Anatomical changes in resection cavity during brain radiotherapy.

BACKGROUND AND PURPOSE: Brain tumors are in general treated with a maximal safe resection followed by radiotherapy of remaining tumor including the resection cavity (RC) and chemotherapy. Anatomical changes of the RC during radiotherapy can have impact on the coverage of the target volume. The aim of the current study was to quantify the potential changes of the RC and to identify risk factors for RC changes. MATERIALS AND METHODS: Sixteen patients treated with pencil beam scanning proton therapy between October 2019 and April 2020 were retrospectively analyzed. The RC was delineated on pre-treatment computed tomography (CT) and magnetic resonance imaging, and weekly CT-scans during treatment. Isotropic expansions were applied to the pre-treatment RC (1-5 mm). The percentage of volume of the RC during treatment within the expanded pre-treatment volumes was quantified. Potential risk factors (volume of RC, time interval surgery-radiotherapy and relationship of RC to the ventricles) were evaluated using Spearman's rank correlation coefficient. RESULTS: The average variation in relative RC volume during treatment was 26.1% (SD 34.6%). An expansion of 4 mm was required to cover > 95% of the RC volume in > 90% of patients. There was a significant relationship between the absolute volume of the pre-treatment RC and the volume changes during treatment (Spearman's ρ = - 0.644; p = 0.007). CONCLUSION: RCs are dynamic after surgery. Potentially, an additional margin in brain cancer patients with an RC should be considered, to avoid insufficient target coverage. Future research on local recurrence patterns is recommended.

Proton and photon radiotherapy in stage III NSCLC: Effects on hematological toxicity and adjuvant immune therapy.

BACKGROUND AND PURPOSE: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. MATERIALS AND METHODS: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. RESULTS: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0-4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9-12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16-0.79, P = 0.01). CONCLUSION: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.

The existence of cranial bone flap displacement during brain radiotherapy.

This retrospective study examined bone flap displacement during radiotherapy in 25 post-operative brain tumour patients. Though never exceeding 2.5 mm, the sheer frequency of displacement highlights the need for future research on larger populations to validate its presence and assess the potential clinical impact on planning tumour volume margins.

Linear Energy Transfer and Relative Biological Effectiveness Investigation of Various Structures for a Cohort of Proton Patients With Brain Tumors.

Purpose: The current knowledge on biological effects associated with proton therapy is limited. Therefore, we investigated the distributions of dose, dose-averaged linear energy transfer (LETd), and the product between dose and LETd (DLETd) for a patient cohort treated with proton therapy. Different treatment planning system features and visualization tools were explored. Methods and Materials: For a cohort of 24 patients with brain tumors, the LETd, DLETd, and dose was calculated for a fixed relative biological effectiveness value and 2 variable models: plan-based and phenomenological. Dose threshold levels of 0, 5, and 20 Gy were imposed for LETd visualization. The relationship between physical dose and LETd and the frequency of LETd hotspots were investigated. Results: The phenomenological relative biological effectiveness model presented consistently higher dose values. For lower dose thresholds, the LETd distribution was steered toward higher values related to low treatment doses. Differences up to 26.0% were found according to the threshold. Maximum LETd values were identified in the brain, periventricular space, and ventricles. An inverse relationship between LETd and dose was observed. Frequency information to the domain of dose and LETd allowed for the identification of clusters, which steer the mean LETd values, and the identification of higher, but sparse, LETd values. Conclusions: Identifying, quantifying, and recording LET distributions in a standardized fashion is necessary, because concern exists over a link between toxicity and LET hotspots. Visualizing DLETd or dose × LETd during treatment planning could allow for clinicians to make informed decisions.

Clinical evaluation of synthetic computed tomography methods in adaptive proton therapy of lung cancer patients.

