First application of the BIANCA biophysical model to carbon-ion patient cases.

Objective.The main objective of this work consists of applying, for the first time, the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model to the RBE calculation for C-ion cancer patients, and comparing the outcomes with those obtained by the LEM I model, which is applied in clinics. Indeed, the continuous development of heavy-ion cancer therapy requires modelling of biological effects of ion beams on tumours and normal tissues. The relative biological effectiveness (RBE) of heavy ions is higher than that of protons, with a significant variation along the beam path. Therefore, it requires a precise modelling, especially for the pencil-beam scanning technique. Currently, two radiobiological models, LEM I and MKM, are in use for heavy ions in scanned pencil-beam facilities.Approach.Utilizing an interface with the FLUKA Particle Therapy Tool, BIANCA was applied to re-calculate the RBE-weighted dose distribution for carbon-ion treatment of three patients (chordoma, head-and-neck and prostate) previously irradiated at CNAO, where radiobiological optimization was based on LEM I. The predictions obtained by BIANCA were based either on chordoma cell survival (RBEsurv), or on dicentric aberrations in peripheral blood lymphocytes (RBEab), which are indicators of late normal tissue damage, including secondary tumours. The simulation outcomes were then compared with those provided by LEM I.Main results.While in the target and in the entrance channel BIANCA predictions were lower than those obtained by LEM I, the two models provided very similar results in the considered OAR. The observed differences betweenRBEsurvandRBEab(which were also dependent on fractional dose and LET) suggest that in normal tissues the information on cell survival should be integrated by information more closely related to the induction of late damage, such as chromosome aberrations.Significance.This work showed that BIANCA is suitable for treatment plan optimization in ion-beam therapy, especially considering that it can predict both cell survival and chromosome aberrations and has previously shown good agreement with carbon-ion experimental data.

In Vivo Validation of the BIANCA Biophysical Model: Benchmarking against Rat Spinal Cord RBE Data.

(1) Background: Cancer ion therapy is constantly growing thanks to its increased precision and, for heavy ions, its increased biological effectiveness (RBE) with respect to conventional photon therapy. The complex dependence of RBE on many factors demands biophysical modeling. Up to now, only the Local Effect Model (LEM), the Microdosimetric Kinetic Model (MKM), and the "mixed-beam" model are used in clinics. (2) Methods: In this work, the BIANCA biophysical model, after extensive benchmarking in vitro, was applied to develop a database predicting cell survival for different ions, energies, and doses. Following interface with the FLUKA Monte Carlo transport code, for the first time, BIANCA was benchmarked against in vivo data obtained by C-ion or proton irradiation of the rat spinal cord. The latter is a well-established model for CNS (central nervous system) late effects, which, in turn, are the main dose-limiting factors for head-and-neck tumors. Furthermore, these data have been considered to validate the LEM version applied in clinics. (3) Results: Although further benchmarking is desirable, the agreement between simulations and data suggests that BIANCA can predict RBE for C-ion or proton treatment of head-and-neck tumors. In particular, the agreement with proton data may be relevant if the current assumption of a constant proton RBE of 1.1 is revised. (4) Conclusions: This work provides the basis for future benchmarking against patient data, as well as the development of other databases for specific tumor types and/or normal tissues.

Dosimetric validation of Monte Carlo and analytical dose engines with raster-scanning 1H, 4He, 12C, and 16O ion-beams using an anthropomorphic phantom.

With high-precision radiotherapy on the rise towards mainstream healthcare, comprehensive validation procedures are essential, especially as more sophisticated technologies emerge. In preparation for the upcoming translation of novel ions, case-/disease-specific ion-beam selection and advanced multi-particle treatment modalities at the Heidelberg Ion-beam Therapy Center (HIT), we quantify the accuracy limits in particle therapy treatment planning under complex heterogeneous conditions for the four ions (1H, 4He, 12C, 16O) using a Monte Carlo Treatment Planning platform (MCTP), an independent GPU-accelerated analytical dose engine developed in-house (FRoG) and the clinical treatment planning system (Syngo RT Planning). Attaching an anthropomorphic half-head Alderson RANDO phantom to entrance window of a dosimetric verification water tank, a cubic target spread-out Bragg peak (SOBP) was optimized using the MCTP to best resolve effects of anatomic heterogeneities on dose homogeneity. Subsequent forward calculations were executed in FRoG and Syngo. Absolute and relative dosimetry was performed in the experimental beam room using 1D and 2D array ionization chamber detectors. Mean absolute percent deviation in dose (|%Δ|) between predictions and PinPoint ionization chamber measurements were within ∼2% for all investigated ions for both MCTP and FRoG. For protons and carbon ions, |%Δ| values were ∼4% for Syngo. For the four ions, 3D-γ analysis (3%/3mm criteria) of FLUKA and FRoG presented mean passing rates of 97.0(±2.4)% and 93.6(±4.2)%. FRoG demonstrated satisfactory agreement with gold standard Monte Carlo simulation and measurement, superior to the commercial system. Our pre-clinical trial landmarks the first measurements taken in anthropomorphic settings for helium, carbon and oxygen ion-beam therapy.

Measurement of PET isotope production cross sections for protons and carbon ions on carbon and oxygen targets for applications in particle therapy range verification.

Measured cross sections for the production of the PET isotopes [Formula: see text], [Formula: see text] and [Formula: see text] from carbon and oxygen targets induced by protons (40-220 [Formula: see text]) and carbon ions (65-430 [Formula: see text]) are presented. These data were obtained via activation measurements of irradiated graphite and beryllium oxide targets using a set of three scintillators coupled by a coincidence logic. The measured cross sections are relevant for the PET particle range verification method where accurate predictions of the [Formula: see text] emitter distribution produced by therapeutic beams in the patient tissue are required. The presented dataset is useful for validation and optimization of the nuclear reaction models within Monte Carlo transport codes. For protons the agreement of a radiation transport calculation using the measured cross sections with a thick target PET measurement is demonstrated.

A novel method for assessment of fragmentation and beam-material interactions in helium ion radiotherapy with a miniaturized setup.

Radiotherapy with protons and carbon ions enables to deliver dose distributions of high conformation to the target. Treatment with helium ions has been suggested due to their physical and biological advantages. A reliable benchmarking of the employed physics models with experimental data is required for treatment planning. However, experimental data for helium interactions is limited, in part due to the complexity and large size of conventional experimental setups. We present a novel method for the investigation of helium interactions with matter using miniaturized instrumentation based on highly integrated pixel detectors. The versatile setup consisted of a monitoring detector in front of the PMMA phantom of varying thickness and a detector stack for investigation of outgoing particles. The ion type downstream from the phantom was determined by high-resolution pattern recognition analysis of the single particle signals in the pixelated detectors. The fractions of helium and hydrogen ions behind the used targets were determined. As expected for the stable helium nucleus, only a minor decrease of the primary ion fluence along the target depth was found. E.g. the detected fraction of hydrogen ions on axis of a 220MeV/u 4He beam was below 6% behind 24.5cm of PMMA. Monte-Carlo simulations using Geant4 reproduce the experimental data on helium attenuation and yield of helium fragments qualitatively, but significant deviations were found for some combinations of target thickness and beam energy. The presented method is promising to contribute to the reduction of the uncertainty of treatment planning for helium ion radiotherapy.

Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams.

We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.