Modulated Proton Research Articles

Оценка возможности верификации дозовых распределений протонов методом наведенной позитронной активности в тканях человека

A computational assessment was made of the possibility of verifying dose distributions during proton radiation therapy using PET imaging of positron activity in human tissues, which was formed as a result of proton irradiation. To compare the dose distribution of a particle energy-modulated proton beam with a diameter of 10 mm with an initial particle energy of 100 MeV, ensuring uniform irradiation of the target in a 13 mm zone (at the level of 90 % of the radiation dose) at the end of the particle path, with a map of induced activity from the radionuclides 11C, 13N and 15O, numerical calculations were performed in a Monte–Carlo code using the Geant4 simulation program. In the modeling process, a volume with dimensions of 50 × 50 × 100 mm was used, simulating soft tissues of the human body with a density of 1 g/cm3, consisting of hydrogen atoms (62 %), carbon (12 %), oxygen (24 %) and nitrogen (1.1 %). The cross sections for the formation of radionuclides 11C, 13N and 15O in the reactions 12C(p, pn)11C, 14N(p, α)11C, 16O(p, αpn)11C, 14N(p, pn)13N, 16O(p, α)13N, 16O(p, pn)15O have been calculated, which were used to calculate the distributions of positron activity in the irradiated volume. Taking into account the short half-lives of the radionuclides under consideration (primarily oxygen-15), calculations of isoactivities and depth distributions of accumulated radioactivities were performed for various time intervals after irradiation. The performed computational modeling of the distributions of activities of radionuclides 11C, 13N and 15O during the passage of a modulated proton beam, taking into account the decay of produced radionuclides after irradiation, shows that by recording for 15 minutes the induced activity of PET radionuclides 2 minutes after irradiation, it is possible to obtain data on the compliance of the planned and irradiation of tumors performed during proton therapy. However, small levels of generated activity (at a level of 2 Gy for finely fractionated irradiations) require a device with high efficiency in recording annihilation radiation and high spatial resolution at the level of 1.5–2.0 mm.

Comparison of the Effectiveness of Radiotherapy with 3D-CRT, IMRT, VMAT and PT for Newly Diagnosed Glioblastoma: A Bayesian Network Meta-Analysis

Background: This study aimed to assess the relative efficacy of modern radiotherapy strategies in patients with newly diagnosed glioblastoma. Method: A comprehensive literature review was conducted through MEDLINE, Embase and the Cochrane Central Registry of Controlled Trials of studies focused on newly diagnosed glioblastoma published up to and counting 15 September 2022. We included randomized controlled trials (RCTs) and comparative nonrandomized studies (NRSs) of radiotherapy for newly diagnosed glioblastoma. Eligible studies included patients treated with three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, volumetric modulated arc therapy or proton therapy reporting either overall survival, progression-free survival or both. The impact of different radiotherapy modalities on survival was evaluated by direct comparisons of indirect evidence and estimated hazard ratios in terms of a Bayesian network meta-analysis. Results: A total of six RCTs or NRSs comprising 816 glioblastoma patients with modern radiotherapy strategies were reviewed, yielding improved overall survival by proton therapy over all other regimens. The network meta-analysis also indicated a significant advantage of proton therapy compared with other radiotherapy strategies in regard to progression-free survival. Conclusion: Our findings suggested PT as a standard RT regime with possibly superior survival outcomes for selected patients with GBM.

MO-0676 Monte Carlo calculated kQ factors for ionization chambers in modulated proton beams

MO-0676 Monte Carlo calculated kQ factors for ionization chambers in modulated proton beams

Adenoid Cystic Carcinoma of the Head and Neck: Patterns of Recurrence and Implications for Radiotherapy

