Advancing knowledge-based intensity modulated proton planning for adaptive treatment of high-risk prostate cancer.

To assess the performance of a knowledge-based planning (KBP) model for generating intensity-modulated proton therapy (IMPT) treatment plans as part of an adaptive radiotherapy (ART) strategy for patients with high-risk prostate cancer. A knowledge-based planning (KBP) model for proton adaptive treatment plan generation was developed based on thirty patient treatment plans utilizing RapidPlanTM PT (Varian Medical Systems, Palo Alto, CA). The model was subsequently validated using an additional eleven patient cases. All patients in the study were administered a prescribed dose of 70.2 Gy to the prostate and seminal vesicle (CTV70.2), along with 46.8 Gy to the pelvic lymph nodes (CTV46.8) through simultaneous integrated boost (SIB) technique. To assess the quality of the validation knowledge-based proton plans (KBPPs), target coverage and organ-at-risk (OAR) dose-volume constraints were compared against those of clinically used expert plans using paired t-tests. The KBP model training statistics (R2) (mean ± SD, 0.763 ± 0.167, range, 0.406 to 0.907) and χ² values (1.162 ± 0.0867, 1.039-1.253) indicate acceptable model training quality. Moreover, the average total treatment planning optimization and calculation time for adaptive plan generation is approximately 10 minutes. The CTV70.2 D98% for the KBPPs (mean ± SD, 69.1 ± 0.08 Gy) and expert plans (69.9 ± 0.04 Gy) shows a significant difference (p < 0.05) but are both within 1.1 Gy of the prescribed dose which is clinically acceptable. While the maximum dose for some organs-at-risk (OARs) such as the bladder and rectum is generally higher in the KBPPs, the doses still fall within clinical constraints. Among all the OARs, most of them received comparable results to the expert plan, except the cauda equina Dmax, which shows statistical significance and was lower in the KBPPs than in expert plans (48.5 ± 0.06 Gy vs 49.3 ± 0.05 Gy). The generated KBPPs were clinically comparable to manually crafted plans by expert treatment planners. The adaptive plan generation process was completed within an acceptable timeframe, offering a quick same-day adaptive treatment option. Our study supports the integration of KBP as a crucial component of an ART strategy, including maintaining plan consistency, improving quality, and enhancing efficiency. This advancement in speed and adaptability promises more precise treatment in proton ART.

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

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

Case Report: Cumulative proton dose reconstruction using CBCT-based synthetic CT for interfraction metallic port variability in breast tissue expanders.

Introduction: Dose perturbation of spot-scanning proton beams passing through a dislocated metallic port (MP) of a breast tissue expander may degrade target dose coverage or deliver excess dose to the ipsilateral lung and heart. The feasibility of utilizing daily cone-beam computed tomography (CBCT)-based synthetic CTs (synCTs) for dose reconstruction was evaluated, and the fractional and cumulative dosimetric impact due to daily MP dislocation is reported. Methods: The synCT was generated by deforming the simulation CT to daily CBCT. The MP structure template was mapped onto all CTs on the basis of daily MP position. Proton treatment plans were generated with two and three fields on the planned CT (pCT, Plan A) and the first verification CT (vCT, Plan B), respectively, for a fractional dose of 1.8 Gy(RBE). Plan A and Plan B were used alternatively, as determined by the daily MP position. The reconstructed fractional doses were calculated with corresponding plans and synCTs, and the cumulative doses were summed with the rigid or deformed fractional doses on pCT and vCT. Results: The planned and reconstructed fractional dose demonstrated a low-dose socket around the planned MP position due to the use of field-specific targets (FSTs). Dose hot spots with >120% of the prescription due to MP dislocation were found behind the planned MP position on most reconstructed fractional doses. The reconstructed cumulative dose shows two low-dose sockets around the two planned MP positions reflecting the two plans used. The doses at the hot spots behind the planned MPs averaged out to 114% of the prescription. The cumulative D95% of the CTV_Chest Wall decreased by up to 2.4% and 4.0%, and the cumulative V20Gy(RBE) of the left lung decreased to 16.1% and 16.8% on pCT and vCT, respectively. The cumulative Dmean of the heart decreased to as low as 0.7 Gy(RBE) on pCT but increased to as high as 1.6 Gy(RBE) on vCT. Conclusion: The robustness of proton plans using FSTs around the magnet in the MP of the tissue expander can be improved by applying multiple fields and plans, which provides forgiveness of dose heterogeneity incurred from dislocation of high-Z materials in this single case.

