chronic rhinosinusitis (PI-CRS) and its association with dysbiosis. STUDY DESIGN: Prospective cohort study. SETTING: Unicenter, Tertiary referral hospital. METHODS: Included patients newly diagnosed with NPC. Samples of ostiomeatal complex mucosa were collected before and after RT. Microbiome analysis was conducted using 16S rRNA sequencing, and statistical analysis was performed. Subgroup analyses based on RT modality (proton therapy or photon therapy) RESULTS: Total of 18 patients were enrolled in the study, with 62.1% receiving intensity-modulated proton therapy (IMPT). Corynebacterium was the most dominant genus identified in both the pre- and post-RT groups, with a visible increase in Staphylococcus and a decrease in Fusobacterium genus in post-RT group. Alpha-diversity did not significantly differ between groups, although the beta-diversity analysis revealed a dispersed microbiota in the post-RT group. The functional prediction indicated a higher relative abundance of taxonomies associated with biofilm formation in the post-RT group. The subgroup analysis revealed the above changes to be more significant in patients who received photon therapy (Intensity modulated radiation therapy, IMRT). CONCLUSIONS: This is the first study to analyze the microbiome of patients with NPC after IMPT. We identified similarities between the post-RT microenvironment and that reported in patients with CRS, with a more apparent change noted in patients treated with IMRT. Further investigation is required to further elucidate the pathogenesis of PI-CRS and its relationship to post-RT dysbiosis, particularly IMPT.

Dosimetric Features of Ultra-Hypofractionated Intensity Modulated Proton Therapy for Prostate Cancer.

Purpose: To report clinical and dosimetric characteristics of 5-fraction stereotactic ablative radiotherapy (SABR) using intensity modulated proton therapy (IMPT) for localized prostate cancer. Materials and Methods: All patients receiving IMPT SABR from 2017 to 2021 for localized prostate cancer at our institution were included. Five fractions were delivered every other day to the prostate +/- seminal vesicles [clinical target volume (CTV)] with 3 mm/3% robustness. A 4-field arrangement with 2 anterior oblique and 2 opposed lateral beams was used in most patients (97%), and most (99%) had a retroprostatic hydrogel spacer. Results: A total of 534 patients with low (14%), favorable intermediate (45%), unfavorable intermediate (36%), high (4.0%), or very high-risk (0.6%) disease are evaluated. Prescription dose was 36.25 Gy (31%), 38 Gy (38%), or 40 Gy (31%) was prescribed. Median volume percentage of CTV receiving at least 100% of prescription dose [V100% (%)] was 100% [interquartile range: 99.99-100]. Rectum V50% (%), V80% (%), and V90% (%) were significantly lower in patients who had spacer, with a mean difference of -9.70%, -6.59%, and -4.42%, respectively, compared to those who did not have spacer. Femoral head dose was lower with a 4-field arrangement. Mean differences in left and right femoral head V40% (%) were -6.99% and -10.74%, respectively. Conclusion: We provide a large, novel report of patients treated with IMPT SABR for localized prostate cancer. Four-field IMPT with hydrogel spacer provides significant sparing of rectum and femoral heads without compromising target coverage.

Cardinality-constrained plan-quality and delivery-time optimization method for proton therapy.

