Challenges and opportunities for proton therapy during pregnancy.

During pregnancy, the use of radiation therapy for cancer treatment is often considered impossible due to the assumed associated fetal risks. However, suboptimal treatment of pregnant cancer patients and unjustifiable delay in radiation therapy until after delivery can be harmful for both patient and child. In non-pregnant patients, proton-radiation therapy is increasingly administered because of its favorable dosimetric properties compared with photon-radiation therapy. Although data on the use of pencil beam scanning proton-radiation therapy during pregnancy are scarce, different case reports and dosimetric studies have indicated a more than 10-fold reduction in fetal radiation exposure compared with photon-radiation therapy. Nonetheless, the implementation of proton-radiation therapy during pregnancy requires complex fetal dosimetry for the neutron-dominated out-of-field radiation dose and faces a lack of clinical guidelines. Further exploration and standardization of proton-radiation therapy during pregnancy will be necessary to improve radiotherapeutic management of pregnant women with cancer and further reduce risks for their offspring.

In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T.

PURPOSE: Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the ß-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy. METHODS AND RESULTS: The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [225Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [177Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [225Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [177Lu]Lu-PSMA-I&T. CONCLUSION: We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.

Targeted alpha therapy: a critical review of translational dosimetry research with emphasis on actinium-225.

This review provides a general overview of the current achievements and challenges in translational dosimetry for targeted alpha therapy (TAT). The concept of targeted radionuclide therapy (TRNT) is described with an overview of its clinical applicability and the added value of TAT is discussed. For TAT, we focused on actinium-225 (225Ac) as an example for alpha particle emitting radionuclides and their features, such as limited range within tissue and high linear energy transfer, which make alpha particle emissions more effective in targeted killing of tumour cells compared to beta radiation. Starting with the state-of-the-art dosimetry for TRNT and TAT, we then describe the challenges that still need to be met in order to move to a personalized dosimetry approach for TAT. Specifically for 225Ac, we discuss the recoiled daughter effect which may provoke significant damage to healthy tissue or organs and should be considered. Next, a broad overview is given of the pre-clinical research on 225Ac-TAT with an extensive description of tools which are only available in a pre-clinical setting and their added value. In addition, we review the preclinical biodistribution and dosimetry studies that have been performed on TAT-agents and more specifically of 225Ac and its multiple progeny, and describe their potential role to better characterize the pharmacokinetic (PK) profile of TAT-agents and to optimize the use of theranostic approaches for dosimetry. Finally, we discuss the support pre-clinical studies may provide in understanding dose-effect relationships, linking radiation dose quantities to biological endpoints and even moving away from macro- to microdosimetry. As such, the translation of pre-clinical findings may provide valuable information and new approaches for improved clinical dosimetry, thus paving the way to personalized TAT.

New optically stimulated luminescence dosimetry film optimized for energy dependence guided by Monte Carlo simulations.

Optically stimulated luminescence (OSL) film dosimeters, based on BaFBr:Eu2+phosphor material, have major dosimetric advantages such as dose linearity, high spatial resolution, film re-usability, and immediate film readout. However, they exhibit an energy-dependent over-response at low photon energies because they are not made of tissue-equivalent materials. In this work, the OSL energy-dependent response was optimized by lowering the phosphor grain size and seeking an optimal choice of phosphor concentration and film thickness to achieve sufficient signal sensitivity. This optimization process combines measurement-based assessments of energy response in narrow x-ray beams with various energy response calculation methods applied to different film metrics. Theoretical approaches and MC dose simulations were used for homogeneous phosphor distributions and for isolated phosphor grains of different dimensions, where the dose in the phosphor grain was calculated. In total 8 OSL films were manufactured with different BaFBr:Eu2+median particle diameters (D50): 3.2µm, 1.5µm and 230 nm and different phosphor concentrations (1.6%, 5.3% and 21.3 %) and thicknesses (from 5.2 to 49µm). Films were irradiated in narrow x-ray spectra (N60, N80, N-150 and N-300) and the signal intensity relative to the nominal dose-to-water value was normalized to Co-60. Finally, we experimentally tested the response of several films in Varian 6MV TrueBeam STx linear accelerator using the following settings: 10 × 10 cm2field, 0deggantry angle, 90 cm SSD, 10 cm depth. The x-ray irradiation experiment reported a reduced energy response for the smallest grain size with an inverse correlation between response and grain size. The N-60 irradiation showed a 43% reduction in the energy over-response when going from 3µm to 230 nm grain size for the 5% phosphor concentration. Energy response calculation using a homogeneous dispersion of the phosphor underestimated the experimental response and was not able to obtain the experimental correlation between grain size and energy response. Isolated grain size modeling combined with MC dose simulations allowed to establish a good agreement with experimental data, and enabled steering the production of optimized OSL-films. The clinical 6 MV beam test confirmed a reduction in energy dependence, which is visible in small-grain films where a decrease in out-of-field over-response was observed.

