Intensity Modulated Proton Therapy Research Articles

Dosimetric and NTCP analyses for selecting parotid gland cancer patients for proton therapy.

To perform a dosimetric and a normal tissue complication probability (NTCP) comparison between intensity modulated proton therapy and photon volumetric modulated arc therapy in a cohort of patients with parotid gland cancers in a post-operative or radical setting. From May 2011 to September 2021, 37 parotid gland cancers patients treated at two institutions were eligible. Inclusion criteria were as follows: patients aged ⩾ 18 years, diagnosis of parotid gland cancers candidate for postoperative radiotherapy or definitive radiotherapy, presence of written informed consent for the use of anonymous data for research purposes. Organs at risk (OARs) were retrospectively contoured. Target coverage goal was defined as D95 > 98%. Six NTCP models were selected. NTCP profiles were calculated for each patient using an internally-developed Python script in RayStation TPS. Average differences in NTCP between photon and proton plans were tested for significance with a two-sided Wilcoxon signed-rank test. Seventy-four plans were generated. A lower Dmean to the majority of organs at risk (inner ear, cochlea, oral cavity, pharyngeal constrictor muscles, contralateral parotid and submandibular gland) was obtained with intensity modulated proton therapy vs volumetric modulated arc therapy with statistical significance (p < .05). Ten (27%) patients had a difference in NTCP (photon vs proton plans) greater than 10% for hearing loss and tinnitus: among them, seven qualified for both endpoints, two patients for hearing loss only, and one for tinnitus. In the current study, nearly one-third of patients resulted eligible for proton therapy and they were the most likely to benefit in terms of prevention of hearing loss and tinnitus.

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

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

Efficient proton arc optimization and delivery through energy layer pre-selection and post-filtering.

Proton arc therapy (PAT) has emerged as a promising approach for improving dose distribution, but also enabling simpler and faster treatment delivery in comparison to conventional proton treatments. However, the delivery speed achievable in proton arc relies on dedicated algorithms, which currently do not generate plans with a clear speed-up and sometimes even result in increased delivery time. This study aims to address the challenge of minimizing delivery time through a hybrid method combining a fast geometry-based energy layer (EL) pre-selection with a dose-based EL filtering, and comparing its performance to a baseline approach withoutfiltering. Three methods of EL filtering were developed: unrestricted, switch-up (SU), and switch-up gap (SU gap) filtering. The unrestricted method filters the lowest weighted EL while the SU gap filtering removes the EL around a new SU to minimize the gantry rotation braking. The SU filtering removes the lowest weighted group of EL that includes a SU. These filters were combined with the RayStation dynamic proton arc optimization framework energy layer selection and spot assignment (ELSA). Four bilateral oropharyngeal and four lung cancer patients' data were used for evaluation. Objective function values, target coverage robustness, organ-at-risk doses and normal tissue complication probability evaluations, as well as comparisons to intensity-modulated proton therapy (IMPT) plans, were used to assess plan quality. The SU gap filtering algorithm performed best in five out of the eight cases, maintaining plan quality within tolerance while reducing beam delivery time, in particular for the oropharyngeal cohort. It achieved up to approximately 22% and 15% reduction in delivery time for oropharyngeal and lung treatment sites, respectively. The unrestricted filtering algorithm followed closely. In contrast, the SU filtering showed limited improvement, suppressing one or two SU without substantial delivery time shortening. Robust target coverage was kept within 1% of variation compared to the PAT baseline plan while organs-at-risk doses slightly decreased or kept about the same for all patients. This study provides insights to accelerate PAT delivery without compromising plan quality. These advancements could enhance treatment efficiency and patientthroughput.