<h3>Purpose/Objective(s)</h3> Radiotherapy (RT) plays a central role in locoregional control for adenoid cystic carcinoma of the head and neck (ACC). Guidelines on the optimal RT dose, treatment volumes, and modality are lacking in the highly conformal era. We sought to evaluate ACC patterns of recurrence to assess the efficacy of highly conformal RT and optimize target volumes and dose. <h3>Materials/Methods</h3> We identified all patients with ACC consecutively treated at our institution with curative-intent adjuvant or definitive RT from 2005 to 2021 and recorded local (LR) and distant metastasis (DM) events. RT plans were compared to diagnostic imaging to identify in-field, out-of-field, and marginal LRs. Marginal LRs were defined as those within the 50 Gy isodose line but outside of the CTV. <h3>Results</h3> Ninety-nine patients were included. Median follow-up was 5.1 years (IQR: 2.2-9.0). Eighty (80.8%) patients underwent surgery prior to RT. Dose was <60 Gy (10, 10.1%), 60 Gy (49, 49.5%), >60/<70 Gy (19, 19.2%), or 70 Gy (21, 21.2%). CTVs included at least one lymph node level in 61 (61.6%) patients. CTVs tracked along cranial nerves (CN) in 67 (67.7%) patients, with 61 (61.6%) receiving RT to CN V and 43 (43.4%) to CN VII. CN were tracked to the skull base and brainstem in 46 (46.5%) and 21 (21.2%) patients, respectively. Thirty-one (31.3%) patients received intensity modulated proton therapy, with the remainder (68, 68.7%) receiving photon-based intensity modulated radiation therapy. The 2- and 5-year LR risk was 3.6% (95% CI: 1.2-10.9) and 12.2% (6.6-22.7). Predictors of LR on univariate analysis included nasal cavity/nasopharynx location [HR 7.30 (1.17-45.66), <i>p</i>=.034] and primary tumor volume [per 10 cc, HR 1.44 (1.05-1.97), <i>p</i>=.023]. All other factors including concurrent chemotherapy and proton therapy were not associated. Although prescribed RT dose was not significant, 7 of the 10 patients with in-field LRs received ≤60 Gy [50 Gy (n=1), 54 Gy (n=1), 56 Gy (n=1), 60 Gy (n=4)]. Only 2 patients experienced a marginal LR, one with an oral cavity primary that recurred in the mandible bone, and the other with a submandibular primary that recurred in the oropharyngeal mucosa. Only 1 patient each had an out-of-field LR and regional nodal recurrence. Six of the 7 patients with a skull base recurrence (SBR) had coverage of CN to the skull base (n=3) or brainstem (n=3). Six recurred in a treated CN (in-field), and the other recurred in an untreated CN (out-of-field). DM risk was 26.9% (18.9-38.2) and 44.0% (33.8-57.3) at 2- and 5-years, respectively. Median overall survival was 9.2 years. <h3>Conclusion</h3> Modern conformal RT provides excellent locoregional control for patients with ACC. Marginal and out-of-field LRs are rare, validating the use of intensity modulated RT, including proton therapy. Given a low rate of regional nodal recurrence, elective nodal coverage may be omitted in well-selected patients. SBR, while uncommon, occurs primarily in those receiving skull base RT, suggesting a potential role for dose escalation in high-risk patients.

Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy

Introduction Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. Material and methods This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. Results Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, p < 0.01), to the left ventricle (0.67 Gy vs 0.03, p < 0.01) and to the valves (1.29 Gy vs. 0.06, p < 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, p < 0.01), for congestive heart failure (2.84 vs. 3.00, p < 0.01), and for valvular disease (1.01 vs. 1.06, p < 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. Conclusion While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

RONC-03. Secondary Neoplasms in Children with Central Nervous System (CNS) Tumors Following Radiotherapy in the Modern Era

PURPOSE: To assess reduction of secondary radiation-induced neoplasms over the past two decades, focusing on children with CNS tumors who received intensity modulated radiotherapy (IMRT) or proton therapy (PT). METHODS: A total of 1044 children received radiotherapy for a primary CNS tumor at 2 institutions between 1999 and 2020, including 99 treated with IMRT and 945 treated with PT. Median age was 8.7 years old. Median follow-up was 6.0 years and included 83 and 510 patients with >5 years follow-up in the IMRT and proton cohorts, respectively. Cumulative incidence method provided estimates of secondary neoplasms encompassing benign and malignant solid tumors as well as leukemia. Multiple variables were assessed using proportional hazard regression for competing risks. RESULTS: Ten-year overall survival was 87.4%. Patients treated with IMRT were significantly older, with a median age of 10.4 vs 8.4 years old (p <0.001), but were more likely to receive craniospinal irradiation (31.3% vs 14.2%, p <0.001) or alkylating chemotherapy (50.5% vs 29.7%, p <0.001). The 5- and 10-year cumulative incidence of second neoplasm was 0.7% and 2.3%, respectively. On multivariate analysis, age <5 (4.9% vs 0.7% at 10 years) and tumor predisposition syndrome (34.3% vs 1.5% at 10 years) were significantly associated with a second neoplasm (p < 0.01 for each). On both univariate and multivariate analyses, PT was not associated with a lower incidence of second neoplasm. Following IMRT, 1/2 second solid tumors occurred outside the target volume, compared to 2/11 after PT. CONCLUSION: Following modern radiotherapy, approximately 2% of children with a CNS tumor will develop a second neoplasm within 10 years of treatment. Compared to IMRT, PT was not associated with an overall reduction in second neoplasms. More events and follow-up beyond 10 years are needed to determine if proton therapy reduces the incidence of second solid tumors occurring specifically in the low dose region.