Assessment of fluence- and dose-averaged linear energy transfer with passive luminescence detectors in clinical proton beams.

Objective.This work investigates the use of passive luminescence detectors to determine different types of averaged linear energy transfer (LET-) for the energies relevant to proton therapy. The experimental results are compared to reference values obtained from Monte Carlo simulations.Approach.Optically stimulated luminescence detectors (OSLDs), fluorescent nuclear track detectors (FNTDs), and two different groups of thermoluminescence detectors (TLDs) were irradiated at four different radiation qualities. For each irradiation, the fluence- (LET-f) and dose-averaged LET (LET-d) were determined. For both quantities, two sub-types of averages were calculated, either considering the contributions from primary and secondary protons or from all protons and heavier, charged particles. Both simulated and experimental data were used in combination with a phenomenological model to estimate the relative biological effectiveness (RBE).Main results.All types ofLET-could be assessed with the luminescence detectors. The experimental determination ofLET-fis in agreement with reference data obtained from simulations across all measurement techniques and types of averaging. On the other hand,LET-dcan present challenges as a radiation quality metric to describe the detector response in mixed particle fields. However, excluding secondaries heavier than protons from theLET-dcalculation, as their contribution to the luminescence is suppressed by ionization quenching, leads to equal accuracy betweenLET-fandLET-d. Assessment of RBE through the experimentally determinedLET-dvalues agrees with independently acquired reference values, indicating that the investigated detectors can determineLET-with sufficient accuracy for proton therapy.Significance.OSLDs, TLDs, and FNTDs can be used to determineLET-and RBE in proton therapy. With the capability to determine dose through ionization quenching corrections derived fromLET-, OSLDs and TLDs can simultaneously ascertain dose,LET-, and RBE. This makes passive detectors appealing for measurements in phantoms to facilitate validation of clinical treatment plans or experiments related to proton therapy.

Extended in-field and out-of-field validation of a compact Monte Carlo model of an IBA PROTEUS®ONE proton beam in TOPAS/GEANT4.

Objective:This study evaluates a compact Monte Carlo (MC) model of a pencil beam scanning clinical proton beam using TOPAS to estimate the dose out-of-field (OOF). Compact modelling means that the model starts from a pristine proton beam at the nozzle exit, customised based on acceptance and commissioning data, instead of modelling the full treatment head and room.Approach: First, in-field validation tests were performed. Then, the OOF dose was validated in an RW3 phantom with bubble detectors for personal neutron dosimetry (measuring the neutron dose equivalent) and thermoluminiescent detectors (measuring the absorbed dose by protons and gammas). Measurements were performed at 15 and 35 cm from the distal edge of the field for five different irradiation plans, covering different beam orientations, proton energies and a 40 mm range shifter. TOPAS simulations were performed with QGSP Binary Cascade HP (BIC) and QGSP Bertini HP (Bertini) hadron physics lists.Main results: In-field validation shows that MC simulations agree with point dose measurements within -2.5 % and +1.5 % at locations on- and off-axis and before, in and after the Bragg peak or plateau. The gamma passing rate 2%/3mm of four simulated treatment plans compared to the dose distribution calculated by the TPS exceeds 97 % agreement score. OOF dose simulations showed an average overestimation of 27 % of the neutron dose equivalent for the BIC hadron physics list and an average underestimation of 20 % for the Bertini hadron physics list. The simulated absorbed dose of protons and gammas showed a systematic underestimation which was on average 21 % and 51 % for BIC and Bertini respectively.Significance: Our study demonstrates that a compact MC model can reliably produce in-field data, while out-of-field dose data are within the uncertainties of the detector systems and MC simulations nuclear models, and do so with shorter modelling and faster calculation time.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy.

