Integrating microdosimetricin vitroRBE models for particle therapy into TOPAS MC using the MicrOdosimetry-based modeliNg for RBE ASsessment (MONAS) tool.

Objective.In this paper, we present MONAS (MicrOdosimetry-based modelliNg for relative biological effectiveness (RBE) ASsessment) toolkit. MONAS is a TOPAS Monte Carlo extension, that combines simulations of microdosimetric distributions with radiobiological microdosimetry-based models for predicting cell survival curves and dose-dependent RBE.Approach.MONAS expands TOPAS microdosimetric extension, by including novel specific energy scorers to calculate the single- and multi-event specific energy microdosimetric distributions at different micrometer scales. These spectra are used as physical input to three different formulations of themicrodosimetric kinetic model, and to thegeneralized stochastic microdosimetric model(GSM2), to predict dose-dependent cell survival fraction and RBE. MONAS predictions are then validated against experimental microdosimetric spectra andin vitrosurvival fraction data. To show the MONAS features, we present two different applications of the code: (i) the depth-RBE curve calculation from a passively scattered proton SOBP and monoenergetic12C-ion beam by using experimentally validated spectra as physical input, and (ii) the calculation of the 3D RBE distribution on a real head and neck patient geometry treated with protons.Main results.MONAS can estimate dose-dependent RBE and cell survival curves from experimentally validated microdosimetric spectra with four clinically relevant radiobiological models. From the radiobiological characterization of a proton SOBP and12C fields, we observe the well-known trend of increasing RBE values at the distal edge of the radiation field. The 3D RBE map calculated confirmed the trend observed in the analysis of the SOBP, with the highest RBE values found in the distal edge of the target.Significance.MONAS extension offers a comprehensive microdosimetry-based framework for assessing the biological effects of particle radiation in both research and clinical environments, pushing closer the experimental physics-based description to the biological damage assessment, contributing to bridging the gap between a microdosimetric description of the radiation field and its application in proton therapy treatment with variable RBE.

Does variable RBE affect toxicity risks for mediastinal lymphoma patients? NTCP-based evaluation after proton therapy treatment.

INTRODUCTION: Mediastinal lymphoma (ML) is a solid malignancy affecting young patients. Modern combined treatments allow obtaining good survival probability, together with a long life expectancy, and therefore with the need to minimize treatment-related toxicities. We quantified the expected toxicity risk for different organs and endpoints in ML patients treated with intensity-modulated proton therapy (IMPT) at our centre, accounting also for uncertainties related to variable RBE. METHODS: Treatment plans for ten ML patients were recalculated with a TOPAS-based Monte Carlo code, thus retrieving information on LET and allowing the estimation of variable RBE. Published NTCP models were adopted to calculate the toxicity risk for hypothyroidism, heart valve defects, coronary heart disease and lung fibrosis. NTCP was calculated assuming both constant (i.e. 1.1) and variable RBE. The uncertainty associated with individual radiosensitivity was estimated by random sampling α/ß values before RBE evaluation. RESULTS: Variable RBE had a minor impact on hypothyroidism risk for 7 patients, while it led to significant increase for the remaining three (+24% risk maximum increase). Lung fibrosis was slightly affected by variable RBE, with a maximum increase of â‰… 1%. This was similar for heart valve dysfunction, with the exception of one patient showing an about 10% risk increase, which could be explained by means of large heart volume and D1 increase. DISCUSSION: The use of NTCP models allows for identifying those patients associated with a higher toxicity risk. For those patients, it might be worth including variable RBE in plan evaluation.

Investigation of In-Field and Out-of-Field Radiation Quality With Microdosimetry and Its Impact on Relative Biological Effectiveness in Proton Therapy.

PURPOSE: Using microdosimetry, this study investigated the relative biological effectiveness (RBE) and quality factor (Q¯) variations in field and out of field as a function of radiation quality for clinical protons. METHODS AND MATERIALS: A water phantom with a spread-out Bragg peak (SOBP) was irradiated to acquire microdosimetric spectra at several distal and lateral depths with a tissue equivalent proportional counter. The measurements were used as inputs to microdosimetric kinetic and Loncol models to determine the RBE spatial distribution and compare it with predictions from the dose-averaged linear energy transfer-based McNamara model. Q¯ values and biological and dose equivalent values were also calculated. RESULTS: The data demonstrated that radiation quality changed more rapidly with depth than lateral distance from the SOBP. In beam, yD ranged from approximately 4 keV/µm at the entrance to 8 keV/µm at the SOBP far end, reaching approximately 15 keV/µm at the penumbra. Out of field, the overall highest value of 23 ± 2 keV/µm was observed at the beam-edge penumbra. Radiation quality changes caused RBE deviations from the clinical value of 1.1, whose extent depends on the approach used for assessing radiation quality as well as on the radiobiological model. For RBE10, microdosimetry-based models appeared to better reproduce the radiobiological data than the dose-averaged linear energy transfer model. Out of field, both the RBE and Q¯ values appeared to have limitations in describing the radiation biological effectiveness. This research also presents a first comprehensive benchmark of TOPAS code against in-field and out-of-field microdosimetric spectra of therapeutic protons. CONCLUSIONS: Further investigation will be necessary to evaluate the quantitative effects of RBE variations on treatment planning and assess the clinical consequences in terms of both tumor control and normal-tissue toxicity. The achievement of this goal calls for accurate radiobiological data to validate the RBE models.