BACKGROUND: While minimizing plan delivery time is beneficial for proton therapy in terms of motion management, patient comfort, and treatment throughput, it often poses a tradeoff with optimizing plan quality. A key component of plan delivery time is the energy switching time, which is approximately proportional to the number of energy layers, that is, the cardinality. PURPOSE: This work aims to develop a novel optimization method that can efficiently compute the pareto surface between plan quality and energy layer cardinality, for the planner to navigate through this quality-and-efficiency tradeoff and select the appropriate plan of a balanced tradeoff. METHODS: A new IMPT method CARD is proposed that (1) explicitly incorporates the minimization of energy layer cardinality as an optimization objective, and (2) automatically generates a set of plans sequentially with a descending order in number of energy layers. The energy layer cardinality is penalized through the l1,0-norm regularization with an upper bound, and the upper bound is monotonically decreased to compute a series of treatment plans with gradually decreased energy layer cardinality on the quality-and-efficiency pareto surface. For any given treatment plan, the plan optimality is enforced using dose-volume planning objectives and the plan deliverability is imposed through minimum-monitor-unit (MMU) constraints, with optimization solution algorithm based on iterative convex relaxation. RESULTS: The new method CARD was validated in comparison with the benchmark plan of all energy layers (P0), and a state-of-the-art method called MMSEL, using prostate, head-and-neck (HN), lung, pancreas, liver and brain cases. While labor-intensive and time-consuming manual parameter tuning was needed for MMSEL to generate plans of predefined energy layer cardinality, CARD automatically and efficiently computed all plans with sequentially decreasing predefined energy layer cardinality all at once. With the acceptable plan quality (i.e., no more than 110% of total optimization objective value from P0), CARD achieved the reduction of number of energy layers to 52% (from 77 to 40), 48% (from 135 to 65), 59% (from 85 to 50), 67% (from 52 to 35), 80% (from 50 to 40), and 30% (from 66 to 20), for prostate, HN, lung, pancreas, liver, and brain cases, respectively, compared to P0, with overall better plan quality than MMSEL. Moreover, due to the nonconvexity of the MMU constraint, CARD provided the similar or even smaller optimization objective than P0, at the same time with fewer number of energy layers, that is, 55 versus 77, 85 versus 135, 45 versus 52, and 25 versus 66 for prostate, HN, pancreas, and brain cases, respectively. CONCLUSIONS: We have developed a novel optimization algorithm CARD that can efficiently and automatically compute a series of treatment plans of any given energy layer sequentially, which allows the planner to navigate through the plan-quality and energy-layer-cardinality tradeoff and select the appropriate plan of a balanced tradeoff.

A new approach to combined proton-photon therapy for metastatic cancer patients.

Objective.Proton therapy is a limited resource and is typically not available to metastatic cancer patients. Combined proton-photon therapy (CPPT), where most fractions are delivered with photons and only few with protons, represents an approach to distribute proton resources over a larger patient population. In this study, we consider stereotactic radiotherapy of multiple brain or liver metastases, and develop an approach to optimally take advantage of a single proton fraction by optimizing the proton and photon dose contributions to each individual metastasis.Approach.CPPT treatments must balance two competing goals: (1) deliver a larger dose in the proton fractions to reduce integral dose, and (2) fractionate the dose in the normal tissue between metastases, which requires using the photon fractions. Such CPPT treatments are generated by simultaneously optimizing intensity modulated proton therapy (IMPT) and intensity modulated radiotherapy (IMRT) plans based on their cumulative biologically effective dose (BEDα/ß). The dose contributions of the proton and photon fractions to each individual metastasis are handled as additional optimization variables in the optimization problem. The method is demonstrated for two patients with 29 and 30 brain metastases, and two patients with 4 and 3 liver metastases.Main results.Optimized CPPT plans increase the proton dose contribution to most of the metastases, while using photons to fractionate the dose around metastases which are large or located close to critical structures. On average, the optimized CPPT plans reduce the mean brain BED2by 29% and the mean liver BED4by 42% compared to IMRT-only plans. Thereby, the CPPT plans approach the dosimetric quality of IMPT-only plans, for which the mean brain BED2and mean liver BED4are reduced by 28% and 58%, respectively, compared to IMRT-only plans.Significance.CPPT with optimized proton and photon dose contributions to individual metastases may benefit selected metastatic cancer patients without tying up major proton resources.

Optimal minimum MU for intensity-modulated proton therapy with pencil-beam scanning proton beams.

PURPOSE: A higher minimum monitor unit (minMU) for pencil-beam scanning proton beams in intensity-modulated proton therapy is preferred for more efficient delivery. However, plan quality may be compromised when the minMU is too large. This study aimed to identify the optimal minMU (OminMU) to improve plan delivery efficiency while maintaining high plan quality. METHODS: We utilized clinical plans including six anatomic sites (brain, head and neck, breast, lung, abdomen, and prostate) from 23 patients previously treated with the Varian ProBeam system. The minMU of each plan was increased from the current clinical minMU of 1.1 to 3-24 MU depending on the daily prescribed dose (DPD). The dosimetric parameters of the plans were evaluated for consistency against a 1.1-minMU plan for target coverage as well as organs-at-risk dose sparing. DPD/minMU was defined as the ratio of DPD to minMU (cGy/MU) to find the OminMU by ensuring that dosimetric parameters did not differ by >1% compared to those of the 1.1-minMU plan. RESULTS: All plans up to 5 minMU showed no significant dose differences compared to the 1.1-minMU plan. Plan qualities remained acceptable when DPD/minMU ≥35 cGy/MU. This suggests that the 35 cGy/MU criterion can be used as the OminMU, which implies that 5 MU is the OminMU for a conventional fraction dose of 180 cGy. Treatment times were decreased by an average of 32% (max 56%, min 7%) and by an average of 1.6 min when the minMU was increased from 1.1 to OminMU. CONCLUSION: A clinical guideline for OminMU has been established. The minMU can be increased by 1 MU for every 35 cGy of DPD without compromising plan quality for most cases analyzed in this study. Significant treatment time reduction of up to 56% was observed when the suggested OminMU is used.