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets.Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with publishedin silicobiophysical models to elucidate the potential biological effects of collimated and uncollimated fields.Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keVµm-1in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keVµm-1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction.Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Calibration and time fading characterization of a new optically stimulated luminescence film dosimeter.

BACKGROUND: Optically stimulated luminescence (OSL) dosimeters produce a signal linear to the dose, which fades with time due to the spontaneous recombination of energetically unstable electron/hole traps. When used for radiotherapy (RT) applications, fading affects the signal-to-dose conversion and causes an error in the final dose measurement. Moreover, the signal fading depends to some extent on treatment-specific irradiation conditions such as irradiation times. PURPOSE: In this work, a dose calibration function for a novel OSL film dosimeter was derived accounting for signal fading. The proposed calibration allows to perform dosimetry evaluation for different RT treatment regimes. METHODS: A novel BaFBr:Eu2+ -based OSL film (Zeff , 6 MV  = 4.7) was irradiated on a TrueBeam STx using a 6 MV beam with setup: 0° gantry angle, 90 cm SSD, 10 cm depth, 10 × 10 cm2 field. A total of 86 measurements were acquired for dose-rates ( D ̇ $\dot{D}$ ) of 600, 300, and 200 MU/min for irradiation times (tir ) of 0.2, 1, 2, 4.5, 12, and 23 min and various readout times (tscan ) between 4 and 1440 min from the start of the exposure (beam-on time). The OSL signal, S ( D ̇ , t i r , t s c a n ) $S(\dot{D},{t}_{ir},{t}_{scan})$ , was modeled via robust nonlinear regression, and two different power-law fading models were tested, respectively, independent (linear model) and dependent on the specific t i r ${t}_{ir}$ (delivery-dependent model). RESULTS: After 1 day from the exposure, the error on the dose measurement can be as high as 48% if a fading correction is not considered. The fading contribution was characterized by two accurate models with adjusted-R2 of 0.99. The difference between the two models is <4.75% for all t i r ${t}_{ir}$ and t s c a n ${t}_{scan}$ . For different beam-on times, 3, 10.5, and 20 min, the optimum t s c a n ${t}_{scan}$ was calculated in order to achieve a signal-to-dose conversion with a model-related error <1%. In the case of a 3 min irradiation, this condition is already met when the OSL-film is scanned immediately after the end of the irradiation. For an irradiation of 10.5 and 20 min, the minimum scanning time to achieve this model-related error increases, respectively, to 30 and 90 min. Under these conditions, the linear model can be used for the signal-to-dose conversion as an approximation of the delivery-dependent model. The signal-to-dose function, D(Mi , j , t s c a n $\ {t}_{scan}$ ), has a residual mean error of 0.016, which gives a residual dose uncertainty of 0.5 mGy in the region of steep signal fading (i.e., t s c a n ${t}_{scan}\ $ = 4 min). The function of two variables is representable as a dose surface depending on the signal (Mi , j ) measured for each i,j-pixel and the time of scan ( t s c a n ${t}_{scan}$ ). CONCLUSIONS: The calibration of a novel OSL-film usable for dosimetry in different RT treatments was corrected for its signal fading with two different models. A linear calibration model independent from the treatment-specific irradiation condition results in a model-related error <1% if a proper scanning time is used for each irradiation length. This model is more practical than the delivery-dependent model because it does not need a pixel-to-pixel fading correction for different t i r ${t}_{ir}$ .

Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures.

Background: In radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment. Materials and methods: Organ doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider et al. Results: Out-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 µSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 µSv (testes) and 48 µSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs. Conclusion: The complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.

Therapeutic efficacy of heterogeneously distributed radiolabelled peptides: Influence of radionuclide choice.

