Relative Biological Effectiveness Research Articles

Solid state microdosimetry of a 148 MeV proton spread-out Bragg peak with a pixelated silicon telescope

A constant value of the Relative Biological Effectiveness (RBE), equal to 1.1, to weight the physical dose of proton therapy treatment planning collides with the experimental evidence of an increase of effectiveness along the depth dose profile, especially at the end of the particle range. In this context, it is desirable to develop new optimized treatment planning systems that account for a variable RBE when weighting the physical dose. In particular, due to the increasing interest on microdosimetry as a possible methodology for measuring physical quantities correlated with the biological effectiveness of the therapeutic beam, the development of new Tissue-Equivalent Proportional Counters (TEPCs) specifically designed for the clinical environment are in progress.In this framework, the silicon technology allows to produce solid state detectors of real micrometric dimensions. This is a valid alternative to the TEPC from a practical point of view, being simple, easy-of-use and more versatile. The feasibility of a solid state microdosimeter based on a monolithic double stage silicon telescope has been previously proposed and deeply investigated by comparing its response to the one obtained by reference TEPCs in various radiation fields. The device is constituted by a matrix of cylindrical elements, 2 μm in thickness and 9 μm in diameter, coupled to a single E stage, 500 μm in thickness. Each segmented ΔE stage acts as a solid state microdosimeter, while the E stage gives information on the energy of the impinging proton up to about 8 MeV.This work is dedicated to the description of the microdosimetric characterization of the 148 MeV energy-modulated proton beam at the radiobiological research line of the Trento Proton Therapy Centre by means of a pixelated silicon microdosimeter. All measurements were carried out at different positions across the spread-out Bragg peak (SOBP) and the corresponding microdosimetric distributions were derived by applying a novel extrapolation algorithm. Finally, microdosimetric assessment of Relative Biological Effectiveness was carried out by weighting the dose distribution of the lineal energy with the Loncol's biological weighting function. Benefits and possible limitations of this approach are discussed.

Quantifying the Dosimetric Impact of Proton Range Uncertainties on RBE-Weighted Dose Distributions in Intensity-Modulated Proton Therapy for Bilateral Head and Neck Cancer.

In current clinical practice, intensity-modulated proton therapy (IMPT) head and neck cancer (HNC) plans are generated using a constant relative biological effectiveness (cRBE) of 1.1. The primary goal of this study was to explore the dosimetric impact of proton range uncertainties on RBE-weighted dose (RWD) distributions using a variable RBE (vRBE) model in the context of bilateral HNC IMPT plans. The current study included the computed tomography (CT) datasets of ten bilateral HNC patients who had undergone photon therapy. Each patient's plan was generated using three IMPT beams to deliver doses to the CTV_High and CTV_Low for doses of 70 Gy(RBE) and 54 Gy(RBE), respectively, in 35 fractions through a simultaneous integrated boost (SIB) technique. Each nominal plan calculated with a cRBE of 1.1 was subjected to the range uncertainties of ±3%. The McNamara vRBE model was used for RWD calculations. For each patient, the differences in dosimetric metrices between the RWD and nominal dose distributions were compared. The constrictor muscles, oral cavity, parotids, larynx, thyroid, and esophagus showed average differences in mean dose (Dmean) values up to 6.91 Gy(RBE), indicating the impact of proton range uncertainties on RWD distributions. Similarly, the brachial plexus, brain, brainstem, spinal cord, and mandible showed varying degrees of the average differences in maximum dose (Dmax) values (2.78-10.75 Gy(RBE)). The Dmean and Dmax to the CTV from RWD distributions were within ±2% of the dosimetric results in nominal plans. The consistent trend of higher mean and maximum doses to the OARs with the McNamara vRBE model compared to cRBE model highlighted the need for consideration of proton range uncertainties while evaluating OAR doses in bilateral HNC IMPT plans.

Evaluation of relative biological effectiveness for diseases of the circulatory system based on microdosimetry.