Background and purpose: Efficient workflows for adaptive proton therapy are of high importance. This study evaluated the possibility to replace repeat-CTs (reCTs) with synthetic CTs (sCTs), created based on cone-beam CTs (CBCTs), for flagging the need of plan adaptations in intensity-modulated proton therapy (IMPT) treatment of lung cancer patients. Materials and methods: Forty-two IMPT patients were retrospectively included. For each patient, one CBCT and a same-day reCT were included. Two commercial sCT methods were applied; one based on CBCT number correction (Cor-sCT), and one based on deformable image registration (DIR-sCT). The clinical reCT workflow (deformable contour propagation and robust dose re-computation) was performed on the reCT as well as the two sCTs. The deformed target contours on the reCT/sCTs were checked by radiation oncologists and edited if needed. A dose-volume-histogram triggered plan adaptation method was compared between the reCT and the sCTs; patients needing a plan adaptation on the reCT but not on the sCT were denoted false negatives. As secondary evaluation, dose-volume-histogram comparison and gamma analysis (2%/2mm) were performed between the reCT and sCTs. Results: There were five false negatives, two for Cor-sCT and three for DIR-sCT. However, three of these were only minor, and one was caused by tumour position differences between the reCT and CBCT and not by sCT quality issues. An average gamma pass rate of 93% was obtained for both sCT methods. Conclusion: Both sCT methods were judged to be of clinical quality and valuable for reducing the amount of reCT acquisitions.

Clinical benefit of range uncertainty reduction in proton treatment planning based on dual-energy CT for neuro-oncological patients.

OBJECTIVE: Several studies have shown that dual-energy CT (DECT) can lead to improved accuracy for proton range estimation. This study investigated the clinical benefit of reduced range uncertainty, enabled by DECT, in robust optimisation for neuro-oncological patients. METHODS: DECT scans for 27 neuro-oncological patients were included. Commercial software was applied to create stopping-power ratio (SPR) maps based on the DECT scan. Two plans were robustly optimised on the SPR map, keeping the beam and plan settings identical to the clinical plan. One plan was robustly optimised and evaluated with a range uncertainty of 3% (as used clinically; denoted 3%-plan); the second plan applied a range uncertainty of 2% (2%-plan). Both plans were clinical acceptable and optimal. The dose-volume histogram parameters were compared between the two plans. Two experienced neuro-radiation oncologists determined the relevant dose difference for each organ-at-risk (OAR). Moreover, the OAR toxicity levels were assessed. RESULTS: For 24 patients, a dose reduction >0.5/1 Gy (relevant dose difference depending on the OAR) was seen in one or more OARs for the 2%-plan; e.g. for brainstem D0.03cc in 10 patients, and hippocampus D40% in 6 patients. Furthermore, 12 patients had a reduction in toxicity level for one or two OARs, showing a clear benefit for the patient. CONCLUSION: Robust optimisation with reduced range uncertainty allows for reduction of OAR toxicity, providing a rationale for clinical implementation. Based on these results, we have clinically introduced DECT-based proton treatment planning for neuro-oncological patients, accompanied with a reduced range uncertainty of 2%. ADVANCES IN KNOWLEDGE: This study shows the clinical benefit of range uncertainty reduction from 3% to 2% in robustly optimised proton plans. A dose reduction to one or more OARs was seen for 89% of the patients, and 44% of the patients had an expected toxicity level decrease.

Quality assurance of scanned proton beams at different gantry angles using an ionization chamber array in a rotational phantom.

PURPOSE: To implement a single set-up monthly QA procedure for 9 different beam parameters at different gantry angles and evaluate its clinical implementation over a 12 month period. METHODS: We developed a QA procedure using an array detector (PTW Octavius 1500XDR) embedded in a rotational unit (PTW Octavius 4D) at our proton facility. With a single set-up we can monitor field central axis position, field symmetry, field size, flatness, penumbrae, output, spot size, spot position and range at different gantry angles (AAPM TG 224). The set-up is irradiated with homogenous 2D fields with dynamic aperture and spot patterns at five gantry angles. A modular top is used to check the range consistency. Absolute γ analysis were performed to compare measured dose distributions to calculated dose. All other parameters are directly extracted from the measurements. Additionally, the sensitivity of the set-up to small changes in beam parameters were compared to the Lynx detector (IBA). RESULTS: Over a 12 month period, output, symmetry, and flatness were within ± 2 %; FWHM, spot positions, penumbra widths, and central axis fields were within ± 1 mm. Range differences were all within 1/2 of the energy spacing (±0.6 MeV) relative to baseline. Most (2 %, 2 mm) γ-analysis showed agreement scores higher than 90 %. The sensitivity is comparable to the Lynx detector and measurement time is reduced by 40 %. CONCLUSION: The time-efficient monthly QA procedure that we developed can accurately be used to measure a large range of beam parameters at different gantry angles, within the TG 224 AAPM recommendations.