PURPOSE: To model dose-response relationships for in vivo experiments with radiolabelled peptides enabling maximum therapeutic efficacy while limiting toxicity to kidney and bone marrow. METHODS: A multiregional murine kidney phantom, with a kinetic model for cortex and outer medulla distribution, were used to predict renal toxicity. Maximum tolerated activities to avoid nephrotoxicity (at 40 Gy Biological Effective Dose BED) and hematologic toxicity (at 2 Gy) were compared. The therapeutic efficacy of 90Y, 161Tb, 177Lu and 213Bi was assessed at their respective maximum tolerated activities based on cellular-level dosimetry accounting for activity and tumor heterogeneity. These results were compared with average tumor-dosimetry-based predictions. RESULTS: The kidney was found to be the dose-limiting organ for all radionuclides, limiting the administered activity to 44 MBq 177Lu, 34 MBq 161Tb, 19 MBq 90Y and 13 MBq 213Bi , respectively. The average S-values for the initial heterogeneous activity distribution in the tumor volume are not significantly different from the homogeneous ones. The in vivo tumor cell survivals predicted by assuming uniform dose rate-distributions are not significantly different from those for heterogeneous dose rate-based predictions. The lowest in vivo survival was found for 213Bi (2%) followed by 161Tb (30%), 177Lu (37%) and 90Y (60%). The minimal effective dose rate for cell kill is 13-14 mGy/h for ß-emitters and 2.2 mGy/h for the α-particle emitter 213Bi, below these values proliferation takes over. CONCLUSIONS: Radionuclides emitting α-particles have the highest potential for improving therapeutic efficacy in tumors and metastases with uniform receptor expression, after careful evaluation of their burden to the healthy organs.

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT).

Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

Experimental Validation of an Analytical Program and a Monte Carlo Simulation for the Computation of the Far Out-of-Field Dose in External Beam Photon Therapy Applied to Pediatric Patients.

Background: The out-of-the-field absorbed dose affects the probability of primary second radiation-induced cancers. This is particularly relevant in the case of pediatric treatments. There are currently no methods employed in the clinical routine for the computation of dose distributions from stray radiation in radiotherapy. To overcome this limitation in the framework of conventional teletherapy with photon beams, two computational tools have been developed-one based on an analytical approach and another depending on a fast Monte Carlo algorithm. The purpose of this work is to evaluate the accuracy of these approaches by comparison with experimental data obtained from anthropomorphic phantom irradiations. Materials and Methods: An anthropomorphic phantom representing a 5-year-old child (ATOM, CIRS) was irradiated considering a brain tumor using a Varian TrueBeam linac. Two treatments for the same planned target volume (PTV) were considered, namely, intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). In all cases, the irradiation was conducted with a 6-MV energy beam using the flattening filter for a prescribed dose of 3.6 Gy to the PTV. The phantom had natLiF : Mg, Cu, P (MCP-N) thermoluminescent dosimeters (TLDs) in its 180 holes. The uncertainty of the experimental data was around 20%, which was mostly attributed to the MCP-N energy dependence. To calculate the out-of-field dose, an analytical algorithm was implemented to be run from a Varian Eclipse TPS. This algorithm considers that all anatomical structures are filled with water, with the exception of the lungs which are made of air. The fast Monte Carlo code dose planning method was also used for computing the out-of-field dose. It was executed from the dose verification system PRIMO using a phase-space file containing 3x109 histories, reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1 ) on all voxels scoring more than 50% of the maximum dose. The standard statistical uncertainty of out-of-field voxels in the Monte Carlo simulation did not exceed 5%. For the Monte Carlo simulation the actual chemical composition of the materials used in ATOM, as provided by the manufacturer, was employed. Results: In the out-of-the-field region, the absorbed dose was on average four orders of magnitude lower than the dose at the PTV. For the two modalities employed, the discrepancy between the central values of the TLDs located in the out-of-the-field region and the corresponding positions in the analytic model were in general less than 40%. The discrepancy in the lung doses was more pronounced for IMRT. The same comparison between the experimental and the Monte Carlo data yielded differences which are, in general, smaller than 20%. It was observed that the VMAT irradiation produces the smallest out-of-the-field dose when compared to IMRT. Conclusions: The proposed computational methods for the routine calculation of the out-of-the-field dose produce results that are similar, in most cases, with the experimental data. It has been experimentally found that the VMAT irradiation produces the smallest out-of-the-field dose when compared to IMRT for a given PTV.

Dosimetric Evaluation of the Effect of Receptor Heterogeneity on the Therapeutic Efficacy of Peptide Receptor Radionuclide Therapy: Correlation with DNA Damage Induction and In Vivo Survival.

Our rationale was to build a refined dosimetry model for 177Lu-DOTATATE in vivo experiments enabling the correlation of absorbed dose with double-strand break (DSB) induction and cell death. Methods: Somatostatin receptor type 2 expression of NCI-H69 xenografted mice, injected with 177Lu-DOTATATE, was imaged at 0, 2, 5, and 11 d. This expression was used as input to reconstruct realistic 3-dimensional heterogeneous activity distributions and tissue geometries of both cancer and heathy cells. The resulting volumetric absorbed dose rate distributions were calculated using the GATE (Geant4 Application for Tomographic Emission) Monte Carlo code and compared with homogeneous dose rate distributions. The absorbed dose (0-2 d) on micrometer-scale sections was correlated with DSB induction, measured by γH2AX foci. Moreover, the absorbed dose on larger millimeter-scale sections delivered over the whole treatment (0-14 d) was correlated to the modeled in vivo survival to determine the radiosensitivity parameters α and ß for comparison with experimental data (cell death assay, volume response) and external-beam radiotherapy. The DNA-damage repair half-life Tµ and proliferation doubling time TD were obtained by fitting the DSB and tumor volume data over time. Results: A linear correlation with a slope of 0.0223 DSB/cell mGy-1 between the absorbed dose and the number of DSBs per cell has been established. The heterogeneous dose distributions differed significantly from the homogeneous dose distributions, with their corresponding average S values diverging at 11 d by up to 58%. No significant difference between modeled in vivo survival was observed in the first 5 d when using heterogeneous and uniform dose distributions. The radiosensitivity parameter analysis for the in vivo survival correlation indicated that the minimal effective dose rates for cell kill was 13.72 and 7.40 mGy/h, with an α of 0.14 and 0.264 Gy-1, respectively, and an α/ß of 100 Gy; decreasing the α/ß led to a decrease in the minimal effective dose rate for cell kill. Within the linear quadratic model, the best matching in vivo survival correlation (α = 0.1 Gy-1, α/ß = 100 Gy, Tµ = 60 h, TD = 14.5 d) indicated a relative biological effectiveness of 0.4 in comparison to external-beam radiotherapy. Conclusion: Our results demonstrated that accurate dosimetric modeling is crucial to establishing dose-response correlations enabling optimization of treatment protocols.

Gamma counting protocols for the accurate quantification of 225Ac and 213Bi without the need for a secular equilibrium between parent and gamma-emitting daughter.

BACKGROUND: Quantification of actinium-225 through gamma counter measurements, when there is no secular equilibrium between actinium-225 and its gamma emitting daughters bismuth-213 and/or francium-221, can provide valuable information regarding the possible relocation of recoiled daughters such that related radiotoxicity effects can be evaluated. This study proposes a multiple time-point protocol using the bismuth-213 photopeak with measurements before secular equilibrium between actinium-225 and bismuth-213, and a single time-point protocol using both the francium-221 and bismuth-213 photopeak while assuming secular equilibrium between actinium-225 and francium-221 but not between bismuth-213 and actinium-225. RESULTS: Good agreement (i.e. 3% accuracy) was obtained when relying on a multiple time-points measurement of bismuth-213 to quantify both actinium-225 and excess of bismuth-213. Following scatter correction, actinium-225 can be accurately quantified using the francium-221 in a single time-point measurement within 3% of accuracy. The analysis performed on the stability data of [225Ac]Ac-DEPA and [225Ac]Ac-DOTA complexes, before secular equilibrium between bismuth-213 and actinium-225 was formed, revealed considerable amounts of unbound bismuth-213 (i.e. more than 90%) after 24 h of the radiolabeling most likely due to the recoiled daughter effect. CONCLUSION: Both protocols were able to accurately estimate 225Ac-activities provided the francium-221 energy window was corrected for the down scatter of the higher-energy gamma-emissions by bismuth-213. This could prove beneficial to study the recoiled daughter effect and redistribution of free bismuth-213 by monitoring the accumulation or clearance of bismuth-213 in different tissues during biodistribution studies or in patient samples during clinical studies. On the other hand, the single gamma counter measurement protocol, although required a 30 min waiting time, is more time and cost efficient and therefore more appropriate for standardized quality control procedures of 225Ac-labeled radiopharmaceuticals.

Modeling Early Radiation DNA Damage Occurring During 177Lu-DOTATATE Radionuclide Therapy.

The aim of this study was to build a simulation framework to evaluate the number of DNA double-strand breaks (DSBs) induced by in vitro targeted radionuclide therapy (TRT). This work represents the first step toward exploring underlying biologic mechanisms and the influence of physical and chemical parameters to enable a better response prediction in patients. We used this tool to characterize early DSB induction by 177Lu-DOTATATE, a commonly used TRT for neuroendocrine tumors. Methods: A multiscale approach was implemented to simulate the number of DSBs produced over 4 h by the cumulated decays of 177Lu distributed according to the somatostatin receptor binding. The approach involves 2 sequential simulations performed with Geant4/Geant4-DNA. The radioactive source is sampled according to uptake experiments on the distribution of activities within the medium and the planar cellular cluster, assuming instant and permanent internalization. A phase space is scored around the nucleus of the central cell. Then, the phase space is used to generate particles entering the nucleus containing a multiscale description of the DNA in order to score the number of DSBs per particle source. The final DSB computations are compared with experimental data, measured by immunofluorescent detection of p53-binding protein 1 foci. Results: The probability of electrons reaching the nucleus was significantly influenced by the shape of the cell compartment, causing a large variance in the induction pattern of DSBs. A significant difference was found in the DSBs induced by activity distributions in cell and medium, as is explained by the specific energy ([Formula: see text]) distributions. The average number of simulated DSBs was 14 DSBs per cell (range, 7-24 DSBs per cell), compared with 13 DSBs per cell (range, 2-30 DSBs per cell) experimentally determined. We found a linear correlation between the mean absorbed dose to the nucleus and the number of DSBs per cell: 0.014 DSBs per cell mGy-1 for internalization in the Golgi apparatus and 0.017 DSBs per cell mGy-1 for internalization in the cytoplasm. Conclusion: This simulation tool can lead to a more reliable absorbed-dose-to-DNA correlation and help in prediction of biologic response.

Out-of-field doses in pediatric craniospinal irradiations with 3D-CRT, VMAT, and scanning proton radiotherapy: A phantom study.

PURPOSE: Craniospinal irradiation (CSI) has greatly increased survival rates for patients with a diagnosis of medulloblastoma and other primitive neuroectodermal tumors. However, as it includes exposure of a large volume of healthy tissue to unwanted doses, there is a strong concern about the complications of the treatment, especially for the children. To estimate the risk of second cancers and other unwanted effects, out-of-field dose assessment is necessary. The purpose of this study is to evaluate and compare out-of-field doses in pediatric CSI treatment using conventional and advanced photon radiotherapy (RT) and advanced proton therapy. To our knowledge, it is the first such comparison based on in-phantom measurements. Additionally, for out-of-field doses during photon RT in this and other studies, comparisons were made using analytical modeling. METHODS: In order to describe the out-of-field doses absorbed in a pediatric patient during actual clinical treatment, an anthropomorphic phantom, which mimics the 10-year-old child, was used. Photon 3D-conformal RT (3D-CRT) and two advanced, highly conformal techniques: photon volumetric-modulated arc therapy (VMAT) and active pencil beam scanning (PBS) proton RT were used for CSI treatment. Radiophotoluminescent and poly-allyl-diglycol-carbonate nuclear track detectors were used for photon and neutron dosimetry in the phantom, respectively. Out-of-field doses from neutrons were expressed in terms of dose equivalent. A two-Gaussian model was implemented for out-of-field doses during photon RT. RESULTS: The mean VMAT photon doses per target dose to all organs in this study were under 50% of the target dose (i.e., <500 mGy/Gy), while the mean 3D-CRT photon dose to oesophagus, gall bladder, and thyroid, exceeded that value. However, for 3D-CRT, better sparing was achieved for eyes and lungs. The mean PBS photon doses for all organs were up to three orders of magnitude lower compared to VMAT and 3D-CRT and exceeded 10 mGy/Gy only for the oesophagus, intestine, and lungs. The mean neutron dose equivalent during PBS for eight organs of interest (thyroid, breasts, lungs, liver, stomach, gall bladder, bladder, prostate) ranged from 1.2 mSv/Gy for bladder to 23.1 mSv/Gy for breasts. Comparison of out-of-field doses in this and other phantom studies found in the literature showed that a simple and fast two-Gaussian model for out-of-field doses as a function of distance from the field edge can be applied in a CSI using photon RT techniques. CONCLUSIONS: PBS is the most promising technique for out-of-field dose reduction in comparison to photon techniques. Among photon techniques, VMAT is a preferred choice for most of out-of-field organs and especially for the thyroid, while doses for eyes, breasts, and lungs are lower for 3D-CRT. For organs outside the field edge, a simple analytical model can be helpful for clinicians involved in treatment planning using photon RT but also for retrospective data analysis for cancer risk estimates and epidemiology in general.