In the next decade, the International Commission on Radiological Protection (ICRP) will issue the next set of general recommendations, for which evaluation of relative biological effectiveness (RBE) for various types of tissue reactions would be needed. ICRP has recently classified diseases of the circulatory system (DCS) as a tissue reaction, but has not recommended RBE for DCS. We therefore evaluated the mean and uncertainty of RBE for DCS by applying a microdosimetric kinetic model specialized for RBE estimation of tissue reactions. For this purpose, we analyzed several RBE data for DCS determined by past animal experiments and evaluated the radius of the subnuclear domain best fit to each experiment as a single free parameter included in the model. Our analysis suggested that RBE for DCS tends to be lower than that for skin reactions, and their difference was borderline significant due to large variances of the evaluated parameters. We also found that RBE for DCS following mono-energetic neutron irradiation of the human body is much lower than that for skin reactions, particularly at the thermal energy and around 1MeV. This tendency is considered attributable not only to the intrinsic difference of neutron RBE between skin reactions and DCS but also to the difference in the contributions of secondary γ-rays to the total absorbed doses between their target organs. These findings will help determine RBE by ICRP for preventing tissue reactions.

Research Trends in the Study of the Relative Biological Effectiveness: A Bibliometric Study.

The relative biological effectiveness is a mathematical quantity first defined in the 1950s. This has resulted in more than 4,000 scientific papers published to date. Yet defining the correct value of the RBE to use in clinical practice remains a challenge. A scientific analysis in the radiation research literature can provide an understanding of how this mathematical quantity has evolved. The purpose of this study is to investigate documents published since 1950 using bibliometric indicators and network visualization. This analysis seeks to provide an assessment of global research activities, key themes, and RBE research within the radiation-related field. It strives to highlight top-performing authors, organizations, and nations that have made major contributions to this research domain, as well as their interactions. The Scopus Collection was searched for articles and reviews pertaining to RBE in radiation research from 1950 through 2023. Scopus and Bibiometrix analytic tools were used to investigate the most productive countries, researchers, collaboration networks, journals, along with the citation analysis of references and keywords. A total of 4,632 documents were retrieved produced by authors originating from 71 countries. Publication trends could be separated in 20-year groupings beginning with slow accrual from 1950 to 1970, an early rise from 1970-1990, followed by a sharp increase in the years 1990s-2010s that matches the development of charged particle therapy in clinics worldwide and opened discussion on the true value of the RBE in proton beam therapy. Since the 2010s, a steady 200 papers, on average, have been published per year. The United States produced the most publications overall (N = 1,378) and Radiation Research was the most likely journal to have published articles related to the RBE (606 publications during this period). J. Debus was the most prolific author (112 contributions, with 2,900 citations). The RBE has captured the research interest of over 7,000 authors in the past decade alone. This study supports that notion that the growth of the body of evidence surrounding the RBE, which started 75 years ago, is far from reaching its end. Applications to medicine have continuously dominated the field, with physics competing with Biochemistry, Genetics and Molecular Biology for second place over the decades. Future research can be predicted to continue.

Secondary neutrons in proton and light ion beam therapy: a review of current status, needs and potential solutions

The advantages of proton and light ion beam therapy compared to conventional photon radiation therapy are well-known, mainly thanks to the characteristic depth dose distribution of ions and their radio-biological effectiveness. Nevertheless, the use of ions implies different nuclear reactions that generate secondary particles, with neutrons among them. These secondary neutrons can travel far away from the treatment volume, their measurement is a challenging complex task, and their biological effects are particularly high for neutrons with energies in the MeV range. In this review, a comprehensive description of secondary neutron dosimetry in proton and light ion beam therapy is given. Many studies have been conducted on the quantification of the secondary neutron dose, most of them have been performed for proton beams, whereas for other ions like carbon, the available information is scarce. The main measurement campaigns are summarised, focusing on the type of detectors used. In line with the detectors’ advantages and limitations, measurements performed inside and outside anthropomorphic phantoms are considered. The role of Monte Carlo radiation transport simulations is discussed since many experimental detection techniques need additional simulations to provide dose estimates. A focus on the current challenges for the measurements of neutrons with energies above 20 MeV is given, as this is one of the main components of secondary neutrons produced by therapeutic ion beams. Finally, the potential clinical relevance of the available and needed secondary neutron dose data is discussed, in terms of its impact on the treatment of patients. For this, the relative biological effectiveness of neutrons and the potential risk of cancer induction re-incidence or secondary cancer due to secondary neutron doses play a key role.

