Carbon ion therapy is a promising evolving modality in radiotherapy to treat tumors that are radioresistant against photon treatments. As carbon ions are more effective in normal and tumor tissue, ...the relative biological effectiveness (RBE) has to be calculated by bio-mathematical models and has to be considered in the dose prescription. This review (i) introduces the concept of the RBE and its most important determinants, (ii) describes the physical and biological causes of the increased RBE for carbon ions, (iii) summarizes available RBE measurements in vitro and in vivo, and (iv) describes the concepts of the clinically applied RBE models (mixed beam model, local effect model, and microdosimetric-kinetic model), and (v) the way they are introduced into clinical application as well as (vi) their status of experimental and clinical validation, and finally (vii) summarizes the current status of the use of the RBE concept in carbon ion therapy and points out clinically relevant conclusions as well as open questions. The RBE concept has proven to be a valuable concept for dose prescription in carbon ion radiotherapy, however, different centers use different RBE models and therefore care has to be taken when transferring results from one center to another. Experimental studies significantly improve the understanding of the dependencies and limitations of RBE models in clinical application. For the future, further studies investigating quantitatively the differential effects between normal tissues and tumors are needed accompanied by clinical studies on effectiveness and toxicity.
The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an ...average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters).
The following task group aims were designed to guide the current clinical practice:
Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained.
Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit.
Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems.
Recommend experiments needed to improve our current understanding of the relationships among in vitro, in vivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well‐defined tumor types and critical structures.
Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor ...available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed.
Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D
1.1
and D
RBE
assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters.
Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D
1.1
distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, D
RBE
using non-harmonized LET calculations increased inter-center dose variations substantially compared to D
1.1
and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in D
RBE
decreased to that observed for D
1.1
.
Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Carbon ion radiotherapy (CIRT) is developing toward a versatile tool in radiotherapy; however, the increased relative biological effectiveness (RBE) of carbon ions in tumors and normal tissues with ...respect to photon irradiation has to be considered by mathematical models in treatment planning. As a consequence, dose prescription and definition of dose constraints are performed in terms of RBE weighted rather than absorbed dose. The RBE is a complex quantity, which depends on physical variables, such as dose and beam quality as well as on normal tissue‐ or tumor‐specific factors. At present, three RBE models are employed in CIRT: (a) the mixed‐beam model, (b) the Microdosimetric Kinetic Model (MKM), and (c) the local effect model. While the LEM is used in Europe, the other two models are employed in Japan, and unfortunately, the concepts of how the nominal RBE‐weighted dose is determined and prescribed differ significantly between the European and Japanese centers complicating the comparison, transfer, and reproduction of clinical results. This has severe impact on the way treatments should be prescribed, recorded, and reported. This contribution reviews the concept of the clinical application of the different RBE models and the ongoing clinical CIRT trials in Japan and Europe. Limitations of the RBE models and the resulting radiobiological issues in clinical CIRT trials are discussed in the context of current clinical evidence and future challenges.
Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, 16O ions are being widely discussed due to their increased LET ...distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with 16O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from 20 up to 750 keV μm−1, oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, 16O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to 12C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where 16O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of 0.15% or lower) and relatively low doses ( 4 Gy or lower) the choice of 16O over 12C or 4He may be justified.
Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and ...normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint. Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed. Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ~1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ~1.1 in the entrance region, to ~1.15 in the center, ~1.35 at the distal edge and ~1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ~1.1. This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels.
Background
Applying tolerance doses for organs at risk (OAR) from photon therapy introduces uncertainties in proton therapy when assuming a constant relative biological effectiveness (RBE) of 1.1.
...Purpose
This work introduces the novel dirty and clean dose concept, which allows for creating treatment plans with a more photon‐like dose response for OAR and, thus, less uncertainties when applying photon‐based tolerance doses.
Methods
The concept divides the 1.1‐weighted dose distribution into two parts: the clean and the dirty dose. The clean and dirty dose are deposited by protons with a linear energy transfer (LET) below and above a set LET threshold, respectively. For the former, a photon‐like dose response is assumed, while for the latter, the RBE might exceed 1.1. To reduce the dirty dose in OAR, a MaxDirtyDose objective was added in treatment plan optimization. It requires setting two parameters: LET threshold and max dirty dose level. A simple geometry consisting of one target volume and one OAR in water was used to study the reduction in dirty dose in the OAR depending on the choice of the two MaxDirtyDose objective parameters during plan optimization. The best performing parameter combinations were used to create multiple dirty dose optimized (DDopt) treatment plans for two cranial patient cases. For each DDopt plan, 1.1‐weighted dose, variable RBE‐weighted dose using the Wedenberg RBE model and dose‐average LETd distributions as well as resulting normal tissue complication probability (NTCP) values were calculated and compared to the reference plan (RefPlan) without MaxDirtyDose objectives.