Validation of a Monte Carlo Framework for Out-of-Field Dose Calculations in Proton Therapy.

Proton therapy enables to deliver highly conformed dose distributions owing to the characteristic Bragg peak and the finite range of protons. However, during proton therapy, secondary neutrons are created, which can travel long distances and deposit dose in out-of-field volumes. This out-of-field absorbed dose needs to be considered for radiation-induced secondary cancers, which are particularly relevant in the case of pediatric treatments. Unfortunately, no method exists in clinics for the computation of the out-of-field dose distributions in proton therapy. To help overcome this limitation, a computational tool has been developed based on the Monte Carlo code TOPAS. The purpose of this work is to evaluate the accuracy of this tool in comparison to experimental data obtained from an anthropomorphic phantom irradiation. An anthropomorphic phantom of a 5-year-old child (ATOM, CIRS) was irradiated for a brain tumor treatment in an IBA Proteus Plus facility using a pencil beam dedicated nozzle. The treatment consisted of three pencil beam scanning fields employing a lucite range shifter. Proton energies ranged from 100 to 165 MeV. A median dose of 50.4 Gy(RBE) with 1.8 Gy(RBE) per fraction was prescribed to the initial planning target volume (PTV), which was located in the cerebellum. Thermoluminescent detectors (TLDs), namely, Li-7-enriched LiF : Mg, Ti (MTS-7) type, were used to detect gamma radiation, which is produced by nuclear reactions, and secondary as well as recoil protons created out-of-field by secondary neutrons. Li-6-enriched LiF : Mg,Cu,P (MCP-6) was combined with Li-7-enriched MCP-7 to measure thermal neutrons. TLDs were calibrated in Co-60 and reported on absorbed dose in water per target dose (µGy/Gy) as well as thermal neutron dose equivalent per target dose (µSv/Gy). Additionally, bubble detectors for personal neutron dosimetry (BD-PND) were used for measuring neutrons (>50 keV), which were calibrated in a Cf-252 neutron beam to report on neutron dose equivalent dose data. The Monte Carlo code TOPAS (version 3.6) was run using a phase-space file containing 1010 histories reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1) on all voxels scoring more than 50% of the maximum dose. The primary beam was modeled following a Fermi-Eyges description of the spot envelope fitted to measurements. For the Monte Carlo simulation, the chemical composition of the tissues represented in ATOM was employed. The dose was tallied as dose-to-water, and data were normalized to the target dose (physical dose) to report on absorbed doses per target dose (mSv/Gy) or neutron dose equivalent per target dose (µSv/Gy), while also an estimate of the total organ dose was provided for a target dose of 50.4 Gy(RBE). Out-of-field doses showed absorbed doses that were 5 to 6 orders of magnitude lower than the target dose. The discrepancy between TLD data and the corresponding scored values in the Monte Carlo calculations involving proton and gamma contributions was on average 18%. The comparison between the neutron equivalent doses between the Monte Carlo simulation and the measured neutron doses was on average 8%. Organ dose calculations revealed the highest dose for the thyroid, which was 120 mSv, while other organ doses ranged from 18 mSv in the lungs to 0.6 mSv in the testes. The proposed computational method for routine calculation of the out-of-the-field dose in proton therapy produces results that are compatible with the experimental data and allow to calculate out-of-field organ doses during proton therapy.

Out-of-Field Doses Produced by a Proton Scanning Beam Inside Pediatric Anthropomorphic Phantoms and Their Comparison With Different Photon Modalities.

