Objective: To investigate the potential impact of two different combinations of neutron and gamma radiation on gene expression and dicentric chromosomes in peripheral blood mononuclear cells (PBMC).

Methods: Whole blood from 3 human donors was exposed to neutrons with an energy spectrum similar to that of the Hiroshima uranium bomb, to gamma radiation from a ⁶⁰Co source and to a 50:50 combination of both radiations, given in two orders of sequence. In all cases the total doses were 0.5, 0.75 and 1.0 ​Gy. Dicentric chromosomes were analyzed by light microscopy and the expression of six known radiation-responsive genes BBC3, CDKN1A, FDXR, GADD45A, MDM2, and XPC were analyzed by RT-qPCR.

Results: Per unit dose, exposure to neutrons lead to a higher level of dicentrics and gene expression as compared to gamma radiation. Dose-response relationships for both endpoints were linear, allowing calculating the expected outcome of combined exposure by arithmetic. For dicentric chromosomes, the RBE values for ⁶⁰Co → neutrons, neutrons → ⁶⁰Co and neutrons were 4.05, 3.62 and 7.30, respectively. For gene expression the RBE values were gene-specific, but showed values in the range of 1.14–3.01 for ⁶⁰Co → neutrons, 1.33–2.68 for neutrons → ⁶⁰Co and 1.39–3.91 for neutrons.

Conclusions: The results demonstrate that combined exposure to neutrons and gamma radiation, regardless of the order of sequence, leads to an additive response at both endpoints. This indicates that calibration curves for mixed beams can be constructed from dose response relationships of the single beam components.

Background: In clinical proton radiotherapy, a constant relative biological effectiveness (RBE) of 1.1 is typically applied. Due to abundant evidence of variable RBE effects from in vitro data, multiple variable RBE models have been suggested, typically by describing the α and β parameters in the linear quadratic (LQ) model as a function of dose averaged linear energy transfer (LETd).

Purpose: This work introduces a new variable RBE model based on the dirty dose concept, where dose deposited in voxels with a corresponding LET exceeding a specific threshold is considered “dirty” in the sense that it has a biological effect above the one predicted by a constant RBE of 1.1. As only one LET level, corresponding to a specific energy for a given particle in a given medium, needs to be monitored, this offers several advantages, such as simplified calculations by removing the need for intricate end of range LET calculations and averaging procedures, as well as opening up for more efficient experimental assessment of the cell specific model parameters.

Methods: Previously published in vitro data were utilized, where surviving fraction (SF), dose and LETd were reported for a pristine proton beam with varying physical PMMA thicknesses placed upstream of the cells. The setup was re-simulated to extract dirty dose metrics for the corresponding reported LETd-values. Models were created by setting the α parameter of the LQ model as a function of the fraction of dirty dose and subsequently benchmarked against models based on other radiation quality metrics by comparing the root-mean-square-error (RMSE) of the predicted and actual cell surviving fraction.

Results: Variable RBE models based on dirty dose perform on par with conventional radiation quality metrics with a RMSE of 0.38 for a dirty dose-based model with a threshold of 7 keV/μ⁢m, compared to 0.42 and 0.36 for a LETd-based and Qeff,d-based model, respectively. Higher chosen LET thresholds typically performed better and lower performed worse.

Conclusion: The results indicate that models based on dirty dose metrics perform equally well as conventional radiation quality metrics. Due to the simplified calculations involved and the potential for more efficient measurement techniques for data generation, dirty dose-based models might be the most conservative and practical approach for creating future proton variable RBE models.

Purpose: To propose a methodology for integrating the out-of-field and imaging doses to the in-field dose received by radiotherapy (RT) patients. In addition, the impact of considering the total dose in planning and radiation-induced second malignancies (RISM) risk assessment will be evaluated in several scenarios comprising photon and proton treatments.

Methods: The total dose is the voxel-wise sum of the doses from the different radiation sources (accounting for the radiobiological effectiveness) produced during the whole RT chain. The dose from the plan and imaging procedures were obtained by measurements for a photon prostate treatment and by calculation (combining treatment planning system, analytical models, and Monte Carlo simulations) for two lymphoma treatments, one using photons and the other, protons. Dose distributions, dose volume histograms (DVHs) metrics, mean organ doses, and RISM risks were evaluated for each radiation exposure in each treatment.