On polling directions for randomized direct-search approaches: application to beam angle optimization in intensity-modulated proton therapy

AbstractDeterministic direct-search methods have been successfully used to address real-world challenging optimization problems, including the beam angle optimization (BAO) problem in radiation therapy treatment planning. BAO is a highly non-convex optimization problem typically treated as the optimization of an expensive multi-modal black-box function which results in a computationally time consuming procedure. For the recently available modalities of radiation therapy with protons (instead of photons) further efficiency in terms of computational time is required despite the success of the different strategies developed to accelerate BAO approaches. Introducing randomization into otherwise deterministic direct-search approaches has been shown to lead to excellent computational performance, particularly when considering a reduced number (as low as two) of random poll directions at each iteration. In this study several randomized direct-search strategies are tested considering different sets of polling directions. Results obtained using a prostate and a head-and-neck cancer cases confirmed the high-quality results obtained by deterministic direct-search methods. Randomized strategies using a reduced number of polling directions showed difficulties for the higher dimensional search space (head-and-neck) and, despite the excellent mean results for the prostate cancer case, outliers were observed, a result that is often ignored in the literature. While, for general global optimization problems, mean results (or obtaining the global optimum once) might be enough for assessing the performance of the randomized method, in real-world problems one should not disregard the worst-case scenario and beware of the possibility of poor results since, many times, it is only possible to run the optimization problem once. This is even more important in healthcare applications where the mean patient does not exist and the best treatment possible must be assured for every patient.

Abstract PO4-22-03: Intensity Modulated Proton Therapy (IMPT) for the Definitive Adjuvant Management of Women with Breast Cancer: A Single Institutional Experience of 5-Year Oncologic Outcomes

Abstract Purpose: There is limited data reporting the oncologic outcomes of breast cancer patients treated definitively with adjuvant proton beam therapy. Here we report a single institutional experience of oncologic outcomes, treating a predominantly vulnerable breast cancer patient population and compare these to historical standards primarily utilizing photon therapy. Materials and Methods: Unver IRB approval, we retrospectively reviewed 453 definitively treated breast cancer patients from 2016 – 2023 using adjuvant IMPT as part of their cancer care. Patients with recurrent disease, receiving re-irradiation, and those with less than 1-year of follow up were excluded from this analysis. Patients were treated with surgery and systemic therapies as per standards of care. Radiation therapy was administered using pencil beam scanning IMPT with daily image guidance. χ2 and Mann-Whitney U tests were performed to determine differences between select variables. Kaplan-Meier analysis and Cox proportional hazard models were used to analyze overall survival (OS). Results: With a median follow up of 22 months for the entire cohort, 453 patients were treated at XXXX as part of definitive adjuvant management for their breast cancer. Nearly 30% of patients self-identified as black (n=135), average patient age was 54 and 56% (n=255) self-identified as being married with approximately 25% (n=109) of patients having Medicare/Medicaid insurance. 198 patients (43.8%) had an intact breast and the remainder mastectomy of which 37.4% had reconstruction at the time of their radiation. 229 patients (50.7%) received neoadjuvant chemotherapy while 55 patients (12%) received concurrent chemotherapy which was either her2+ directed or Xeloda. The number of patients (%) corresponding to the AJCC 8th edition anatomical staging is as follows: Stage 0: 12 (2.7%); Stage I: 91 (20.1%); Stage 2: 197 (43.6%); Stage 3: 152 (33.6%). Median RT dose delivered for patients receiving comprehensive treatment was 50.4 Gy with 81% of patients receiving a boost to either scar, lumpectomy cavity and/or LN regions. Median RT dose delivered for patients receiving whole breast radiation was 42.56 Gy with a 10 Gy lumpectomy cavity boost. 5-yr OS by stage was 0: 100%; stage I: 98.8%; stage 2: 93.5%; stage 3: 90.8%. Five-year OS for black, white and other race patients were 85.3%, 95.8% and 96%, respectively (White as Ref: HR 3.176, 95% CI: 1.313-7.681, p=0.010 for black patients). For the entire cohort, patients with triple negative disease had a 5-yr OS of 80.4% (HR: 4.33, 95% CI 1.87-10.04, p&amp;lt; 0.001) and there was no difference in OS when insurance status was considered (p=0.378). Conclusions: To the best of our knowledge this represents the largest series of definitively treated breast cancer patients utilizing adjuvant proton therapy and the 5-year OS rates in our analysis coincide with published standards1. Results from the on-going randomized RADCOMP study will provide further guidance as to which patients benefit the most from proton therapy and will further support equivalent oncological outcomes when compared to photon therapy. 1. Weiss A, Chavez-MacGregor M, Lichtensztajn DY, et al. Validation study of the American Joint Committee on Cancer eighth edition prognostic stage compared with the anatomic stage in breast cancer. JAMA Oncol. 4(2):203-209, 2018. Citation Format: Elizabeth Nichols, Gurbani Singh, Desiree Lejano, Sarah McAvoy, Mark Mishra, Melissa Vyfhuis. Intensity Modulated Proton Therapy (IMPT) for the Definitive Adjuvant Management of Women with Breast Cancer: A Single Institutional Experience of 5-Year Oncologic Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-03.