Since 2010, EURADOS Working Group 9 (Radiation Dosimetry in Radiotherapy) has been involved in the investigation of secondary and scattered radiation doses in X-ray and proton therapy, especially in the case of pediatric patients. The main goal of this paper is to analyze and compare out-of-field neutron and non-neutron organ doses inside 5- and 10-year-old pediatric anthropomorphic phantoms for the treatment of a 5-cm-diameter brain tumor. Proton irradiations were carried out at the Cyclotron Centre Bronowice in IFJ PAN Krakow Poland using a pencil beam scanning technique (PBS) at a gantry with a dedicated scanning nozzle (IBA Proton Therapy System, Proteus 235). Thermoluminescent and radiophotoluminescent dosimeters were used for non-neutron dose measurements while secondary neutrons were measured with track-etched detectors. Out-of-field doses measured using intensity-modulated proton therapy (IMPT) were compared with previous measurements performed within a WG9 for three different photon radiotherapy techniques: 1) intensity-modulated radiation therapy (IMRT), 2) three-dimensional conformal radiation therapy (3D CDRT) performed on a Varian Clinac 2300 linear accelerator (LINAC) in the Centre of Oncology, Krakow, Poland, and 3) Gamma Knife surgery performed on the Leksell Gamma Knife (GK) at the University Hospital Centre Zagreb, Croatia. Phantoms and detectors used in experiments as well as the target location were the same for both photon and proton modalities. The total organ dose equivalent expressed as the sum of neutron and non-neutron components in IMPT was found to be significantly lower (two to three orders of magnitude) in comparison with the different photon radiotherapy techniques for the same delivered tumor dose. For IMPT, neutron doses are lower than non-neutron doses close to the target but become larger than non-neutron doses further away from the target. Results of WG9 studies have provided out-of-field dose levels required for an extensive set of radiotherapy techniques, including proton therapy, and involving a complete description of organ doses of pediatric patients. Such studies are needed for validating mathematical models and Monte Carlo simulation tools for out-of-field dosimetry which is essential for dedicated epidemiological studies which evaluate the risk of second cancers and other late effects for pediatric patients treated with radiotherapy.

Joint EURADOS WG9-WG11 rem-counter intercomparison in a Mevion S250i proton therapy facility with Hyperscan pulsed synchrocyclotron.

Objective Proton therapy is gaining popularity because of the improved dose delivery over conventional radiation therapy. The secondary dose to healthy tissues is dominated by secondary neutrons. Commercial rem-counters are valuable instruments for the on-line assessment of neutron ambient dose equivalent (H*(10)). In general, however, a priori knowledge of the type of facility and of the radiation field is required for the proper choice of any survey meter. The novel Mevion S250i Hyperscan synchrocyclotron mounts the accelerator directly on the gantry. It provides a scanned 227 MeV proton beam, delivered in pulses with a pulse width of 10 µs at 750 Hz frequency, which is afterwards degraded in energy by a range shifter modulator system. This environment is particularly challenging for commercial rem-counters; therefore, we tested the reliability of some of the most widespread rem-counters to understand their limits in the Mevion S250i stray neutron field. Approach This work, promoted by the European Radiation Dosimetry Group (EURADOS), describes a rem-counter intercomparison at the Maastro Proton Therapy centre in the Netherlands, which houses the novel Mevion S250i Hyperscan system. Several rem-counters were employed in the intercomparison (LUPIN, LINUS, WENDI-II, LB6411, NM2B-458, NM2B-495Pb), which included simulation of a patient treatment protocol employing a water tank phantom. The outcomes of the experiment were compared with models and data from the literature. Main results We found that only the LUPIN allowed for a correct assessment of H*(10) within a 20% uncertainty. All other rem-counters underestimated the reference H*(10) by factors from 2 to more than 10, depending on the detector model and on the neutron dose per pulse. In pulsed fields, the neutron dose per pulse is a fundamental parameter, while the average neutron dose rate is a secondary quantity. An average 150-200 µSv/GyRBE neutron H*(10) at various positions around the phantom and at distances between 186 cm and 300 cm from it was measured per unit therapeutic dose delivered to the target. Significance Our results are partially in line with results obtained at similar Mevion facilities employing passive energy modulation. Comparisons with facilities employing active energy modulation confirmed that the neutron H*(10) can increase up to more than a factor of 10 when passive energy modulation is employed. The challenging environment of the Mevion stray neutron field requires the use of specific rem-counters sensitive to high-energy neutrons (up to a few hundred MeV) and specifically designed to withstand pulsed neutron fields.