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The original rationale for proton therapy was its highly conformal depth‐dose distributions compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors versus normal tissues. Moreover, the smaller “dose bath,” that is, the compact nature of proton dose distributions, has been found to reduce the exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes. Protons accelerated to energies ranging from 70 to 250 MeV enter the treatment head mounted typically on a rotating gantry. Initially, the beams of protons are narrow and, to be suitable for treatments, must be spread laterally and longitudinally and shaped appropriately. Such spreading and shaping may be accomplished electro‐mechanically for the “passively scattered proton therapy” (PSPT) mode; or it may be achieved through magnetic scanning of thin “beamlets” of protons. Intensities of scanning beamlets are optimized to deliver intensity‐modulated proton therapy (IMPT), which optimally balances tumor dose and the sparing of normal tissues. IMPT is presumably the most powerful form of proton therapy. The planning and evaluation of proton dose distributions require substantially different techniques compared to photon therapy. This is mainly due to the fact that proton dose distributions are highly sensitive to inter‐ and intra‐fractional variations in anatomy. In addition, for the same physical dose, the biological effectiveness of protons is different from photons. In the current practice of proton therapy, the RBE is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a highly complex function of numerous variables including energy of protons, dose per fraction, tissue and its environment, cell type, end point, and possibly other factors. While the theoretical potential of proton therapy is high, the clinical evidence in support of its use has so far been mixed. The uncertainties and assumptions mentioned above and the limitations of the still evolving technology of proton therapy may have diminished its true clinical potential. Although promising results have been reported for many types of cancers, they are often based on small studies. At the same time, there have been reports of unforeseen toxicities. Furthermore, because of the high cost of proton therapy, questions are often raised about its value. The general consensus is that there is a need for continued improvement in the state of the art of proton therapy. There is also a need to generate high level evidence of the potential of protons. Fortuitously, such efforts are taking place currently. Current research, aimed at enhancing the therapeutic potential of proton therapy, includes the determination and mitigation of the impact of the physical uncertainties on proton dose distributions through advanced image‐guidance and adaptive radiotherapy techniques. Since residual uncertainties will remain, robustness evaluation and robust optimization techniques are being developed to render dose distributions more resilient and to improve confidence in them. The ongoing research also includes improving our understanding of the biological and immunomodulatory effects of proton therapy. Such research and continuing technological advancements in planning and delivery methods are likely to help demonstrate the superiority of protons.

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 β-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 [ 225 Ac]Ac-PSMA-I&T and [ 177 Lu]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 [ 225 Ac]Ac-PSMA-I&T and [ 177 Lu]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 [ 225 Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [ 177 Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [ 225 Ac]Ac-PSMA-I&T and [ 177 Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [ 225 Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [ 177 Lu]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 [ 225 Ac]Ac-PSMA-I&T compared to [ 177 Lu]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 [ 225 Ac]Ac-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.

In this study, we report our experience in commissioning a commercial treatment planning system (TPS) for fast-raster scanning of carbon-ion beams. This TPS uses an analytical dose calculation algorithm, a pencil-beam model with a triple Gaussian form for the lateral-dose distribution, and a beam splitting algorithm to consider lateral heterogeneity in a medium. We adopted the mixed beam model as the relative biological effectiveness (RBE) model for calculating the RBE values of the scanned carbon-ion beam. To validate the modeled physical dose, we compared the calculations with measurements of various relevant quantities as functions of the field size, range and width of the spread-out Bragg peak (SOBP), and depth–dose and lateral-dose profiles for a 6-mm SOBP in water. To model the biological dose, we compared the RBE calculated with the newly developed TPS to the RBE calculated with a previously validated TPS that is in clinical use and uses the same RBE model concept. We also performed patient-specific measurements to validate the dose model in clinical situations. The physical beam model reproduces the measured absolute dose at the center of the SOBP as a function of field size, range, and SOBP width and reproduces the dose profiles for a 6-mm SOBP in water. However, the profiles calculated for a heterogeneous phantom have some limitations in predicting the carbon-ion-beam dose, although the biological doses agreed well with the values calculated by the validated TPS. Using this dose model for fast-raster scanning, we successfully treated more than 900 patients from October 2018 to October 2020, with an acceptable agreement between the TPS-calculated and measured dose distributions. We conclude that the newly developed TPS can be used clinically with the understanding that it has limited accuracies for heterogeneous media.