A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients.

Simple SummaryThe role of proton therapy as a radiation treatment option for locally advanced sinonasal cancer patients has increased in the last years, showing promising results in terms of clinical outcomes. Definition of strategies to identify patients who would benefit the most from proton therapy in terms of reduced toxicity is highly desirable, due to limited availability and higher costs of this treatment option. The novelty of our in silico study relies on assessing the suitability of a mixed dose volume histograms and normal tissue complication probability model-based approach, aiming at providing, to the scientific community, a patient selection criteria possibly leading the therapeutic choice between proton therapy and advanced photon techniques.(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the NTCP and DVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to NTCP > 3% for at least one severe toxicity, 4 (18.2%) due to NTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of NTCP and DVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.

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.

Knowledge-Based Models for NRG HN001 Proton Plan Quality Analysis

<h3>Purpose/Objective(s)</h3> Radiotherapy treatment plan quality is essential to the success of clinical trials. Knowledge-based models have been used extensively for photon-based plan quality evaluation. With an increasing number of intensive modulated proton therapy (IMPT) plans submitted to clinical trials, we built knowledge-based proton planning (KBP) models for nasopharyngeal cancer cases. We report on the testing and the implementation of the models for the review of the quality of NRG-HN001 proton plans. <h3>Materials/Methods</h3> IMPT plans were manually created for 50 cases submitted to NRG-HN001. These plans were used to train a KBP model. Iterations of KBP-based re-optimization of model plans were performed to enhance the model performance. The final model was then used for generating 20 IMPT plans on the original proton cohort of patients to compare with submitted plans for quality evaluation. <h3>Results</h3> Among the 20 IMPT plans to date submitted to HN001, 11 plans showed deviation unacceptable for target coverage and 7 plans for OARs sparing. Compared with submitted plans, all KBP plans meet per protocol or variation acceptable values for both target and OAR volumes. The 20-plan average target volume VRxGy[%] increased 8% (<i>P</i> = 0.00371), meanwhile, brain stem D0.03 cc [Gy] decreased 8 Gy (<i>P</i> < 0.00001), optic nerves D0.03 cc [Gy] decreased 11 Gy (<i>P</i> = 0.0002), chiasm D0.03 cc [Gy] decreased 12 Gy (<i>P</i> = 0.0006), parotids mean dose decreased 4Gy (<i>P</i> = 0.002). Doses to other OARs (spinal cord, mandible, TM joint, temporal lobes, eyes, lens, larynx, cochlea, and esophagus) showed no statistically significant changes. <h3>Conclusion</h3> This is the first successful application of KBP for clinical trial IMPT plan quality assurance. KBP-aided IMPT plans demonstrate better target coverage with reduced OAR doses compared with submitted plans from multi-institutions, showing improvement opportunities for IMPT planning. It is feasible to use these KBP models for current and future nasopharyngeal cancer clinical trials to improve proton radiotherapy plan quality.

3D Dosimetry Based on LiMgPO4 OSL Silicone Foils: Facilitating the Verification of Eye-Ball Cancer Proton Radiotherapy.

A direct verification of the three-dimensional (3D) proton clinical treatment plan prepared for tumor in the eyeball, using the Eclipse Ocular Proton Planning system (by Varian Medical Systems), has been presented. To achieve this, a prototype of the innovative two-dimensional (2D) circular silicone foils, made of a polymer with the embedded optically stimulated luminescence (OSL) material in powder form (LiMgPO4), and a self-developed optical imaging system, consisting of an illuminating light source and a high-sensitive CCD camera has been applied. A specially designed lifelike eyeball phantom has been used, constructed from 40 flat sheet LMP-based silicone foils stacked and placed together behind a spherical phantom made by polystyrene, all to reflect the curvature of the real eyeball. Two-dimensional OSL signals were captured and further analyzed from each single silicone foil after irradiation using a dedicated patient collimator and a 58.8 MeV modulated proton beam. The reconstructed 3D proton depth dose distribution matches very well with the clinical treatment plan, allowing for the consideration of the new OSL system for further 3D dosimetry applications within the proton radiotherapy area.

Technical Note: A simple and fast daily quality assurance solution for modulated scanning proton and carbon ion beams.

A typical ion beam treatment facility has multiple treatment rooms and may treat with more than one ion species, thus requiring a significant quality assurance (QA) effort. The goal of this work was to perform daily QA using a single irradiation per ion species to obtain the beam dosimetry parameters of dose per monitor unit (D/MU), range, and spot position. The X-ray alignment system should also be checked and the entire procedure performed by therapists. This goal was achieved by designing a jig for the Sun Nuclear Daily QA™ 3 device and combining it with specific brass boluses, a standard QA plan, and a cuboid polyethylene phantom for positioning/repositioning tests. The design of the plan used for each ion species delivery ensured that there was no interference between the tests of the various characteristics. The 1-year monitoring results showed the proposed daily QA procedure was reliable and able to reflect each of the specified QA items of the proton and carbon ion beams. To simplify the daily analysis, the tolerances for the D/MU, beam range, and spot position (±1.5%, ±0.3mm, ±1.5mm, respectively) are checked using only the detector readings without the need for additional data processing. The proposed daily QA procedure was clinically implemented in our facility in April 2019 and has run smoothly for the first 2 years of operation. The total daily QA time for the four-room facility decreased from 1 to 1.5h to 30 to 40 min and was achieved not by reducing QA tests but rather by implementing new technology and procedures permitting acquisition of multiple beam information.

Mixed Effect Modeling of Dose and Linear Energy Transfer Correlations With Brain Image Changes After Intensity Modulated Proton Therapy for Skull Base Head and Neck Cancer

Purpose:Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT.Methods and Materials:For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LETd) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve.Results:An overall statistically significant RAIC association with dose and LETd was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30–2.72) for dose and 2.68 (1.93–4.93) for LETd, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LETd effect demonstrated increased risk of RAIC with increasing LETd for the majority of patients. Estimated probability of RAIC with LETd = 1 keV/μm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD15 were estimated to be 63.6 and 50.1 Gy with LETd equal to 2 and 5 keV/μm, respectively.Conclusions:Our results suggest that the LETd effect could be of clinical significance for some patients; LETd assessment in clinical treatment plans should therefore be taken into consideration.

Preliminary results of phase 2 trial of preoperative image guided intensity modulated proton radiation therapy (IMPT) with simultaneously integrated boost (SIB) to the high-risk margin for retroperitoneal sarcomas (RPS).

11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) &gt;18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had &gt; 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.

Dosimetric properties of a newly developed thermoluminescent sheet-type dosimeter for clinical proton beams.

PurposeThis study aimed to evaluate the dosimetric properties of a newly developed thermoluminescent sheet‐type dosimeter (TLD‐sheet) for clinical proton beams.Materials and MethodsThe TLD‐sheet is composed mainly of manganese doped lithium triborate, with a physical size and thickness of 150 mm × 150 mm and 0.15 mm respectively. It is flexible and can be cut freely for usage. The TLD‐sheet has an effective atomic number of 7.3 and tissue‐equivalent properties. We tested the reproducibility, fading effect, dose linearity, homogeneity, energy dependence, and water equivalent thickness (WET) of the TLD‐sheet for clinical proton beams. We conducted tests with both unmodulated and modulated proton beams at energies of 150 and 210 MeV.ResultsThe measurement reproducibility was within 4%, which included the inhomogeneity of the TLD‐sheet. The fading rates were approximately 20% and 30% after 2 and 7 days respectively. The TLD‐sheet showed notable energy dependence in the Bragg peak and distal end of the spread‐out Bragg peak regions. However, the dose–response characteristics of the TLD‐sheet remained linear up to a physical dose of 10 Gy in this study. This linearity was highly superior to those of commonly used radiochromic film. The thin WET of the TLD‐sheet had little effect on the range.ConclusionAlthough notable energy dependences were observed in Bragg peak region, the response characteristics examined in this study, such as reproducibility, fading effects, dose linearity, dose homogeneity and WET, showed that the TLD‐sheet can be a useful and effective dosimetry tool. With its flexible and reusable characteristics, it may also be an excellent in vivo skin dosimetry tool for proton therapy.

TriB-RT: Simultaneous optimization of photon, electron and proton beams

Purpose. To develop a novel treatment planning process (TPP) with simultaneous optimization of modulated photon, electron and proton beams for improved treatment plan quality in radiotherapy. Methods. A framework for fluence map optimization of Monte Carlo (MC) calculated beamlet dose distributions is developed to generate treatment plans consisting of photon, electron and spot scanning proton fields. Initially, in-house intensity modulated proton therapy (IMPT) plans are compared to proton plans created by a commercial treatment planning system (TPS). A triple beam radiotherapy (TriB-RT) plan is generated for an exemplary academic case and the dose contributions of the three particle types are investigated. To investigate the dosimetric potential, a TriB-RT plan is compared to an in-house IMPT plan for two clinically motivated cases. Benefits of TriB-RT for a fixed proton beam line with a single proton field are investigated. Results. In-house optimized IMPT are of at least equal or better quality than TPS-generated proton plans, and MC-based optimization shows dosimetric advantages for inhomogeneous situations. Concerning TriB-RT, for the academic case, the resulting plan shows substantial contribution of all particle types. For the clinically motivated case, improved sparing of organs at risk close to the target volume is achieved compared to IMPT (e.g. myelon and brainstem −37%) at cost of an increased low dose bath (healthy tissue V 10% +22%). In the scenario of a fixed proton beam line, TriB-RT plans are able to compensate the loss in degrees of freedom to substantially improve plan quality compared to a single field proton plan. Conclusion. A novel TPP which simultaneously optimizes photon, electron and proton beams was successfully developed. TriB-RT shows the potential for improved treatment plan quality and is especially promising for cost-effective single-room proton solutions with a fixed beamline in combination with a conventional linac delivering photon and electron fields.

Microdosimetry of a therapeutic proton beam with a mini-TEPC and a MicroPlus-Bridge detector for RBE assessment

Proton beams are widely used worldwide to treat localized tumours, the lower entrance dose and no exit dose, thus sparing surrounding normal tissues, being the main advantage of this treatment modality compared to conventional photon techniques. Clinical proton beam therapy treatment planning is based on the use of a general relative biological effectiveness (RBE) of 1.1 along the whole beam penetration depth, without taking into account the documented increase in RBE at the end of the depth dose profile, in the Bragg peak and beyond. However, an inaccurate estimation of the RBE can cause both underdose or overdose, in particular it can cause the unfavourable situation of underdosing the tumour and overdosing the normal tissue just beyond the tumour, which limits the treatment success and increases the risk of complications. In view of a more precise dose delivery that takes into account the variation of RBE, experimental microdosimetry offers valuable tools for the quality assurance of LET or RBE-based treatment planning systems. The purpose of this work is to compare the response of two different microdosimetry systems: the mini-TEPC and the MicroPlus-Bridge detector. Microdosimetric spectra were measured across the 62 MeV spread out Bragg peak of CATANA with the mini-TEPC and with the Bridge microdosimeter. The frequency and dose distributions of lineal energy were compared and the different contributions to the spectra were analysed, discussing the effects of different site sizes and chord length distributions. The shape of the lineal energy distributions measured with the two detectors are markedly different, due to the different water-equivalent sizes of the sensitive volumes: 0.85 μm for the TEPC and 17.3 μm for the silicon detector. When the Loncol’s biological weighting function is applied to calculate the microdosimetric assessment of the RBE, both detectors lead to results that are consistent with biological survival data for glioma U87 cells. Both the mini-TEPC and the MicroPlus-Bridge detector can be used to assess the RBE variation of a 62 MeV modulated proton beam along its penetration depth. The microdosimetric assessment of the RBE based on the Loncol’s weighting function is in good agreement with radiobiological results when the 10% biological uncertainty is taken into account.

Therapeutic proton beams: LET, RBE and microdosimetric spectra with gas and silicon detectors

A sealed mini-TEPC able to work in gas-steady modality, a monolithic silicon device composed by a matrix of micrometric cylindrical diodes and a residual energy measurement stage and the silicon MicroPlus Bridge detector were used to perform microdosimetric measurements at the 62 MeV proton clinical SOBP of CATANA at the Southern National Laboratories of INFN (LNS – INFN, Catania, Italy). Measurements were taken at the same different positions in a PMMA phantom, in order to analyse the detector response differences.Finally, a weighting function was applied to the spectra to see if the microdosimetric detectors are able to monitor RBE data for glioma cells (U87) irradiated at six positions along the same modulated 62-MeV proton beam. The results obtained with the three microdosimeters are compared and discussed.

