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 ... -  《-》

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 ... -  《-》

Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

Nachankar A ，Schafasand M ，Hug E ，Martino G ，Góra J ，Carlino A ，Stock M ，Fossati P ... -  《-》

RBE-weighted dose in carbon ion therapy for ACC patients: Impact of the RBE model translation on treatment outcomes.

The purpose of this study is to assess the impact of the conversion scheme for relative biological effectiveness (RBE)-weighted dose (DRBE), implemented at our center, on treatment outcomes of adenoid cystic carcinoma (ACC) patients. Treatment plans of 78 ACC patients, optimized with the Local Effect Model (LEM), were recalculated with the modified Microdosimetric Kinetic Model (mMKM). DRBE to 95%, 50% and 2% (DV%) of the clinical target volume (CTV), were selected as relevant parameters to compare LEM and mMKM DRBE. The pattern of failure of ACC treatments was analyzed in relation to uncertainties involved in the DRBE translation methodology. mMKM recalculations of LEM plans, optimized to a prescription dose of 68.8 Gy(RBE), showed a D50% 8% higher, on average, than the expected value (60.8 Gy(RBE)), closer to the most frequently used mMKM prescription DRBE (64 Gy(RBE)). D95% and D2% deviations, with respect to the optimization goals in the two RBE systems, increased of 0.5% and 14.2%, respectively, due to the steeper mMKM RBE variation along the beam path. Local recurrences were mainly (63%) reported in areas where CTV coverage was not satisfactory in the original LEM plan and the mMKM analysis showed that OARs constraints were too conservative. No case of local recurrence could be explained by inadequate mMKM target coverage that was not already present in the LEM plan. New constraints have been defined for optic pathways and brainstem to improve target coverage with no expected increase in tissue complications.

Molinelli S ，Bonora M ，Magro G ，Casale S ，Dale JE ，Fossati P ，Hasegawa A ，Mirandola A ，Ronchi S ，Russo S ，Preda L ，Valvo F ，Orecchia R ，Ciocca M ，Vischioni B ... -  《-》

RBE-weighted doses in target volumes of chordoma and chondrosarcoma patients treated with carbon ion radiotherapy: Comparison of local effect models I and IV.

To compare the relative biological effectiveness (RBE)-weighted dose distributions in the target volume of chordoma and chondrosarcoma patients when using two different versions of the local effect model (LEM I vs. IV) under identical conditions. The patient collective included 59 patients treated with 20 fractions of carbon ion radiotherapy for chordoma and low-grade chondrosarcoma of the skull base at the Helmholtzzentrum für Schwerionenforschung (GSI) in 2002 and 2003. Prescribed doses to the planning target volume (PTV) were 60 (n = 49), 66 (n = 2) and 70 (n = 8) Gy (RBE). The original treatment plans that were initially biologically optimized with LEM I, were now recalculated using LEM IV based on the absorbed dose distributions. The resulting RBE-weighted dose distributions were quantitatively compared to assess the clinical impact of LEM IV relative to LEM I in the target volume. LEM IV predicts 20-30 Gy (RBE) increased maximum doses as compared to LEM I, while minimum doses are decreased by 2-5 Gy (RBE). Population-based mean and median doses deviated by less than 2 Gy (RBE) between both models. LEM I and LEM IV-based RBE-weighted doses in the target volume may be significantly different. Replacing the applied model in patient treatments may therefore lead to local over- or underdosages in the tumor. If LEM IV is to be tested clinically, comparisons of the RBE-weighted dose distributions of both models are required for the individual patients to assess whether the LEM IV-plan would also be acceptable and prescribed dose as well as clinical outcome data have to be carefully reassessed.

Gillmann C ，Jäkel O ，Karger CP 《-》