Results: In general, the contribution of the imaging doses is low compared to the dose administered during RT treatment, being higher in proton therapy. However, for some organs, for instance testes in the prostate case, the imaging dose becomes higher than the scattered dose from the treatment fields. Plan evaluations revealed shifts in cumulative DVHs with the inclusion of out-of-field and imaging doses, though minimal clinical impact is expected. Risk assessment showed increased estimates with total dose.

Conclusions: The methodology enables accounting for the total dose for optimization of plans and imaging protocols, prospective risk predictions and retrospective epidemiological analyses.

Purpose: We investigate the feasibility of using a biophysically guided approach for delineating the Clinical Target Volume (CTV) in Glioblastoma Multiforme (GBM) by evaluating its impact on the treatment outcomes, specifically Overall Survival (OS) time.

Methods: An established reaction–diffusion model was employed to simulate the spatiotemporal evolution of cancerous regions in T1-MRI images of GBM patients. The effects of the parameters of this model on the simulated tumor borders were quantified and the optimal values were used to estimate the distribution of infiltrative cells (CTVmodel). Radiomics and deep learning models were examined to predict the OS time by analyzing the GTV, clinical CTV, and CTVmodel.

Results: The study involves 126 subjects for model development and 62 independent subjects for testing. Evaluation of the proposed approach demonstrates comparable predictive power for OS time that is achieved with the clinically defined CTV. Specifically, for the binary survival prediction, short vs. long time, the proposed CTVmodel resulted in improvements of prognostic power, in terms of AUROC, both for the validation (0.77 from 0.75) and the testing (0.73 from 0.71) set. Quantitative comparisons for three-class prediction and survival regression models exhibited a similar trend of comparable performance.

Conclusion: The findings highlight the potential of biophysical modeling for estimating and incorporating the spread of infiltrating cells into CTV delineation. Further clinical investigations are required to validate the clinical efficacy.

Radiation therapy is a primary and effective treatment strategy for NasoPharyngeal Carcinoma (NPC). The precise delineation of Gross Tumor Volumes (GTVs) and Organs-At-Risk (OARs) is crucial in radiation treatment, directly impacting patient prognosis. Despite that deep learning has achieved remarkable performance on various medical image segmentation tasks, its performance on OARs and GTVs of NPC is still limited, and high-quality benchmark datasets on this task are highly desirable for model development and evaluation. To alleviate this problem, the SegRap2023 challenge was organized in conjunction with MICCAI2023 and presented a large-scale benchmark for OAR and GTV segmentation with 400 Computed Tomography (CT) scans from 200 NPC patients, each with a pair of pre-aligned non-contrast and contrast-enhanced CT scans. The challenge aimed to segment 45 OARs and 2 GTVs from the paired CT scans per patient, and received 10 and 11 complete submissions for the two tasks, respectively. In this paper, we detail the challenge and analyze the solutions of all participants. The average Dice similarity coefficient scores for all submissions ranged from 76.68% to 86.70%, and 70.42% to 73.44% for OARs and GTVs, respectively. We conclude that the segmentation of relatively large OARs is well-addressed, and more efforts are needed for GTVs and small or thin OARs. The benchmark remains available at: https://segrap2023.grand-challenge.org.