Diamond energy-dispersive dosimeter for measuring linear energy deposition distributions in clinical carbon beam therapy

A thin diamond membrane energy-dispersive dosimeter 50 μm thick was fabricated for estimating clinical dose distribution. In contrast to conventional semiconductors, diamond wide-bandgap semiconductors are expected to have excellent radiation tolerance and biological compatibility based on the linear relationship of stopping power ratio for clinical carbon particles. Linear energy transfer (LET) spectra were obtained along with the Bragg curve for a clinical carbon beam generated at Gunma University Heavy Ion Medical Center. The relative biological effectiveness (RBE) distributions were estimated from the LET spectra for both the mono-energy and spread-out Bragg peak irradiation configurations. The diamond detector was also used as a solid ionization chamber to obtain the radiation-induced current (RIC) distribution, which represents the physical dose distribution. The clinical dose distribution was estimated from the RIC and RBE distributions as proof of concept for the clinical carbon beam therapy field with a single-chip diamond energy-dispersive dosimeter.

Proton therapy for intracranial meningioma: a single-institution retrospective analysis of efficacy, survival and toxicity outcomes.

To report the outcomes of a large series of intracranial meningiomas (IMs) submitted to proton therapy (PT) with curative intent. We conducted a retrospective analysis on all consecutive IM patients treated between 2014 and 2021. The median PT prescription dose was 55.8Gy relative biological effectiveness (RBE) and 66 GyRBE for benign/radiologically diagnosed and atypical/anaplastic IMs, respectively. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), overall survival (OS), and radionecrosis-free survival (RNFS) were evaluated with the Kaplan-Meier method. Univariable analysis was performed to identify potential prognostic factors for clinical outcomes. Toxicity was reported according to the latest Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Overall, 167 patients were included. With a median follow-up of 41 months (range, 6-99), twelve patients (7%) developed tumor local recurrence after a median time of 39 months. The 5-year LRFS was 88% for the entire cohort, with a significant difference between benign/radiologically diagnosed and atypical/anaplastic IMs (98% vs. 47%, p < 0.001); this significant difference was maintained also for the 5-year OS and the 5-year DRFS rates. Patients aged ≤ 56 years reported significantly better outcomes, whereas lower prescription doses and skull base location were associated with better RNFS rates. Two patients experienced G3 acute toxicities (1.2%), and three patients G3 late toxicities (1.8%). There were no G4-G5 adverse events. PT proved to be effective with an acceptable toxicity profile. To the best of our knowledge this is one of the largest series including IM patients submitted to PT.

An updated variable RBE model for proton therapy

Objective. While a constant relative biological effectiveness (RBE) of 1.1 forms the basis for clinical proton therapy, variable RBE models are increasingly being used in plan evaluation. However, there is substantial variation across RBE models, and several new in vitro datasets have not yet been included in the existing models. In this study, an updated in vitro proton RBE database was collected and used to examine current RBE model assumptions, and to propose an up-to-date RBE model as a tool for evaluating RBE effects in clinical settings. Approach. A proton database (471 data points) was collected from the literature, almost twice the size of the previously largest model database. Each data point included linear-quadratic model parameters and linear energy transfer (LET). Statistical analyses were performed to test the validity of commonly applied assumptions of phenomenological RBE models, and new model functions were proposed for RBEmax and RBEmin (RBE at the lower and upper dose limits). Previously published models were refitted to the database and compared to the new model in terms of model performance and RBE estimates. Main results. The statistical analysis indicated that the intercept of the RBEmax function should be a free fitting parameter and RBE estimates were clearly higher for models with free intercept. RBEmin increased with increasing LET, while a dependency of RBEmin on the reference radiation fractionation sensitivity ( α/βx ) did not significantly improve model performance. Evaluating the models, the new model gave overall lowest RMSE and highest R2 score. RBE estimates in the distal part of a spread-out-Bragg-peak in water ( α/βx = 2.1 Gy) were 1.24–1.51 for original models, 1.25–1.49 for refits and 1.42 for the new model. Significance. An updated RBE model based on the currently largest database among published phenomenological models was proposed. Overall, the new model showed better performance compared to refitted published RBE models.

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 of LET― could be assessed with the luminescence detectors. The experimental determination of LET―f is in agreement with reference data obtained from simulations across all measurement techniques and types of averaging. On the other hand, LET―d can present challenges as a radiation quality metric to describe the detector response in mixed particle fields. However, excluding secondaries heavier than protons from the LET―d calculation, as their contribution to the luminescence is suppressed by ionization quenching, leads to equal accuracy between LET―f and LET―d . Assessment of RBE through the experimentally determined LET―d values agrees with independently acquired reference values, indicating that the investigated detectors can determine LET― with sufficient accuracy for proton therapy. Significance. OSLDs, TLDs, and FNTDs can be used to determine LET― and RBE in proton therapy. With the capability to determine dose through ionization quenching corrections derived from LET― , 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.

Novel radiation quality metrics accounting for proton energy spectra for RBE proton models.

For proton therapy, a relative biological effectiveness (RBE) of 1.1 is widely applied clinically. However, due to abundant evidence of variable RBE in vitro, and as suggested in studies of patient outcomes, RBE might increase by the end of the proton tracks, as described by several proposed variable RBE models. Typically, the dose averaged linear energy transfer ( ) has been used as a radiation quality metric (RQM) for these models. However, the optimal choice of RQM has not been fullyexplored. This study aims to propose novel RQMs that effectively weight protons of different energies, and assess their predictive power for variable RBE in proton therapy. The overall objective is to identify an RQM that better describes the contribution of individual particles to the RBE of protonbeams. High-throughput experimental set-ups of in vitro cell survival studies for proton RBE determination are simulated utilizing the SHIELD-HIT12A Monte Carlo particle transport code. For every data point, the proton energy spectra are simulated, allowing the calculation of novel RQMs by applying different power levels to the spectra of LET or effective ( ) values. A phenomenological linear-quadratic-based RBE model is then applied to the in vitro data, using various RQMs as input variables, and the model performance is evaluated by root-mean-square-error (RMSE) for the logarithm of cell surviving fractions of each datapoint. Increasing the power level, that is, putting an even higher weight on higher LET particles when constructing the RQM is generally associated with an increased model performance, with dose averaged (i.e., dose averaged cubed LET, ) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) , with similar trends also observed for track averaged and -basedRQMs. The results indicate that improved proton variable RBE models can be constructed assuming a non-linear RBE(LET) relationship for individual protons. If similar trends hold also for an in vitro-environment, variable RBE effects are likely better described by or tracked averaged cubed LET ( ), or corresponding -based RQM, rather than linearly weighted or which is conventionally applied today.

Preliminary result of combined treatment with scanning carbon-ion radiotherapy and image-guided brachytherapy for locally advanced cervical adenocarcinoma.

Although there is growing evidence of the efficacy of carbon-ion radiotherapy (CIRT) for locally advanced cervical adenocarcinoma, reports on combined treatment with CIRT and image-guided brachytherapy (IGBT) are scarce. We retrospectively analyzed patients with International Federation of Gynecology and Obstetrics (2008) stage II-IVA locally advanced cervical adenocarcinoma who received combined scanning CIRT (sCIRT) and IGBT between April 2019 and March 2022. sCIRT consisted of whole-pelvic irradiation with 36Gy (relative biological effectiveness [RBE]) in 12 fractions and subsequent local boost irradiation with 19.2Gy (RBE) in 4 fractions. Three sessions of IGBT were administered after completion of sCIRT. Concurrent chemotherapy using weekly cisplatin (40mg/m2/week) was also administered. Efficacy, toxicity and dose-volume parameters were analyzed. Fifteen patients were included in the analysis. The median follow-up period was 25months. The 2-year overall survival, progression-free survival and local control rates were 92.3% (95% confidence interval [CI] = 77.8-100%), 52.5% (95% CI = 26.9-78.1%) and 84.8% (95% CI = 65.2-100%), respectively. Neither severe acute toxicity necessitating treatment cessation nor grade 3 or higher late toxicity were observed. The sigmoid D2cm3 of the patient who developed grade 2 late sigmoid hemorrhage was 65.6Gy, which exceeded the standard deviation and target dose. The combination of sCIRT and IGBT for locally advanced cervical adenocarcinoma showed acceptable efficacy and safety. Further large-scale and long-term studies are warranted to confirm the efficacy and safety of this treatment.

A phase I/IIa of [212Pb]VMT01 targeted a-particle therapy for unresectable or metastatic melanoma.

TPS9610 Background: Melanoma is an aggressive skin cancer with potential to metastasize early in disease development. Unresectable and metastatic melanoma accounts for 12% of cases and, despite recent advances in treatment, 5-year overall survival for this disease remains low at 35%. The melanocortin 1 receptor (MC1R) is highly expressed in melanoma with low expression in normal tissues and is therefore a target for radiopharmaceutical therapy. We developed [212Pb]VMT01, a MC1R-targeting peptide conjugated to a lead-specific chelator. Targeted therapy with 212Pb has the potential to be efficacious due to the high relative biological effectiveness of α-particles emitted upon its decay. The short physical half-life of 212Pb (10.6 h) and fast tumor targeting and clearance properties of [212Pb]VMT01 can achieve highly efficient delivery of α-particles to MC1R-expressing cancers while sparing healthy tissues. We hypothesize that [212Pb]VMT01 can be safely administered to patients with metastatic or unresectable melanoma and can enable disease control. Methods: This is an open-label, multi-center, dose-escalation/dose expansion, phase I/IIa clinical trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of [212Pb]VMT01 (NCT05655312). Phase I of the trial follows a mTPI-2 design. The first two cohorts incorporate dosimetry, where participants receive up to 925 MBq or 278 MBq of the therapeutic surrogate [203Pb]VMT01 or [68Ga]VMT02, respectively, prior to receiving treatment cycles. In these participants, SPECT/CT or PET/CT imaging is obtained up to 24 hours post-injection. Up to 3 treatment cycles of [212Pb]VMT01, co-administered with renal protective amino acids, are given 8 weeks apart, with a dose-limiting toxicity observation period of 6 weeks. The cohort 1 dose was 111 MBq, while the ongoing cohort 2 utilizes 185 MBq. Eligibility criteria include MC1R+ disease as determined by SPECT or PET, melanoma stage III or IV and progressive disease by RECIST 1.1. Study participants must have progressed on at least one prior SOC therapy. As part of the study, CT and/or MRI, and FDG PET are acquired at baseline, during, and at the end of treatment. Safety is assessed weekly during cycle 1 and bi-weekly for subsequent cycles. The total in-trial follow-up period is 18 months following final administration of drug. Efficacy is assessed by RECIST 1.1 criteria. The primary objectives are evaluation of the safety of [212Pb]VMT01, determination of the maximum tolerated or maximum feasible dose, and determination of the anti-tumor efficacy of [212Pb]. All primary, secondary, and exploratory objectives’ data will be collected for all participants. An interim futility evaluation may be performed after ~10 participants in the dose escalation phase for participants who have completed their first post-treatment response assessment. The trial is open for recruitment. Clinical trial information: NCT05655312 .

Deep learning based linear energy transfer calculation for proton therapy

Objective. This study aims to address the limitations of traditional methods for calculating linear energy transfer (LET), a critical component in assessing relative biological effectiveness (RBE). Currently, Monte Carlo (MC) simulation, the gold-standard for accuracy, is resource-intensive and slow for dose optimization, while the speedier analytical approximation has compromised accuracy. Our objective was to prototype a deep-learning-based model for calculating dose-averaged LET (LETd) using patient anatomy and dose-to-water (DW) data, facilitating real-time biological dose evaluation and LET optimization within proton treatment planning systems. Approach. 275 4-field prostate proton Stereotactic Body Radiotherapy plans were analyzed, rendering a total of 1100 fields. Those were randomly split into 880, 110, and 110 fields for training, validation, and testing. A 3D Cascaded UNet model, along with data processing and inference pipelines, was developed to generate patient-specific LETd distributions from CT images and DW. The accuracy of the LETd of the test dataset was evaluated against MC-generated ground truth through voxel-based mean absolute error (MAE) and gamma analysis. Main results. The proposed model accurately inferred LETd distributions for each proton field in the test dataset. A single-field LETd calculation took around 100 ms with trained models running on a NVidia A100 GPU. The selected model yielded an average MAE of 0.94 ± 0.14 MeV cm−1 and a gamma passing rate of 97.4% ± 1.3% when applied to the test dataset, with the largest discrepancy at the edge of fields where the dose gradient was the largest and counting statistics was the lowest. Significance. This study demonstrates that deep-learning-based models can efficiently calculate LETd with high accuracy as a fast-forward approach. The model shows great potential to be utilized for optimizing the RBE of proton treatment plans. Future efforts will focus on enhancing the model’s performance and evaluating its adaptability to different clinical scenarios.

Outcomes of definitive carbon-ion radiotherapy for cT1bN0M0 esophageal squamous cell carcinoma.

A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size. This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4Gy relative biological effectiveness in 12 fractions, between 2012 and 2022. Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9-62.4), 74.9% (95% CI, 90.7-59.0), and 66.4% (95% CI, 83.3-49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis. Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma.

Helium Ion Therapy for Advanced Juvenile Nasopharyngeal Angiofibroma.

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications.

Impact of Relative Biologic Effectiveness for Proton Therapy for Head and Neck and Skull-Base Tumors: A Technical and Clinical Review.

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy's potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning

Objective. Treatment plans of ion-beam therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation dose. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study is to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for ion-beam therapy treatment planning. Approach. The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case, assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned for a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account. Main results. The cell survival fraction and corresponding RBE-weighted dose were formulated based on the HMK model. The first derivative of the RBE-weighted dose distribution was also derived, which is needed for fast biological optimization. For the patient plan, the biological optimization increased the dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-induced reduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness due to the heterogeneity was pronounced for low linear energy transfer (LET) beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam. Significance. Optimal treatment plans that consider intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model.

DNA-damage RBE assessment for combined boron and gadolinium neutron capture therapy.

Neutron capture therapy (NCT) by 10B and 157Gd agents is a unique irradiation-based method which can be used to treat brain tumors. Current study aims to quantitatively evaluate the relative biological effectiveness (RBE) and dose distributions during the combined BNCT and GdNCT modalities through a hybrid Monte Carlo (MC) simulation approach. Snyder head phantom as well as a cubic hypothetical tumor was at first modeled by Geant4 MC Code. Then, the energy spectra and dose distribution relevant to the released secondary particles during the combined Gd/BNCT were scored for different concentrations of 157Gd and 10B inside tumor volume. Finally, the scored energy spectra were imported to the MCDS code to estimate both RBESSB and RBEDSB values for different 157Gd concentrations. The results showed that combined Gd/BNCT increases the fluence-averaged RBESSB values by about 1.7 times when 157Gd concentration increments from 0 to 2000µg/g for both considered cell oxygen levels (pO2=10% and 100%). Besides, a reduction of about 26% was found for fluence-averaged RBEDSB values with an increment of 157Gd concentration in tumor volume. From the results, it can be concluded that combined Gd/BNCT technique can improve tumor coverage with higher dose levels but in the expense of RBEDSB reduction which can affect the clinical efficacy of the NCT technique.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96–0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

Moderately hypofractionated proton beam therapy for localized prostate cancer: 5-year outcomes of a phase II trial.

The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96months (range: 60-119months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70Gy (RBE) in 28 fractions, indicating the safety of this schedule.