Clinical implementation and validation of an automated adaptive workflow for proton therapy.

Background and purpose: Treatment quality of proton therapy can be monitored by repeat-computed tomography scans (reCTs). However, manual re-delineation of target contours can be time-consuming. To improve the workflow, we implemented an automated reCT evaluation, and assessed if automatic target contour propagation would lead to the same clinical decision for plan adaptation as the manual workflow. Materials and methods: This study included 79 consecutive patients with a total of 250 reCTs which had been manually evaluated. To assess the feasibility of automated reCT evaluation, we propagated the clinical target volumes (CTVs) deformably from the planning-CT to the reCTs in a commercial treatment planning system. The dose-volume-histogram parameters were extracted for manually re-delineated (CTVmanual) and deformably mapped target contours (CTVauto). It was compared if CTVmanual and CTVauto both satisfied/failed the clinical constraints. Duration of the reCT workflows was also recorded. Results: In 92% (N = 229) of the reCTs correct flagging was obtained. Only 4% (N = 9) of the reCTs presented with false negatives (i.e., at least one clinical constraint failed for CTVmanual, but all constraints were satisfied for CTVauto), while 5% (N = 12) of the reCTs led to a false positive. Only for one false negative reCT a plan adaption was made in clinical practice, i.e., only one adaptation would have been missed, suggesting that automated reCT evaluation was possible. Clinical introduction hereof led to a time reduction of 49 h (from 65 to 16 h). Conclusion: Deformable target contour propagation was clinically acceptable. A script-based automatic reCT evaluation workflow has been introduced in routine clinical practice.

Independent validation of a dysphagia dose response model for the selection of head and neck cancer patients to proton therapy.

Background and purpose: The model based approach involves the use of normal tissue complication models for selection of head and neck cancer patients to proton therapy. Our goal was to validate the clinical utility of the related dysphagia model using an independent patient cohort. Materials and Methods: A dataset of 277 head and neck cancer (pharynx and larynx) patients treated with (chemo)radiotherapy between 2019 and 2021 was acquired. For the evaluation of the model discrimination we used statistical metrics such as the sensitivity, specificity and the area under the receiver operating characteristic curve. After the validation we evaluated if the dysphagia model can be improved using the closed testing procedure, the Brier and the Hosmer-Lemeshow score. Results: The performance of the original normal tissue complication probability model for dysphagia grade II-IV at 6 months was good (AUC = 0.80). According to the graphical calibration assessment, the original model showed underestimated dysphagia risk predictions. The closed testing procedure indicated that the model had to be updated and selected a revised model with new predictor coefficients as an optimal model. The revised model had also satisfactory discrimination (AUC = 0.83) with improved calibration. Conclusion: The validation of the normal tissue complication probability model for grade II-IV dysphagia was successful in our independent validation cohort. However, the closed testing procedure indicated that the model should be updated with new coefficients.

Treatment planning and 4D robust evaluation strategy for proton therapy of lung tumors with large motion amplitude.