Clinical implementation of pencil beam scanning proton therapy for liver cancer with forced deep expiration breath hold.

PURPOSE: To present our technique for liver cancer treatments with proton therapy in pencil beam scanning mode and to evaluate the impact of uncertainties on plan quality. MATERIALS AND METHODS: Seventeen patients affected by liver cancer were included in this study. Patients were imaged and treated in forced breath-hold using the Active Breathing Coordinator system and monitored with an optical tracking system. Three simulation CTs were acquired to estimate the anatomical variability between breath-holds and generate an internal target volume (ITV). The treatment plans were optimized with a Single Field Optimization technique aimed at minimizing the use of range shifter. Plan robustness was tested simulating systematic range and setup uncertainties, as well as the interplay effect between breath-holds. The appropriateness of margin was further verified based on the actual positioning data acquired during treatment. RESULTS: The dose distributions of the nominal plans achieved a satisfactory target coverage in 11 out of 17 patients, while in the remaining 6 D95 to the PTV was affected by the constraint on mean liver dose. The constraints for all other organs at risk were always within tolerances. The interplay effect had a limited impact on the dose distributions: the worst case scenario showed a D95 reduction in the ITV < 3.9 GyRBE and no OAR with D1 > 105% of the prescription dose. The robustness analysis showed that for 13 out of 17 patients the ITV coverage in terms of D95 was better than D95 of the PTV in the nominal plan. For the remaining 4 patients, the maximum difference between ITV D95 and PTV D95 was ≤0.7% even for the largest simulated setup error and it was deemed clinically acceptable. Hot spots in the OARs were always lower than 105% of the prescription dose. Positioning images confirmed that the breath hold technique and the PTV margin were adequate to compensate for inter- and intra-breath-hold variations in liver position. CONCLUSION: We designed and clinically applied a technique for the treatment of liver cancer with proton pencil beam scanning in forced deep expiration breath-hold. The initial data on plan robustness and patient positioning suggest that the choices in terms of planning technique and treatment margins are able to reach the desired balance between target coverage and organ at risk sparing.

Proton pencil beam scanning reduces secondary cancer risk in breast cancer patients with internal mammary chain involvement compared to photon radiotherapy.

PURPOSE: Proton pencil beam scanning (PBS) represents an interesting option for the treatment of breast cancer (BC) patients with nodal involvement. Here we compare tangential 3D-CRT and VMAT to PBS proton therapy (PT) in terms of secondary cancer risk (SCR) for the lungs and for contralateral breast. METHODS: Five BC patients including supraclavicular (SVC) nodes in the target (Group 1) and five including SVC plus internal-mammary-nodes (IMNs, Group 2) were considered. The Group 1 patients were planned by PT versus tangential 3D-CRT in free-breathing (FB). The Group 2 patients were planned by PT versus VMAT considering both FB and deep-inspiration breath hold (DIBH) irradiation. The prescription dose to the target volume was 50 Gy (2 Gy/fraction). A constant RBE = 1.1 was assumed for PT. The SCR was evaluated with the excess absolute risk (EAR) formalism, considering also the age dependence. A cumulative EAR was finally computed. RESULTS: According to the linear, linear-exponential and linear-plateau dose response model, the cumulative EAR for Group 1 patients after PT was equal to 45 ± 10, 17 ± 3 and 15 ± 3, respectively. The corresponding relative increase for tangential 3D-CRT was equal to a factor 2.1 ± 0.5, 2.1 ± 0.4 and 2.3 ± 0.4. Group 2 patients showed a cumulative EAR after PT in FB equal to 65 ± 3, 21 ± 1 and 20 ± 1, according to the different models; the relative risk obtained with VMAT increased by a factor 3.5 ± 0.2, 5.2 ± 0.3 and 5.1 ± 0.3. Similar values emerge from DIBH plans. Contrary to photon radiotherapy, PT appears to be not sensitive to the age dependence due to the very low delivered dose. CONCLUSIONS: PBS PT is associated to significant SCR reduction in BC patients compared to photon radiotherapy. The benefits are maximized for young patients with both SVC and IMNs involvement. When combined with the improved sparing of the heart, this might contribute to the establishment of effective patient-selection criteria for proton BC treatments.