Objective. A four-dimensional robust optimisation (4DRO) is usually employed when the tumour respiratory motion needs to be addressed. However, it is computationally demanding, and an automated method is preferable for adaptive planning to avoid manual trial-and-error. This study proposes a 4DRO technique based on dose mimicking for automated adaptive planning. Approach. Initial plans for 4DRO intensity modulated proton therapy were created on an average CT for four patients with clinical target volume (CTV) in the lung, oesophagus, or pancreas, respectively. These plans were robustly optimised using three phases of four-dimensional computed tomography (4DCT) and accounting for setup and density uncertainties. Weekly 4DCTs were used for adaptive replanning, using a constant relative biological effectiveness (cRBE) of 1.1. Two methods were used: (1) template-based adaptive (TA) planning and (2) dose-mimicking-based adaptive (MA) planning. The plans were evaluated using variable RBE (vRBE) weighted doses and biologically consistent dose accumulation (BCDA). Main results. MA and TA plans had comparable CTV coverage except for one patient where the MA plan had a higher D98 and lower D2 but with an increased D2 in few organs at risk (OARs). CTV D98 deviations in non-adaptive plans from the initial plans were up to −7.2 percentage points (p.p.) in individual cases and −1.8 p.p. when using BCDA. For the OARs, MA plans showed a reduced mean dose and D2 compared to the TA plans, with few exceptions. The vRBE-weighted accumulated doses had a mean dose and D2 difference of up to 0.3 Gy and 0.5 Gy, respectively, in the OARs with respect to cRBE-weighted doses. Significance. MA plans indicate better performance in target coverage and OAR dose sparing compared to the TA plans in 4DRO adaptive planning. Moreover, MA method is capable of handling both forms of anatomical variation, namely, changes in density and relative shifts in the position of OARs.

BACKGROUND AND OBJECTIVES: Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios.

METHODS: Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy3), 5 (Gy10), 10 (Gy10), and 15 (Gy15).

RESULTS: Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy15, P = .006), while for LC and physical dose was 79% (P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant (P = .02 and .03). Fractional polynomial regression revealed BED (Gy10 and Gy15) as statistically significant (P = .05) with BED of more than 63 Gy10 or 49 Gy15 as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC (P = .001), particularly less than 40 minutes (LC below 90%, P = .05).

CONCLUSION: BED Gy10 and particularly Gy15 were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts.

Purpose: To assess the impact of rigid and deformable image registration methods (RIR, DIR) on the outcome of a hypoxia-based dose painting strategy.

Materials and methods: Thirty head and neck cancer patients were imaged with [¹⁸F]FMISO-PET/CT before radiotherapy. [¹⁸F]FMISO-PET/CT images were registered to the planning-CT by RIR or DIR. The [¹⁸F]FMISO uptake was converted into oxygen partial pressure (pO₂) maps. Hypoxic Target Volumes were contoured on pO₂ maps for the deformed (HTV_def) and non-deformed (HTV) cases. A dose escalation strategy by contours, aiming at 95 % tumour control probability (TCP), was applied.

HTVs were characterised based on geometry-related metrics, the underlying pO₂ distribution, and the dose boost level. A dosimetric and radiobiological evaluation of selected treatment plans made considering RIR and DIR was performed. Moreover, the TCP of the RIR dose distribution was evaluated when considering the deformed [¹⁸F]FMISO-PET image as an indicator of the actual target radiosensitivity to determine the potential impact of an unalignment.

Results: Statistically significant differences were found between HTV and HTV_def for volume-based metrics and underlying pO₂ distribution. Eight out of nine treatment plans for HTV and HTV_def showed differences on the level 10 %/3 mm on a gamma analysis. The TCP difference, however, between RIR and the case when the RIR dose distribution was used with the deformed radiosensitivity map was below 2 pp.

Conclusions: Although the choice of the CT_plan-to-PET registration method pre-treatment impacts the HTV localisation and morphology and the corresponding dose distribution, it negligibly affects the TCP in the proposed dose escalation strategy by contours.

Background: Daily CTs generated by CBCT correction are required for daily replanning in online-adaptive proton therapy (APT) to effectively deal with inter-fractional changes. Out of the currently available methods, the suitability of a daily CT generation method for proton dose calculation also depends on the anatomical site.

Purpose: We propose an anatomy-preserving virtual CT (APvCT) method as a hybrid method of CBCT correction, which is especially suitable for large anatomy deformations. The accuracy of the hybrid method was assessed by comparison with the corrected CBCT (cCBCT) and virtual CT (vCT) methods in the context of online APT.