PURPOSE: Intensity-modulated proton therapy (IMPT) for lung tumors with a large tumor movement is challenging due to loss of robustness in the target coverage. Often an upper cut-off at 5-mm tumor movement is used for proton patient selection. In this study, we propose (1) a robust and easily implementable treatment planning strategy for lung tumors with a movement larger than 5 mm, and (2) a four-dimensional computed tomography (4DCT) robust evaluation strategy for evaluating the dose distribution on the breathing phases. MATERIALS AND METHODS: We created a treatment planning strategy based on the internal target volume (ITV) concept (aim 1). The ITV was created as a union of the clinical target volumes (CTVs) on the eight 4DCT phases. The ITV expanded by 2 mm was the target during robust optimization on the average CT (avgCT). The clinical plan acceptability was judged based on a robust evaluation, computing the voxel-wise min and max (VWmin/max) doses over 28 error scenarios (range and setup errors) on the avgCT. The plans were created in RayStation (RaySearch Laboratories, Stockholm, Sweden) using a Monte Carlo dose engine, commissioned for our Mevion S250i Hyperscan system (Mevion Medical Systems, Littleton, MA, USA). We developed a new 4D robust evaluation approach (4DRobAvg; aim 2). The 28 scenario doses were computed on each individual 4DCT phase. For each scenario, the dose distributions on the individual phases were deformed to the reference phase and combined to a weighted sum, resulting in 28 weighted sum scenario dose distributions. From these 28 scenario doses, VWmin/max doses were computed. This new 4D robust evaluation was compared to two simpler 4D evaluation strategies: re-computing the nominal plan on each individual 4DCT phase (4DNom) and computing the robust VWmin/max doses on each individual phase (4DRobInd). The treatment planning and dose evaluation strategies were evaluated for 16 lung cancer patients with tumor movement of 4-26 mm. RESULTS: The ratio of the ITV and CTV volumes increased linearly with the tumor amplitude, with an average ratio of 1.4. Despite large ITV volumes, a clinically acceptable plan fulfilling all target and organ at risk (OAR) constraints was feasible for all patients. The 4DNom and 4DRobInd evaluation strategies were found to under- or overestimate the dosimetric effect of the tumor movement, respectively. 4DRobInd showed target underdosage for five patients, not observed in the robust evaluation on the avgCT or in 4DRobAvg. The accuracy of dose deformation used in 4DRobAvg was quantified and found acceptable, with differences for the dose-volume parameters below 1 Gy in most cases. CONCLUSION: The proposed ITV-based planning strategy on the avgCT was found to be a clinically feasible approach with adequate tumor coverage and no OAR overdosage even for large tumor movement. The new proposed 4D robust evaluation, 4DRobAvg, was shown to give an easily interpretable understanding of the effect of respiratory motion dose distribution, and to give an accurate estimate of the dose delivered in the different breathing phases.

Beam commissioning of the first compact proton therapy system with spot scanning and dynamic field collimation.

OBJECTIVES: To describe the measurements and to present the results of the beam commissioning and the beam model validation of a compact, gantry-mounted, spot scanning proton accelerator system with dynamic layer-by-layer field collimation. METHODS: We performed measurements of depth dose distributions in water, spot and scanned field size in air at different positions from the isocenter plane, spot position over the 20 × 20 cm2 scanned area, beam monitor calibration in terms of absorbed dose to water and specific field collimation measurements at different gantry angles to commission the system. To validate the beam model in the treatment planning system (TPS), we measured spot profiles in water at different depths, absolute dose in water of single energy layers of different field sizes and inversely optimised spread-out Bragg peaks (SOBP) under normal and oblique beam incidence, field size and penumbra in water of SOBPs, and patient treatment specific quality assurance in homogeneous and heterogeneous phantoms. RESULTS: Energy range, spot size, spot position and dose output were consistent at all gantry angles with 0.3 mm, 0.4 mm, 0.6 mm and 0.5% maximum deviations, respectively. Uncollimated spot size (one sigma) in air with an air-gap of 10 cm ranged from 4.1 to 16.4 mm covering a range from 32.2 to 1.9 cm in water, respectively. Absolute dose measurements were within 3% when comparing TPS and experimental data. Gamma pass rates >98% and >96% at 3%/3 mm were obtained when performing 2D dose measurements in homogeneous and in heterogeneous media, respectively. Leaf position was within ±1 mm at all gantry angles and nozzle positions. CONCLUSIONS: Beam characterisation and machine commissioning results, and the exhaustive end-to-end tests performed to assess the proper functionality of the system, confirm that it is safe and accurate to treat patients. ADVANCES IN KNOWLEDGE: This is the first paper addressing the beam commissioning and the beam validation of a compact, gantry-mounted, pencil beam scanning proton accelerator system with dynamic layer-by-layer multileaf collimation.

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation.

BACKGROUND AND PURPOSE: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations. MATERIALS AND METHODS: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans. RESULTS: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R2 > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R2 > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively. CONCLUSIONS: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation.