Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy.

Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose-averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)-weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV-HD) larger than 250 cm 3 $250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE-weighted median dose prescription with the local effect model (LEM) was D RBE , 50 % = 73.6 Gy $\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: L min = 60 keV / μ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ , L min = 80 keV / μ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and L min = 100 keV / μ m $\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$ . To compare the LETd optimized against reference plans, LETd and RBE-weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios ( ± 3.5 % $\pm 3.5\%$ range uncertainty and ± 3 mm $\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). The optimization method with L min = 60 keV / μ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) in the CTV-HD by 8.9 ± 1.5 keV / μ m $8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ ( 27 % $27\%$ ) (and 6.9 ± 1.3 keV / μ m $6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ ( 17 % $17\%$ )), without significant difference in the RBE-weighted dose. By allowing ± 5 % $\pm 5\%$ over- and under-dosage in the target, the LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) can be increased by 11.3 ± 1.2 keV / μ m $11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ ( 34 % $34\%$ ) (and 11.7 ± 3.4 keV / μ m $11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ ( 29 % $29\%$ )), using the optimization parameters L min = 80 keV / μ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ . The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE-weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE-weighted dose robustness and acquiring more in-room images remain crucial and inevitable aspects during treatment.

Schafasand M ，Resch AF ，Nachankar A ，Góra J ，Martino G ，Traneus E ，Glimelius L ，Georg D ，Fossati P ，Carlino A ，Stock M ... -  《-》

Investigation on the physical dose filtered by linear energy transfer for treatment plan evaluation in carbon ion therapy.

Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. Purpose of this study was to investigate on a novel dosimetric quantity, namely high-LET-dose ( D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ , the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumor volume. Ten cTPs with a planning target volume, PTV ≥ 500 cm 3 $\mathrm{PTV}\ge {500}\,{{\rm cm}^{3}}$ (large) and nine with a PTV < 500 cm 3 $\mathrm{PTV}&lt;{500}\,{{\rm cm}^{3}}$ (small) were selected for this study. To find a reasonable LET threshold ( L thr $\textrm {L}_{\textrm {thr}}$ ) that results in a significant difference in terms of D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ , the voxel based normalized high-LET-dose ( D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ ) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ distributions within the target of all 19 cTPs at the before determined L thr $\textrm {L}_{\textrm {thr}}$ . Statistical significance of the difference between the two groups in terms of mean D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ volume histogram parameters was evaluated by means of (two-sided) t-test or Mann-Whitney-U-test. In addition, the minimum target coverage at the above determined L thr $\textrm {L}_{\textrm {thr}}$ was compared and validated against three other thresholds to verify its potential in differentiation between small and large volume tumors. An L thr $\textrm {L}_{\textrm {thr}}$ of approximately 30 keV / μ m ${30}\,{\rm keV/}\umu {\rm m}$ was found to be a reasonable threshold to classify the two groups. At this threshold, the D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ were significantly larger ( p < 0.05 $p&lt;0.05$ ) in small CTVs. For the small tumor group, the near-minimum and median D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ (and D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ ) in the CTV were in average 9.3 ± 1.5 Gy $9.3\pm {1.5}\,{\rm Gy}$ (0.31 ± 0.08) and 13.6 ± 1.6 Gy $13.6\pm {1.6}\,{\rm Gy}$ (0.46 ± 0.06), respectively. For the large tumors, these parameters were 6.6 ± 0.2 Gy $6.6\pm {0.2}\,{\rm Gy}$ (0.20 ± 0.01) and 8.6 ± 0.4 Gy $8.6\pm {0.4}\,{\rm Gy}$ (0.28 ± 0.02). The difference between the two groups in terms of mean near-minimum and median D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ ( D ̂ > L thr $\hat{\textrm {D}}_{&gt;\textrm {L}_{\textrm {thr}}}$ ) was 2.7 Gy (11%) and 5.0 Gy (18%), respectively. The feasibility of high-LET-dose based evaluation was shown in this study where a lower D > L thr $\textrm {D}_{&gt;\textrm {L}_{\textrm {thr}}}$ was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high-LET-dose based studies.

Schafasand M ，Resch AF ，Nachankar A ，Gora J ，Traneus E ，Glimelius L ，Georg D ，Stock M ，Carlino A ，Fossati P ... -  《-》

How LEM-based RBE and dose-averaged LET affected clinical outcomes of sacral chordoma patients treated with carbon ion radiotherapy.

To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LETd) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT). Clinical plans of 50 SC patients consecutively treated before August 2018 with a local effect model-based optimization were recalculated with the modified microdosimetric kinetic RBE model (mMKM). Twenty-six patients were classified as progressive disease and the relapse volume was contoured on the corresponding follow-up diagnostic sequence. The remaining 24 patients populated the control group. Target prescription dose (DRBE|50%), near-to-minimum- (DRBE|95%) and near-to-maximum- (DRBE|2%) doses were compared between the two cohorts in both RBE systems. LETd distribution was evaluated for in-field relapsed cases with respect to the control group. Target DMKM|50% and DMKM|95% were respectively 10% and 18% lower than what we aimed at. Dosimetric evaluators showed no significant difference, in neither of the RBE frameworks, between relapsed and control sets. Half of the relapse volumes were located in a well-covered high dose region. On average, over these cases, median target LETd was significantly lower than the control cohort mean value (27 vs 30 keV/μm). Most notably, the volume receiving dose from high-LET particles (>50 keV/μm) lay substantially below recently reported data in the literature. A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas.