Methods: Seventy-one daily CBCTs of four prostate cancer patients treated with intensity modulated proton therapy (IMPT) were converted to daily CTs using cCBCT, vCT, and the newly proposed APvCT method. In APvCT, planning CT (pCT) were mapped to CBCT geometry using deformable image registration with boundary conditions on controlling regions of interest (ROIs) created with deep learning segmentation on cCBCT. The relative frequency distribution (RFD) of HU, mass density and stopping power ratio (SPR) values were assessed and compared with the pCT. The ROIs in the APvCT and vCT were compared with cCBCT in terms of Dice similarity coefficient (DSC) and mean distance-to-agreement (mDTA). For each patient, a robustly optimized IMPT plan was created on the pCT and subsequent daily adaptive plans on daily CTs. For dose distribution comparison on the same anatomy, the daily adaptive plans on cCBCT and vCT were recalculated on the corresponding APvCT. The dose distributions were compared in terms of isodose volumes and 3D global gamma-index passing rate (GPR) at γ(2%, 2 mm) criterion.

Results: For all patients, no noticeable difference in RFDs was observed amongst APvCT, vCT, and pCT except in cCBCT, which showed a noticeable difference. The minimum DSC value was 0.96 and 0.39 for contours in APvCT and vCT respectively. The average value of mDTA for APvCT was 0.01 cm for clinical target volume and ≤0.01 cm for organs at risk, which increased to 0.18 cm and ≤0.52 cm for vCT. The mean GPR value was 90.9%, 64.5%, and 67.0% for APvCT versus cCBCT, vCT versus cCBCT, and APvCT versus vCT, respectively. When recalculated on APvCT, the adaptive cCBCT and vCT plans resulted in mean GPRs of 89.5 ± 5.1% and 65.9 ± 19.1%, respectively. The mean DSC values for 80.0%, 90.0%, 95.0%, 98.0%, and 100.0% isodose volumes were 0.97, 0.97, 0.97, 0.95, and 0.91 for recalculated cCBCT plans, and 0.89, 0.88, 0.87, 0.85, and 0.81 for recalculated vCT plans. Hausdorff distance for the 100.0% isodose volume in some cases of recalculated cCBCT plans on APvCT exceeded 1.00 cm.

Conclusions: APvCT contours showed good agreement with reference contours of cCBCT which indicates anatomy preservation in APvCT. A vCT with erroneous anatomy can result in an incorrect adaptive plan. Further, slightly lower values of GPR between the APvCT and cCBCT-based adaptive plans can be explained by the difference in the cCBCT's SPR RFD from the pCT.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is a useful alternative for small- to medium-sizedvestibular schwannoma. To evaluate whether biologically effective dose (BEDGy2.47), calculated for mean (BEDGy2.47 mean)and maximal (BEDGy2.47 max) cochlear dose, is relevant for hearing preservation. METHODS: This is a retrospective longitudinal single-center study. Were analyzed 213 patients with useful baselinehearing. Risk of hearing decline was assessed for Gardner–Robertson classes and pure tone average (PTA) loss. The meanfollow-up period was 39 months (median 36, 6-84).RESULTS: Hearing decline (Gardner–Robertson class) 3 years after SRS was associated with higher cochlear BEDGy2.47 mean(odds ratio [OR] 1.39, P = .009). Moreover, BEDGy2.47 mean was more relevant as compared with BEDGy2.47 max (OR 1.13, P = .04).Risk of PTA loss (continuous outcome, follow-up minus baseline) was significantly corelated with BEDGy2.47 mean at 24 (betacoefficient 1.55, P = .002) and 36 (beta coefficient 2.01, P = .004) months after SRS. Risk of PTA loss (>20 dB vs ≤) was associatedwith higher BEDGy2.47 mean at 6 (OR 1.36, P = .002), 12 (OR 1.36, P = .007), and 36 (OR 1.37, P = .02) months. Risk of hearingdecline at 36 months for the BEDGy2.47 mean of 7–8, 10, and 12 Gy2.47 was 28%, 57%, and 85%, respectively. CONCLUSION: Cochlear BEDGy2.47 mean is relevant for hearing decline after SRS and more relevant as compared withBEDGy2.47 max. Three years after SRS, this was sustained for all hearing decline evaluation modalities. Our data suggestthe BEDGy2.47 mean cut-off of ≤8 Gy2.47 for better hearing preservation rates.