Results
In the water phantom studies, LET thresholds between 1.5 and 2.5 keV/µm yielded the best plans and were subsequently used. For the patient cases, nearly all DDopt plans led to a reduced Wedenberg dose in critical OAR. This reduction resulted from an LET reduction and translated into an NTCP reduction of up to 19 percentage points compared to the RefPlan. The 1.1‐weighted dose in the OARs was slightly increased (patient 1: 0.45 Gy(RBE), patient 2: 0.08 Gy(RBE)), but never exceeded clinical tolerance doses. Additionally, slightly increased 1.1‐weighted dose in healthy brain tissue was observed (patient 1: 0.81 Gy(RBE), patient 2: 0.53 Gy(RBE)). The variation of NTCP values due to variation of α/β from 2 to 3 Gy was much smaller for DDopt (2 percentage points (pp)) than for RefPlans (5 pp).
Conclusions
The novel dirty and clean dose concept allows for creating biologically more robust proton treatment plans with a more photon‐like dose response. The reduced uncertainties in RBE can, therefore, mitigate uncertainties introduced by using photon‐based tolerance doses for OAR.
. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions ...in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges.
. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams.
. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases.
From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.
An improved biological weighting function (IBWF) is proposed to phenomenologically relate microdosimetric lineal energy probability density distributions with the relative biological effectiveness ...(RBE) for the in vitro clonogenic cell survival (surviving fraction = 10%) of the most commonly used mammalian cell line, i.e. the Chinese hamster lung fibroblasts (V79). The IBWF, intended as a simple and robust tool for a fast RBE assessment to compare different exposure conditions in particle therapy beams, was determined through an iterative global-fitting process aimed to minimize the average relative deviation between RBE calculations and literature in vitro data in case of exposure to various types of ions from 1H to 238U. By using a single particle- and energy- independent function, it was possible to establish an univocal correlation between lineal energy and clonogenic cell survival for particles spanning over an unrestricted linear energy transfer range of almost five orders of magnitude (0.2 keV µm−1 to 15 000 keV µm−1 in liquid water). The average deviation between IBWF-derived RBE values and the published in vitro data was ∼14%. The IBWF results were also compared with corresponding calculations (in vitro RBE10 for the V79 cell line) performed using the modified microdosimetric kinetic model (modified MKM). Furthermore, RBE values computed with the reference biological weighting function (BWF) for the in vivo early intestine tolerance in mice were included for comparison and to further explore potential correlations between the BWF results and the in vitro RBE as reported in previous studies. The results suggest that the modified MKM possess limitations in reproducing the experimental in vitro RBE10 for the V79 cell line in case of ions heavier than 20Ne. Furthermore, due to the different modelled endpoint, marked deviations were found between the RBE values assessed using the reference BWF and the IBWF for ions heavier than 2H. Finally, the IBWF was unchangingly applied to calculate RBE values by processing lineal energy density distributions experimentally measured with eight different microdosimeters in 19 1H and 12C beams at ten different facilities (eight clinical and two research ones). Despite the differences between the detectors, irradiation facilities, beam profiles (pristine or spread out Bragg peak), maximum beam energy, beam delivery (passive or active scanning), energy degradation system (water, PMMA, polyamide or low-density polyethylene), the obtained IBWF-based RBE trends were found to be in good agreement with the corresponding ones in case of computer-simulated microdosimetric spectra (average relative deviation equal to 0.8% and 5.7% for 1H and 12C ions respectively).
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
AcAc-PSMA-I&T and
177
LuLu-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
AcAc-PSMA-I&T and
177
LuLu-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
AcAc-PSMA-I&T had slower DSB repair kinetics compared to cells treated with
177
LuLu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with
225
AcAc-PSMA-I&T and
177
LuLu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of
225
AcAc-PSMA-I&T was found to be 4.2 times higher compared to
177
LuLu-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
AcAc-PSMA-I&T compared to
177
LuLu-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
AcAc-PSMA-I&T compared to
177
LuLu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.
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