Molinelli S ，Magro G ，Mairani A ，Allajbej A ，Mirandola A ，Chalaszczyk A ，Imparato S ，Ciocca M ，Fiore MR ，Orlandi E ... -  《-》

Technical note: In silico benchmarking of the linear energy transfer-based functionalities for carbon ion beams in a commercial treatment planning system.

The increasing number of studies dealing with linear energy transfer (LET)-based evaluation and optimization in the field of carbon ion radiotherapy (CIRT) indicates the rising demand for LET implementation in commercial treatment planning systems (TPS). Benchmarking studies could play a key role in detecting (and thus preventing) computation errors prior implementing such functionalities in a TPS. This in silico study was conducted to benchmark the following two LET-related functionalities in a commercial TPS against Monte Carlo simulations: (1) dose averaged LET (LETd ) scoring and (2) physical dose filtration based on LET for future LET-based treatment plan evaluation and optimization studies. The LETd scoring and LET-based dose filtering (in which the deposited dose can be separated into the dose below and above the user specified LET threshold) functionalities for carbon ions in the research version RayStation (RS) 9A-IonPG TPS (RaySearch Laboratories, Sweden) were benchmarked against GATE/Geant4 simulations. Pristine Bragg peaks (BPs) and cuboid targets, positioned at different depths in a homogeneous water phantom and a setup with heterogeneity were used for this study. For all setups (homogeneous and heterogeneous), the mean absolute (and relative) LETd difference was less than 1 keV/ μ $\umu$ m (3.5%) in the plateau and target and less than 2 keV/ μ $\umu$ m (8.3%) in the fragmentation tail. The maximum local differences were 4 and 6 keV/ μ $\umu$ m, respectively. The mean absolute (and relative) physical dose differences for both low- and high-LET doses were less than 1 cGy (1.5%) in the plateau, target and tail with a maximum absolute difference of 2 cGy. No computation error was found in the tested functionalities except for LETd in lateral direction outside the target, showing the limitation of the implemented monochrome model in the tested TPS version.

Schafasand M ，Resch AF ，Traneus E ，Glimelius L ，Fossati P ，Stock M ，Gora J ，Georg D ，Carlino A ... -  《-》

Quantitative analysis of dose-averaged linear energy transfer (LET(d) ) robustness in pencil beam scanning proton lung plans.

The primary objective of our study was to perform a quantitative robustness analysis of the dose-averaged linear energy transfer (LETd ) and related RBE-weighted dose in robustly optimized (in terms of the range and set up uncertainties) pencil beam scanning (PBS) proton lung cancer plans. In this study, we utilized the 4DCT dataset of six anonymized lung patients. PBS lung plans were generated using a robust optimization technique (range uncertainty: ±3.5% and setup errors: ±5 mm) on the CTV for a total dose of 5000 cGy (RBE) in five fractions using the RBE of 1.1. For each patient, the LETd distributions were calculated for the nominal plan and three groups. Group 1: two plan robustness scenarios for range uncertainties of ±3.5%; Group 2: twelve plan robustness scenarios (range uncertainty (±3.5%) in conjunction with setup errors (±5 mm)); and Group 3: ten different breathing phases of the 4DCT dataset. The RBE-weighted dose to the OARs was evaluated for all robustness scenarios and breathing phases. The variation (∆) in the mean LETd and mean RBE-weighted dose from each group was recorded. The mean LETd in the CTV of nominal PBS lung plans among six patients ranged from 2.2 to 2.6 keV/µm. On average, for the combined range and setup uncertainties, the ∆ in the mean LETd among 12 scenarios of all six patients was 0.6 keV/µm, which is slightly higher than when only the range uncertainties were considered (0.4 keV/µm). The ∆ in the mean LETd in a patient was ≤1.7 keV/µm in the heart and ≤1.2 keV/µm in the esophagus and total lung. The ∆ in the mean RBE-weighted dose in a patient was up to 79 cGy for the total lung, 165 cGy for the heart, and 258 cGy for the esophagus. For ten breathing phases, the ∆ in the mean LETd in a patient was ≤0.3 keV/µm in the CTV, ≤0.5 keV/µm in the heart, ≤0.4 keV/µm in the esophagus, and ≤0.7 keV/µm in the total lung. The addition of setup errors to the range uncertainties resulted in slightly less homogeneous LETd distributions. The variations in the mean LETd among the ten breathing phases were slightly larger in the total lung than in the heart and esophagus. The combination of setup and range uncertainties had a greater impact than the effect of breathing phases on the variations in the mean RBE-weighted dose to the OARs. Overall, the LETd distributions in the CTV were less sensitive than those in the OARs to setup errors, range uncertainties, and breathing phases for robustly optimized (in terms of range and setup uncertainities) PBS proton lung cancer plans.

Rana S ，Traneus E ，Jackson M ，Tran L ，Rosenfeld AB ... -  《-》