Implementation of novel measurement-based patient-specific QA for pencil beam scanning proton FLASH radiotherapy.

BACKGROUND: Several studies have shown pencil beam scanning (PBS) proton therapy is a feasible and safe modality to deliver conformal and ultra-high dose rate (UHDR) FLASH radiation therapy. However, it would be challenging and burdensome to conduct the quality assurance (QA) of the dose rate along with conventional patient-specific QA (psQA). PURPOSE: To demonstrate a novel measurement-based psQA program for UHDR PBS proton transmission FLASH radiotherapy (FLASH-RT) using a high spatiotemporal resolution 2D strip ionization chamber array (SICA). METHODS: The SICA is a newly designed open-air strip-segmented parallel plate ionization chamber, which is capable of measuring spot position and profile through 2 mm-spacing-strip electrodes at a 20 kHz sampling rate (50 µs per event) and has been characterized to exhibit excellent dose and dose rate linearity under UHDR conditions. A SICA-based delivery log was collected for each irradiation containing the measured position, size, dwell time, and delivered MU for each planned spot. Such spot-level information was compared with the corresponding quantities in the treatment planning system (TPS). The dose and dose rate distributions were reconstructed on patient CT using the measured SICA log and compared to the planned values in volume histograms and 3D gamma analysis. Furthermore, the 2D dose and dose rate measurements were compared with the TPS calculations of the same depth. In addition, simulations using different machine-delivery uncertainties were performed, and QA tolerances were deduced. RESULTS: A transmission proton plan of 250 MeV for a lung lesion was planned and measured in a dedicated ProBeam research beamline (Varian Medical System) with a nozzle beam current between 100 to 215 nA. The worst gamma passing rates for dose and dose rate of the 2D SICA measurements (four fields) compared to TPS prediction (3%/3 mm criterion) were 96.6% and 98.8%, respectively, whereas the SICA-log reconstructed 3D dose distribution achieved a gamma passing rate of 99.1% (2%/2 mm criterion) compared to TPS. The deviations between SICA measured log, and TPS were within 0.3 ms for spot dwell time with a mean difference of 0.069 ± 0.11 s, within 0.2 mm for spot position with a mean difference of -0.016 ± 0.03 mm in the x-direction, and -0.036 ± 0.059 mm in the y-direction, and within 3% for delivered spot MUs. Volume histogram metric of dose (D95) and dose rate (V40Gy/s ) showed minimal differences, within less than 1%. CONCLUSIONS: This work is the first to describe and validate an all-in-one measurement-based psQA framework that can fulfill the goals of validating the dose rate accuracy in addition to dosimetric accuracy for proton PBS transmission FLASH-RT. The successful implementation of this novel QA program can provide future clinical practice with more confidence in the FLASH application.

Commissioning a 250 MeV research beamline for proton FLASH radiotherapy preclinical experiments.

BACKGROUND: The potential reduction of normal tissue toxicities during FLASH radiotherapy (FLASH-RT) has inspired many efforts to investigate its underlying mechanism and to translate it into the clinic. Such investigations require experimental platforms of FLASH-RT capabilities. PURPOSE: To commission and characterize a 250 MeV proton research beamline with a saturated nozzle monitor ionization chamber for proton FLASH-RT small animal experiments. METHODS: A 2D strip ionization chamber array (SICA) with high spatiotemporal resolution was used to measure spot dwell times under various beam currents and to quantify dose rates for various field sizes. An Advanced Markus chamber and a Faraday cup were irradiated with spot-scanned uniform fields and nozzle currents from 50 to 215 nA to investigate dose scaling relations. The SICA detector was set up upstream to establish a correlation between SICA signal and delivered dose at isocenter to serve as an in vivo dosimeter and monitor the delivered dose rate. Two off-the-shelf brass blocks were used as apertures to shape the dose laterally. Dose profiles in 2D were measured with an amorphous silicon detector array at a low current of 2 nA and validated with Gafchromic films EBT-XD at high currents of up to 215 nA. RESULTS: Spot dwell times become asymptotically constant as a function of the requested beam current at the nozzle of greater than 30 nA due to the saturation of monitor ionization chamber (MIC). With a saturated nozzle MIC, the delivered dose is always greater than the planned dose, but the desired dose can be achieved by scaling the MU of the field. The delivered doses exhibit excellent linearity with R 2 > 0.99 ${R^2} > 0.99$ with respect to MU, beam current, and the product of MU and beam current. If the total number of spots is less than 100 at a nozzle current of 215 nA, a field-averaged dose rate greater than 40 Gy/s can be achieved. The SICA-based in vivo dosimetry system achieved excellent estimates of the delivered dose with an average (maximum) deviation of 0.02 Gy (0.05 Gy) over a range of delivered doses from 3 to 44 Gy. Using brass aperture blocks reduced the 80%-20% penumbra by 64% from 7.55 to 2.75 mm. The 2D dose profiles measured by the Phoenix detector at 2 nA and the EBT-XD film at 215 nA showed great agreement, with a gamma passing rate of 95.99% using 1 mm/2% criterion. CONCLUSION: A 250 MeV proton research beamline was successfully commissioned and characterized. Challenges due to the saturated monitor ionization chamber were mitigated by scaling MU and using an in vivo dosimetry system. A simple aperture system was designed and validated to provide sharp dose fall-off for small animal experiments. This experience can serve as a foundation for other centers interested in implementing FLASH radiotherapy preclinical research, especially those equipped with a similar saturated MIC.