The particle irradiation data ensemble (PIDE) is the largest database of cell survival data measured after exposure to ion beams and photon reference radiation. We report here on the updated version of the PIDE database and demonstrate how to investigate generic properties of radiation dose response using these sets of raw data. The database now contains information of over 1100 pairs of photon and ion dose response curves. It provides the originally published raw data of cell survival in addition to given linear quadratic (LQ) model parameters. If available, the raw data were used to derive LQ model parameters in the same way for all experiments. To demonstrate the extent of the database and the variability among experiments we focus on the dose response curves after ion and photon radiation separately in a first step. Furthermore, we discuss the capability and the limitations of the database for analyzing properties of low and high linear energy transfer (LET) radiation response based on multiple experiments. PIDE is freely available to the research community under www.gsi.de/bio-pide.

Epidemiological studies of Japanese atomic bomb survivors indicate that the risk of cancer from radiation exposure is higher in individuals who are relatively young at the time of exposure, with women facing a more significant risk compared to men. However, this type of data is limited for other radiation types, such as particle radiations. Low linear energy transfer (LET) carbon ions are a type of particle radiation to which humans may be exposed as cosmic radiation during long-duration space missions and as radiation passing through healthy tissue during carbon ion radiotherapy. This raises concerns about the risk of late complications, including cancer development. To address these issues, we examined the lifespan of mice after exposure to γ rays or low-LET carbon-ion beams, assessed the effects of sex and age at the time of exposure, and calculated the RBE. Male and female B6C3F1 mice of various ages (embryonic days 3, 13, and 17, and postnatal weeks 1, 3, 7, and 15) were whole-body irradiated a single time with 137 Cs γ rays (662 keV) or 290-MeV/u monoenergetic carbon ions (LET, ~ 13 keV/µm), and their lifespan was analyzed. For both γ rays and carbon ions, the hazard ratio for mortality increased in a dose-dependent manner, was higher for females than for males, and peaked at 1 week of age at the time of exposure. The RBE of low-LET carbon ions for lifespan shortening was 0.9–1.8 for females and 1.2–2.0 for males, regardless of the age at exposure. Thus, the risk associated with low-LET carbon ion exposure varied with age and sex, but RBE did not. These findings provide essential data for assessing the impacts of low-LET carbon ion exposure.

For tumor therapy with light ions and for experimental aspects in particle radiobiology the relative biological effectiveness (RBE) is an important quantity to describe the increased effectiveness of particle radiation. By establishing and analysing a database of ion and photon cell survival data, some remarkable properties of RBE-related quantities were observed. The database consists of 855 in vitro cell survival experiments after ion and photon irradiation. The experiments comprise curves obtained in different labs, using different ion species, different irradiation modalities, the whole range of accessible energies and linear energy transfers (LETs) and various cell types. Each survival curve has been parameterized using the linear-quadratic (LQ) model. The photon parameters, α and β, appear to be slightly anti-correlated, which might point toward an underlying biological mechanism. The RBE values derived from the survival curves support the known dependence of RBE on LET, on particle species and dose. A positive correlation of RBE with the ratio α/β of the photon LQ parameters is found at low doses, which unexpectedly changes to a negative correlation at high doses. Furthermore, we investigated the course of the β coefficient of the LQ model with increasing LET, finding typically a slight initial increase and a final falloff to zero. The observed fluctuations in RBE values of comparable experiments resemble overall RBE uncertainties, which is of relevance for treatment planning. The database can also be used for extensive testing of RBE models. We thus compare simulations with the local effect model to achieve this goal.

Background/Aim: Dose distributions of carbon-ion radiotherapy (C-ion RT) have been created with the relative biological effectiveness (RBE) of human salivary gland cells (HSG). However, no dose distributions have been created using various tumor cell-specific RBE values. Hence, we conducted in vitro experiments to determine the RBE of human osteosarcoma cells (U2OS) and used this RBE value (RBEU2OS) to calculate the dose distribution for C-ion RT. Materials and Methods: To obtain RBE values for various linear energy transfer (LET) levels, we exposed U2OS cells to different doses of X-rays and varying doses and LET levels of C-ion beams (13, 30, 50, and 70 keV/μm). Subsequently, we converted the RBE of HSG (RBEHSG) to RBEU2OS in the treatment planning system and reconstructed the dose distribution for a typical osteosarcoma case. We performed a dose-volume histogram (DVH) analysis, evaluating the percentage of the minimum dose that covered 98%, 50%, and 2% (D98%, D50%, and D2%, respectively), as well as the homogeneity index [HI; calculated as (D2%-D98%)/D50%]. Results: The RBEU2OS values for C-ion beams with LET of 13, 30, 50, and 70 keV/μm were 1.77, 2.25, 2.72, and 4.50, respectively. When comparing DVH parameters with the planning target volume, we observed the following values: D98%, D50%, D2%, and HI for RBEHSG were 64.1, 70.1, 72.4 Gy (RBE), and 0.12, respectively. For RBEU2OS, these values were 86.2, 95.0, 107.9 Gy (RBE), and 0.23, respectively. Conclusion: We utilized RBEU2OS to calculate the dose distribution of carbon ion radiotherapy, revealing potential degradation in dose distribution and particularly worsening of the HI.