Optimizing spot intensity with lower bound constraints for IMPT: Exposing shortcomings and introducing an enhanced strategy.

BACKGROUND: Intensity Modulated Proton Therapy (IMPT) is a sophisticated radiation treatment allowing for precise dose distributions. However, conventional spot selection strategies in IMPT face challenges, particularly with minimum monitor unit (MU) constraints, affecting planning quality and efficiency. PURPOSE: This study introduces an innovative Two-Stage Mixed Integer Linear Programming (MILP) method to optimize spot intensity in IMPT with Lower Bound (LB) constraints. This method seeks to improve treatment planning efficiency and precision, overcoming limitations of existing strategies. METHODS: Our approach evaluates prevalent IMPT spot selection strategies, identifying their limitations, especially concerning MU constraints. We integrated LB constraints into a MILP framework, using a novel three-phase strategy for spot pool selection, to enhance performance over traditional heuristic methods and L1 + L∞ strategies. The method's efficacy was tested in eight study cases, using Dose-Volume Histograms (DVHs), spot selection efficiency, and computation time analysis for benchmarking against established methods. RESULTS: The proposed method showed superior performance in DVH quality, adhering to LB constraints while maintaining high-quality treatment plans. It outperformed existing techniques in spot selection, reducing unnecessary spots and balancing precision with efficiency. Cases studies confirmed the method's effectiveness in producing clinically feasible plans with enhanced dose distributions and reduced hotspots, especially in cases with elevated LB constraints. CONCLUSIONS: Our Two-Stage MILP strategy signifies a significant advancement in IMPT treatment planning. By incorporating LB constraints directly into the optimization process, it achieves superior plan quality and deliverability compared to current methods. This approach is particularly advantageous in clinical settings requiring minimum spot number and high MU LB constraints, offering the potential for improved patient outcomes through more precise and efficient radiation therapy plans.

The first investigation of the dosimetric perturbations from the spot position errors in spot-scanning arc therapy (SPArc).

Objective. To quantitatively investigate the impact of spot position error (PE) on the dose distribution in (Spot-scanning arc therapy) SPArc plans compared to Intensity-Modulated Proton Therapy (IMPT).Approach.Twelve representative cases, including brain, lung, liver, and prostate cancers, were retrospectively selected. Spot PEs were simulated during dynamic SPArc treatment delivery. Two types of errors were generated, including random error and systematic error. Two different probability distributions of random errors were used (1) Gaussian distribution (PEran-GS) (2) uniform distribution (PEran-UN). In PEran-UN, four sub-scenarios were considered: 25%, 50%, 75%, and 100% spots were randomly selected in various directions on the scale of 0-1 mm or 0-2 mm of PE. Additionally, systematic error was simulated by shifting all the spot uniformly by 1 or 2 mm in various directions (PEsys). Gamma-index Passing Rate (GPR) is applied to assess the dosimetric perturbation quantitatively.Main results.For PEran-GSin the 1 mm scenario, both SPArc and IMPT are comparable with a GPR exceeding 99%. However, for PEran-GSin 2 mm scenario, SPArc could provide better GPR. As PEsysof 2 mm, SPArc plans have a much better GPR compared to IMPT plans: SPArc's GPR is 99.59 ± 0.47%, 93.82 ± 4.07% and 64.58 ± 15.83% for 3 mm/3%, 2 mm/2% and 1 mm/1% criteria compared to IMPT with 97.49 ± 2.44%, 84.59 ± 4.99% and 42.02 ± 6.31%.Significance.Compared to IMPT, SPArc shows better dosimetric robustness in spot PEs. This study presents the first simulation results and the methodology that serves as a reference to guide future investigations into the accuracy and quality assurance of SPArc treatment delivery.

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

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