Impact of respiratory motion on proton pencil beam scanning FLASH radiotherapy: anin silicoand phantom measurement study.

Objective. To investigate the effects of respiratory motion on the delivered dose in the context of proton pencil beam scanning (PBS) transmission FLASH radiotherapy (FLASH-RT) by simulation and phantom measurements.Approach. An in-house simulation code was employed to performin silicosimulation of 2D dose distributions for clinically relevant proton PBS transmission FLASH-RT treatments. A moving simulation grid was introduced to investigate the impacts of various respiratory motion and treatment delivery parameters on the dynamic PBS dose delivery. A strip-ionization chamber array detector and an IROC motion platform were employed to perform phantom measurements of the 2D dose distribution for treatment fields similar to those used for simulation.Main results. Clinically relevant respiratory motion and treatment delivery parameters resulted in degradation of the delivered dose compared to the static delivery as translation and distortion. Simulation showed that the gamma passing rates (2 mm/2% criterion) and target coverage could drop below 50% and 80%, respectively, for certain scenarios if no mitigation strategy was used. The gamma passing rates and target coverage could be restored to more than 95% and 98%, respectively, for short beams delivered at the maximal inhalation or exhalation phase. The simulation results were qualitatively confirmed in phantom measurements with the motion platform.Significance. Respiratory motion could cause dose quality degradation in a clinically relevant proton PBS transmission FLASH-RT treatment if no mitigation strategy is employed, or if an adequate margin is not given to the target. Besides breath-hold, gated delivery can be an alternative motion management strategy to ensure high consistency of the delivered dose while maintaining minimal dose to the surrounding normal tissues. To the best of our knowledge, this is the first study on motion impacts in the context of proton transmission FLASH radiotherapy.

A 2D strip ionization chamber array with high spatiotemporal resolution for proton pencil beam scanning FLASH radiotherapy.

PURPOSE: Experimental measurements of two-dimensional (2D) dose rate distributions in proton pencil beam scanning (PBS) FLASH radiation therapy (RT) are currently lacking. In this study, we characterize a newly designed 2D strip-segmented ionization chamber array (SICA) with high spatial and temporal resolution and demonstrate its applications in a modern proton PBS delivery system at both conventional and ultrahigh dose rates. METHODS: A dedicated research beamline of the Varian ProBeam system was employed to deliver a 250-MeV proton PBS beam with nozzle currents up to 215 nA. In the research and clinical beamlines, the spatial, temporal, and dosimetric performances of the SICA were characterized and compared with measurements using parallel-plate ion chambers (IBA PPC05 and PTW Advanced Markus chamber), a 2D scintillator camera (IBA Lynx), Gafchromic films (EBT-XD), and a Faraday cup. A novel reconstruction approach was proposed to enable the measurement of 2D dose and dose rate distributions using such a strip-type detector. RESULTS: The SICA demonstrated a position accuracy of 0.12 ± 0.02 mm at a 20-kHz sampling rate (50 µs per event) and a linearity of R2  > 0.99 for both dose and dose rate with nozzle beam currents ranging from 1 to 215 nA. The 2D dose comparison to the film measurement resulted in a gamma passing rate of 99.8% (2 mm/2%). A measurement-based proton PBS 2D FLASH dose rate distribution was compared to simulation results and showed a gamma passing rate of 97.3% (2 mm/2%). CONCLUSIONS: The newly designed SICA demonstrated excellent spatial, temporal, and dosimetric performances and is well suited for commissioning, quality assurance, and a wide range of clinical applications in proton PBS clinical and FLASH-RT.