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

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

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

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

Simultaneous reduction of number of spots and energy layers in intensity modulated proton therapy for rapid spot scanning delivery.

Reducing proton treatment time improves patient comfort and decreases the risk of error from intrafractional motion, but must be balanced against clinical goals and treatment planquality. To improve the delivery efficiency of spot scanning proton therapy by simultaneously reducing the number of spots and energy layers using the reweighted regularizationmethod. We formulated the proton treatment planning problem as a convex optimization problem with a cost function consisting of a dosimetric plan quality term plus a weighted regularization term. We iteratively solved this problem and adaptively updated the regularization weights to promote the sparsity of both the spots and energy layers. The proposed algorithm was tested on four head-and-neck cancer patients, and its performance, in terms of reducing the number of spots and energy layers, was compared with existing standard and group regularization methods. We also compared the effectiveness of the three methods ( , group , and reweighted ) at improving plan delivery efficiency without compromising dosimetric plan quality by constructing each of their Pareto surfaces charting the trade-off between plan delivery and planquality. The reweighted regularization method reduced the number of spots and energy layers by an average over all patients of and , respectively, with an insignificant cost to dosimetric plan quality. From the Pareto surfaces, it is clear that reweighted provided a better trade-off between plan delivery efficiency and dosimetric plan quality than standard or group regularization, requiring the lowest cost to quality to achieve any given level of deliveryefficiency. Reweighted regularization is a powerful method for simultaneously promoting the sparsity of spots and energy layers at a small cost to dosimetric plan quality. This sparsity reduces the time required for spot scanning and energy layer switching, thereby improving the delivery efficiency of protonplans.

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

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

Comparison of deep inspiration breath hold and free breathing intensity modulated proton therapy of locally advanced lung cancer

Background and purposeFor locally advanced non-small cell lung cancer (LA-NSCLC), intensity-modulated proton therapy (IMPT) can reduce organ at risk (OAR) doses compared to intensity-modulated radiotherapy (IMRT). Deep inspiration breath hold (DIBH) reduces OAR doses compared to free breathing (FB) in IMRT. In IMPT, differences in dose distributions and robustness between DIBH and FB are unclear. In this study, we compare DIBH to FB in IMPT, and IMPT to IMRT. Materials and methodsFortyone LA-NSCLC patients were prospectively included. 4D computed tomography images (4DCTs) and DIBH CTs were acquired for treatment planning and during weeks 1 and 3 of treatment. A new system for automated robust planning was developed and used to generate a FB and a DIBH IMPT plan for each patient. Plans were compared in terms of dose-volume parameters and normal tissue complication probabilities (NTCPs). Dose recalculations on repeat CTs were used to compare inter-fraction plan robustness. ResultsIn IMPT, DIBH reduced median lungs Dmean from 9.3 Gy(RBE) to 8.0 Gy(RBE) compared to FB, and radiation pneumonitis NTCP from 10.9 % to 9.4 % (p < 0.001). Inter-fraction plan robustness for DIBH and FB was similar. Median NTCPs for radiation pneumonitis and mortality were around 9 percentage points lower with IMPT than IMRT (p < 0.001). These differences were much larger than between FB and DIBH within each modality. ConclusionDIBH IMPT resulted in reduced lung dose and radiation pneumonitis NTCP compared to FB IMPT. Inter-fraction robustness was comparable. OAR doses were far lower in IMPT than IMRT.

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

PurposeTo report clinical and dosimetric characteristics of five-fraction stereotactic ablative radiotherapy (SABR) using intensity modulated proton therapy (IMPT) for localized prostate cancer. Materials and MethodsAll 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 four-field arrangement with two anterior oblique and two opposed lateral beams was used in most patients (97%), and most (99%) had a retroprostatic hydrogel spacer. ResultsA 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 four-field arrangement. Mean differences in left and right femoral head V40% (%) were -6.99% and -10.74%, respectively. ConclusionWe 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.