Beam commissioning of the 35 MeV section in an intensity modulated proton linear accelerator for proton therapy

This paper presents the experimental results on the Terapia Oncologica con Protoni-Intensity Modulated Proton Linear Accelerator (TOP-IMPLART) beam that is currently accelerated up to 35 MeV, with a final target of 150 MeV. The TOP-IMPLART project, funded by the Innovation Department of Regione Lazio (Italy), is led by Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA) in collaboration with the Italian Institute of Health and the Oncological Hospital Regina Elena-IFO. The accelerator, under construction and test at ENEA-Frascati laboratories, employs a commercial 425 MHz, 7 MeV injector followed by a sequence of 3 GHz accelerating modules consisting of side coupled drift tube linac (SCDTL) structures up to 71 MeV and coupled cavity linac structures for higher energies. The section from 7 to 35 MeV, consisting on four SCDTL modules, is powered by a single 10 MW klystron and has been successfully commissioned. This result demonstrates the feasibility of a ``fully linear'' proton therapy accelerator operating at a high frequency and paves the way to a new class of machines in the field of cancer treatment.

Robust Optimization for Intensity Modulated Proton Therapy to Redistribute High Linear Energy Transfer from Nearby Critical Organs to Tumors in Head and Neck Cancer

We propose linear energy transfer (LET)-guided robust optimization in intensity modulated proton therapy for head and neck cancer. This method simultaneously considers LET and physical dose distributions of tumors and organs at risk (OARs) with uncertainties. Fourteen patients with head and neck cancer were included in this retrospective study. Cord, brain stem, brain, and oral cavity were considered. Two algorithms, voxel-wise worst-case robust optimization and LET-guided robust optimization (LETRO), were used to generate intensity modulated proton therapy plans for each patient. The latter method directly optimized LET distributions rather than indirectly as in previous methods. LET-volume histograms (LETVHs) were generated, and high LET was redistributed from nearby OARs to tumors in a user-defined way via LET-volume constraints. Dose-volume histogram indices, such as clinical target volume (CTV) D98% and D2%-D98%, cord Dmax, brain stem Dmax, brain Dmax, and oral cavity Dmean, were calculated. Plan robustness was quantified using the worst-case analysis method. LETVH indices analogous to dose-volume histogram indices were used to characterize LET distributions. The Wilcoxon signed rank test was performed to measure statistical significance. In the nominal scenario, LETRO provided higher LET distributions in the CTV (unit: keV/μm; CTV LET98%: 1.18 vs 1.08, LETRO vs RO, P = .0031) while preserving comparable physical dose and plan robustness. LETRO achieved significantly reduced LET distributions in the cord, brain stem, and oral cavity compared with RO (cord LETmax: 7.20 vs 8.20, P=.0010; brain stem LETmax: 10.95 vs 12.05, P = .0007; oral cavity LETmean: 2.11 vs 3.12, P = .0052) and had comparable physical dose and plan robustness in all OARs. In the worst-case scenario, LETRO achieved significantly higher LETmean in the CTV, reduced LETmax in the brain, and was comparable to other LETVH indices (CTV LETmean: 3.26 vs 3.35, P= .0012; brain LETmax: 24.80 vs 22.00, P = .0016). LETRO robustly optimized LET and physical dose distributions simultaneously. It redistributed high LET from OARs to targets with slightly modified physical dose and plan robustness.

Monte Carlo calculation of beam quality correction factors in proton beams using PENH

This work calculates beam quality correction factors () in both modulated and unmodulated proton beams using the Monte Carlo (MC) code . The latest ICRU 90 recommendations on key data for ionizing-radiation dosimetry were adopted to calculate the electronic stopping powers and to select the mean energy to create an ion pair in dry air (). For modulated proton beams, factors were calculated in the middle of a spread-out Bragg peak, while for monoenergetic proton beams they were calculated at the entrance region. Fifteen ionization chambers were simulated. The factors calculated in this work were found to agree within 0.8% or better with the experimental data reported in the literature. For some ionization chambers, the simulation of proton nuclear interactions were found to have an effect on the factors of up to 1%; while for some others, perturbation factors were found to differ from unity by more than 1%. In addition, the combined standard uncertainty in the MC calculated factors in proton beams was estimated to be of the order of 1%. Thus, the results of this work seem to indicate that: (i) the simulation of proton nuclear interactions should be included in the MC calculation of factors in proton beams, (ii) perturbation factors in proton beams should not be neglected, and (iii) the detailed MC simulation of ionization chambers allows for an accurate and precise calculation of factors in clinical proton beams.