Tumor phase recognition using cone-beam computed tomography projections and external surrogate information.

PURPOSE: Directly extracting the respiratory phase pattern of the tumor using cone-beam computed tomography (CBCT) projections is challenging due to the poor tumor visibility caused by the obstruction of multiple anatomic structures on the beam's eye view. Predicting tumor phase information using external surrogate also has intrinsic difficulties as the phase patterns between surrogates and tumors are not necessary to be congruent. In this work, we developed an algorithm to accurately recover the primary oscillation components of tumor motion using the combined information from both CBCT projections and external surrogates. METHODS: The algorithm involved two steps. First, a preliminary tumor phase pattern was acquired by applying local principal component analysis (LPCA) on the cropped Amsterdam Shroud (AS) images. In this step, only the cropped image of the tumor region was used to extract the tumor phase pattern in order to minimize the impact of pattern recognition from other anatomic structures. Second, by performing multivariate singular spectrum analysis (MSSA) on the combined information containing both external surrogate signal and the original waveform acquired in the first step, the primary component of the tumor phase oscillation was recovered. For the phantom study, a QUASAR respiratory motion phantom with a removable tumor-simulator insert was employed to acquire CBCT projection images. A comparison between LPCA only and our method was assessed by power spectrum analysis. Also, the motion pattern was simulated under the phase shift or various amplitude conditions to examine the robustness of our method. Finally, anatomic obstruction scenarios were simulated by attaching a heart model, PVC tubes, and RANDO® phantom slabs to the phantom, respectively. Each scenario was tested with five real-patient breathing patterns to mimic real clinical situations. For the patient study, eight patients with various tumor locations were selected. The performance of our method was then evaluated by comparing the reference waveform with the extracted signal for overall phase discrepancy, expiration phase discrepancy, peak, and valley accuracy. RESULTS: In tests of phase shifts and amplitude variations, the overall peak and valley accuracy was -0.009 ± 0.18 sec, and no time delay was found compared to the reference. In anatomical obstruction tests, the extracted signal had 1.6 ± 1.2 % expiration phase discrepancy, -0.12 ± 0.28 sec peak accuracy, and 0.01 ± 0.15 sec valley accuracy. For patient studies, the extracted signal using our method had -1.05 ± 3.0 % overall phase discrepancy, -1.55 ± 1.45% expiration phase discrepancy, 0.04 ± 0.13 sec peak accuracy, and -0.01 ± 0.15 sec valley accuracy, compared to the reference waveforms. CONCLUSIONS: An innovative method capable of accurately recognizing tumor phase information was developed. With the aid of extra information from the external surrogate, an improvement in prediction accuracy, as compared with traditional statistical methods, was obtained. It enables us to employ it as the ground truth for 4D-CBCT reconstruction, gating treatment, and other clinic implementations that require accurate tumor phase information.

A self-checking treatment couch coordinate calculation system in radiotherapy.

PURPOSE: Traditionally, the treatment couch coordinates (TCCs) for patients undergoing radiotherapy can only be determined at the time of treatment, placing pressure on the treating therapists and leaving several pathways for errors such as wrong-site treatment or wrong treatment table shift from a reference point. The purpose of this work is to propose an accurate, robust, and streamlined system that calculates TCC in advance. METHODS: The proposed system combines the advantages of two different calculation methods that use an indexed immobilization device. The first method uses an array of reference ball bearings (BBs) embedded in the CT scanner's couch-top. To obtain the patient-specific TCC, the spatial offset of the treatment planning isocenter from the reference BB is used. The second method performs a calculation using the one-to-one mapping relationship between the CT scanner's DICOM (Digital Imaging and Communications in Medicine) coordinate system and the TCC system. Both methods use a reference point in the CT coordinate system to correlate a point in the TCC system to perform the coordinate transfer between the two systems. Both methods were used to calculate the TCC and the results were checked against each other, creating an integrated workflow via automated self-checking. The accuracy of the calculation system was retrospectively evaluated with 275 patients, where the actual treatment position determined with cone-beam CT was used as a reference. RESULTS: An efficient workflow transparent to the therapists at both CT simulation and treatment was created. It works with any indexed immobilization device and can be universally applied to all treatment sites. The two methods had comparable accuracy, with 95% of the calculations within 3 mm. The inter-fraction variation was within ± 1.0 cm for 95% of the coordinates across all the treatment sites. CONCLUSIONS: A robust, accurate, and streamlined system was implemented to calculate TCCs in advance. It eases the pressure on the treating therapists, reduces patient setup time, and enhances the patient safety by preventing setup errors.

Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study.

BACKGROUND: Whole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT). METHODS: Forty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS-WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non-coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study. RESULTS: Scores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that dosimetric parameters specific to left sided hippocampus exerted an influence on immediate recall of verbal memory (adjusted odds ratio, 4.08; p-value, 0.042, predicting patients' neurocognitive decline after receiving HS-WBRT). CONCLUSIONS: Functional preservation by hippocampal sparing during WBRT is indeed achieved in our study. Providing that modern VMAT techniques can reduce the dose irradiating bilateral hippocampi below dosimetric threshold, patients should be recruited in prospective trials of hippocampal sparing during cranial irradiation to accomplish neurocognitive preservation while maintaining intracranial control. TRIAL REGISTRATION: Current Controlled Trials NCT02504788.

Clinical practice and evaluation of electronic portal imaging device for VMAT quality assurance.

Volumetric-modulated arc therapy (VMAT) is a novel extension of the intensity-modulated radiation therapy (IMRT) technique, which has brought challenges to dose verification. To perform VMAT pretreatment quality assurance, an electronic portal imaging device (EPID) can be applied. This study's aim was to evaluate EPID performance for VMAT dose verification. First, dosimetric characteristics of EPID were investigated. Then 10 selected VMAT dose plans were measured by EPID with the rotational method. The overall variation of EPID dosimetric characteristics was within 1.4% for VMAT. The film system serving as a conventional tool for verification showed good agreement both with EPID measurements ([94.1 ± 1.5]% with 3 mm/3% criteria) and treatment planning system (TPS) calculations ([97.4 ± 2.8]% with 3 mm/3% criteria). In addition, EPID measurements for VMAT presented good agreement with TPS calculations ([99.1 ± 0.6]% with 3 mm/3% criteria). The EPID system performed the robustness of potential error findings in TPS calculations and the delivery system. This study demonstrated that an EPID system can be used as a reliable and efficient quality assurance tool for VMAT dose verification.

The feasibility study of using multiple partial volumetric-modulated arcs therapy in early stage left-sided breast cancer patients.

The purpose of this study was to assess the feasibility of using a multiple partial volumetric-modulated arcs therapy (MP-VMAT) technique on the left breast irradiation and to evaluate the dosimetry and treatment efficiency. Ten patients with left-sided breast cancer who had been treated by whole breast irradiation were selected for the treatment plan evaluation by using six partial volumetric modulated arcs. Each arc consisted of a 50° gantry rotation. The planning target volumes and the normal organs, including the right breast, the bilateral lungs, left ventricle, heart, and unspecified tissue, were contoured on the CT images. Dose-volume histograms were generated and the delivery time for each arc was recorded. The PTV received greater than 95% of the V(95) for all cases, and the maximum dose was within ± 1% of 110% of the prescription dose. The mean homogeneity index (HI) was 10.61 ± 0.99, and mean conformity index (CI) was 1.21 ± 0.03. The mean dose, V(5), V(10), V(25), and V(30) of the heart were 7.61 ± 1.38 Gy, 59.73% ± 15.87%, 24.39%± 6.82%, 2.52%± 1.11%, and 1.57% ± 0.71%, respectively. The volume of the left ventricle receiving 25 Gy was 5.15% ± 2.23%. The total lung mean dose was 5.57 ± 0.36 Gy, with V(5) of 25.39% ± 3.88% and V(20) of 5.66% ± 0.89%. The right breast received a mean dose of 2.13 ± 0.22 Gy, with V(5) of 1.83% ± 1.22% and V(10) of 0.04% ± 0.12%. The mean dose of unspecified tissue was 5.34 ± 0.37 Gy and V(5) was 22.23% ± 1.57%. The volume of the unspecified tissue receiving 50 Gy was 0.50% ± 0.14%. The mean delivery time for each arc was 13.9 seconds. The average MU among ten patients was 511 MU (range 443 to 594 MUs). The MP-VMAT technique for the left-sided breast cancer patients achieved adequate target dose coverage while maintaining low doses to organs-at-risk, and therefore reduced the potential for induction of second malignancy and side effects. The highly efficient treatment delivery would be beneficial for improving patient throughput, providing patient comfort, and achieving precise treatment with the breathing control system.