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

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

Probability of normal tissue complications for hematologic and gastrointestinal toxicity in postoperative whole pelvic radiotherapy for gynecologic malignancies using intensity-modulated proton therapy with robust optimization.

This retrospective treatment-planning study was conducted to determine whether intensity-modulated proton therapy with robust optimization (ro-IMPT) reduces the risk of acute hematologic toxicity (H-T) and acute and late gastrointestinal toxicity (GI-T) in postoperative whole pelvic radiotherapy for gynecologic malignancies when compared with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated X-ray (IMXT) and single-field optimization proton beam (SFO-PBT) therapies. All plans were created for 13 gynecologic-malignancy patients. The prescribed dose was 45 GyE in 25 fractions for 95% planning target volume in 3D-CRT, IMXT and SFO-PBT plans and for 99% clinical target volume (CTV) in ro-IMPT plans. The normal tissue complication probability (NTCP) of each toxicity was used as an in silico surrogate marker. Median estimated NTCP values for acute H-T and acute and late GI-T were 0.20, 0.94 and 0.58 × 10-1 in 3D-CRT; 0.19, 0.65 and 0.24 × 10-1 in IMXT; 0.04, 0.74 and 0.19 × 10-1 in SFO-PBT; and 0.06, 0.66 and 0.15 × 10-1 in ro-IMPT, respectively. Compared with 3D-CRT and IMXT plans, the ro-IMPT plan demonstrated significant reduction in acute H-T and late GI-T. The risk of acute GI-T in ro-IMPT plan is equivalent with IMXT plan. The ro-IMPT plan demonstrated potential clinical benefits for reducing the risk of acute H-T and late GI-T in the treatment of gynecologic malignances by reducing the dose to the bone marrow and bowel bag while maintaining adequate dose coverage to the CTV. Our results indicated that ro-IMPT may reduce acute H-T and late GI-T risk with potentially improving outcomes for postoperative gynecologic-malignancy patients with concurrent chemotherapy.

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

Objective. In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offlineTB re-planning) schedule, including extensive robustness analyses. Approach. The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offlineTB re-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations. Main results. For 14/67 repeat-CTs, offlineTB re-planning resulted in <50% probability of D 98% ≥ 95% of the prescribed dose (D pres) in one or both CTVs, which never happened with online re-optimization. With offlineTB re-planning, eight repeat-CTs had zero probability of obtaining D 98% ≥ 95%D pres for CTV7000, while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] (p < 10−5 for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average. Significance. The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing.

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

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

Esophageal Cancer Outcomes After Definitive Chemotherapy With Intensity Modulated Proton Therapy

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

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

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

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

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

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

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

Single high-energy arc proton therapy with Bragg peak boost (SHARP).

Because of the co-location of critical organs at risk, base of skull tumours require steep dose gradients to achieve the prescribed dosimetric criteria. When available, proton beam therapy (PBT) is often considered a desirable modality for these cases, but in many instances, compromises in target coverage are still required to achieve critical organ at risk (OAR) tolerance doses. A number of techniques have been proposed to further improve the penumbra of PBT. In the current study, we propose a novel, collimator-free treatment planning technique that combines high-energy shoot-through proton beams with conventional Bragg peak spot placement. The small spot size of the high-energy pencil beams provides a sharp penumbra at the target boundary, and the Bragg peak spots provide a higher linear energy transfer (LET) boost to the target centre. Three base of skull chordoma patients were retrospectively planned with three different PBT treatment planning techniques: (1) conventional intensity-modulated proton therapy (IMPT); (2) high-energy proton arc therapy (HE-PAT); and (3) the novel technique combining HE-PAT and IMPT, referred to as single high-energy arc with Bragg peak boost (SHARP). The Monaco 6 treatment planning system was used. SHARP was found to improve the PBT penumbra in the plane perpendicular to the HE-PAT beams. Minimal penumbra differences were observed in the plane of the HE-PAT beams. SHARP reduced dose-averaged LET to surrounding organs at risk. A novel PBT treatment planning technique was successfully implemented. Initial results indicate the potential for SHARP to improve the penumbra of PBT treatments for base of skull tumours.