The irradiation field of boron neutron capture therapy (BNCT) consists of multiple dose components including thermal, epithermal and fast neutron, and gamma. The objective of this work was to establish a methodology of dosimetric quality assurance (QA), using the most standard and reliable measurement methods, and to determine tolerance level for each QA measurement for a commercially available accelerator-based BNCT system. In order to establish a system of dosimetric QA suitable for BNCT, the following steps were taken. First, standard measurement points based on tissue-administered doses in BNCT for brain tumors were defined, and clinical tolerances of dosimetric QA measurements were derived from the contribution to total tissue relative biological effectiveness factor-weighted dose for each dose component. Next, a QA program was proposed based on TG-142 and TG-198, and confirmed that it could be assessed whether constancy of each dose component was assured within the limits of tolerances or not by measurements of the proposed QA program. Finally, the validity of the BNCT QA program as an evaluation system was confirmed in a demonstration experiment for long-term measurement over 1 year. These results offer an easy, reliable QA method that is clinically applicable with dosimetric validity for the mixed irradiation field of accelerator-based BNCT.

Currently, treatment planning systems (TPSs) that can compute the intensities of intensity-modulated carbon-ion therapy (IMCT) using scanned carbon-ion beams are limited. In the present study, the computational efficacy of the newly designed IMCT algorithms was analyzed for the first time based on the mixed beam model with respect to the physical and biological doses; moreover, the validity and effectiveness of the robust radiobiological optimization were verified. A dose calculation engine was independently generated to validate a clinical dose determined in the TPS. A biological assay was performed using the HSGc-C5 cell line to validate the calculated surviving fraction (SF). Both spot control (SC) and voxel-wise worst-case scenario (WC) algorithms were employed for robust radiobiological optimization followed by their application in a Radiation Therapy Oncology Group benchmark phantom under homogeneous and heterogeneous conditions and a clinical case for range and position errors. Importantly, for the first time, both SC and WC algorithms were implemented in the integrated TPS platform that can compute the intensities of IMCT using scanned carbon-ion beams for robust radiobiological optimization. For assessing the robustness, the difference between the maximum and minimum values of a dose–volume histogram index in the examined error scenarios was considered as a robustness index. The relative biological effectiveness (RBE) determined by the independent dose calculation engine exhibited a −0.6% difference compared with the RBE defined by the TPS at the isocenter, whereas the measured and the calculated SF were similar. Regardless of the objects, compared with the conventional IMCT, the robust radiobiological optimization enhanced the sensitivity of the examined error scenarios by up to 19% for the robustness index. The computational efficacy of the novel IMCT algorithms was verified according to the mixed beam model with respect to the physical and biological doses. The robust radiobiological optimizations lowered the impact of range and position uncertainties considerably in the examined scenarios. The robustness of the WC algorithm was more enhanced compared with that of the SC algorithm. Nevertheless, the SC algorithm can be used as an alternative to the WC IMCT algorithm with respect to the computational cost.

Cholangiocarcinoma (CCA) is an aggressive cancer that is prevalent in the northeastern part of Thailand. Surgical treatment is the gold standard for CCA treatment, but some CCA patients are inoperable. Chemotherapy and radiotherapy are alternative treatments to improve the quality of life of patients. However, the effect of radiotherapy on CCA treatment is still unclear. In this study, we aimed to investigate the effect of X-rays and neutron beams on the human CCA cell line (KKU-055). First, KKU-055 cells were irradiated using 6 MV X-rays with a dose range of 0–5 Gy at King Chulalongkorn Memorial Hospital (KCMH) to obtain reference data. Next, cells were exposed to thermal neutron beams with doses ranging from 0 to 5 Gy using the Thai Research Reactor-1/Modification 1 (TRR-1/M1) at the Thailand Institute of Nuclear Technology (TINT). After neutron irradiation, survival curves were studied, and the relative biological effectiveness (RBE) was investigated. The findings revealed that the survival rate of the KKU-055 cells under X-ray irradiation is lower than that of neutron beams. To increase neutron interaction with the DNA of CCA cell lines, we plan to introduce boron compounds to CCA cell lines prior to neutron irradiation. This technique is referred to as boron neutron capture therapy (BNCT).