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The interplay between respiratory tumor motion and dose application by intensity modulated radiotherapy (IMRT) techniques can potentially lead to undesirable and non-intuitive deviations from the planned dose distribution. We developed a 4D Monte Carlo (MC) dose recalculation framework featuring statistical breathing curve sampling, to precisely simulate the dose distribution for moving target volumes aiming at a comprehensive assessment of interplay effects.We implemented a dose accumulation tool that enables dose recalculations of arbitrary breathing curves including the actual breathing curve of the patient. This MC dose recalculation framework is based on linac log-files, facilitating a high temporal resolution up to 0.1 s. By statistical analysis of 128 different breathing curves, interplay susceptibility of different treatment parameters was evaluated for an exemplary patient case. To facilitate prospective clinical application in the treatment planning stage, in which patient breathing curves or linac log-files are not available, we derived a log-file free version with breathing curves generated by a random walk approach. Interplay was quantified by standard deviations σ in DInterplay induced dose deviations for single fractions were observed and evaluated for IMRT and volumetric arc therapy (σIt is feasible to combine statistically sampled breathing curves with MC dose calculations. The universality of the presented framework allows comprehensive assessment of interplay effects in retrospective and prospective clinically relevant scenarios.

The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI).We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed.Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90% after seven years. Median progression free survival had not yet been reached with surviving fraction of 54% after seven years. The incidence of temporary or clinically silent radiation induced contrast enhancement was significantly higher than previously assumed, however, symptomatic radiation necrosis was only detected in one patient. These radiation-induced contrast-enhancing lesions were almost exclusively seen at the distal beam end of the proton beam. In 22 out of 23 patients, the average LET of voxels inside contrast-enhancing lesions was significantly increased, compared to dose-matched voxels outside the lesions.Symptomatic radiation necrosis following PRT was as rare as conventional photon-based treatment series suggest. However, the increased incidence of asymptomatic radiation-induced brain injuries with an increased average LET observed in this cohort provides strong clinical evidence to support the hypothesis that the relative biological effectiveness of protons is variable and different to the fixed factor of 1.1 currently used worldwide.

Background Cure- and toxicity rates after intensity-modulated radiotherapy (IMRT) of prostate cancer are dose-and volume dependent. We prospectively studied the potential for organ at risk (OAR) sparing and compensation of tumor movement with the coverage probability (CovP) concept. Patients and methods Twenty-eight prostate cancer patients (median age 70) with localized disease (cT1c–2c, N0, M0) and intermediate risk features (prostate-specific antigen [PSA] < 20, Gleason score ≤ 7b) were treated in a prospective study with the CovP concept. Planning-CTs were performed on three subsequent days to capture form changes and movement of prostate and OARs. The clinical target volume (CTV) prostate and the OARs (bladder and rectum) were contoured in each CT. The union of CTV1–3 was encompassed by an isotropic margin of 7 mm to define the internal target volume (ITV). Dose prescription/escalation depended on coverage of all CTVs within the ITV. IMRT was given in 39 fractions to 78 Gy using the Monte-Carlo algorithm. Short-term androgen deprivation was recommended and given in 78.6% of patients. Results Long-term toxicity was evaluated in 26/28 patients after a median follow-up of 7.1 years. At last follow-up, late bladder toxicity (Radiation Therapy Oncology Group, RTOG) G1 was observed in 14.3% of patients and late rectal toxicities (RTOG) of G1 (7.1%) and of G2 (3.6%) were observed. No higher graded toxicity occurred. After 7.1 years, biochemical control (biochemically no evidence of disease, bNED) was 95.5%, prostate cancer-specific survival and the distant metastasis-free survival after 7.1 years were 100% each. Conclusions CovP-based IMRT was feasible in a clinical study. Dose escalation with the CovP concept was associated by a low rate of toxicity and a high efficacy regarding local and distant control.

Background: Lung cancer patients struggle with high toxicity rates. This study investigates if IMRT plans with individually set beam angles or uni-lateral VMAT plans results in dose reduction to OARs. We investigate if introduction of a RapidPlan model leads to reduced dose to OARs. Finally, the model is validated prospectively. Material and methods: Seventy-four consecutive lung cancer patients treated with IMRT were included. For all patients, new IMRT plans were made by an experienced dose planner re-tuning beam angles aiming for minimized dose to the lungs and heart. Additionally, VMAT plans were made. The IMRT plans were selected as input for a RapidPlan model, which was used to generate 74 new IMRT plans. The new IMRT plans were used as input for a second RapidPlan model. This model was clinically implemented and used for generation of clinical treatment plans. Dosimetric parameters were compared using a Wilcoxon signed rank test or a 1-sided student’s t-test. p

The area under the ROC curve (AUC) is commonly used as a measure for the discriminative performance of NTCP models. Here, we demonstrate that for typical patient cohorts, the AUC is an unsuitable measure for that purpose since it is typically limited to values below 0.8 and it exhibits large statistical variation.

Purpose Magnetic resonance-guided radiotherapy (MRgRT) has recently been introduced in our institution. As MRgRT requires high patient compliance compared to conventional techniques and can be associated with prolonged treatment times, feasibility and patient tolerance were prospectively assessed using patient-reported outcome questionnaires (PRO-Q). Materials and methods Forty-three patients were enrolled in a prospective observational study and treated with MRgRT on a low-field hybrid Magnetic Resonance Linear Accelerator system (MR-Linac) between April 2018 and April 2019. For assistance in gated breath-hold delivery using cine-MRI, a video feedback system was installed. PRO-Qs consisted of questions on MR-related complaints and also assessed aspects of active patient participation. Results The most commonly treated anatomic sites were nodal metastases and liver lesions. The mean treatment time was 34 min with a mean beam-on time of 2:17 min. Gated stereotactic body radiotherapy (SBRT) was applied in 47% of all patients. Overall, patients scored MRgRT as positive or at least tolerable in the PRO‑Q. Almost two thirds of patients (65%) complained about at least one item of the PRO‑Q (score ≥4), mainly concerning coldness, paresthesia, and uncomfortable positioning. All patients reported high levels of satisfaction with their active role using the video feedback system in breath-hold delivery. Conclusion MRgRT was successfully implemented in our clinic and well tolerated by all patients, despite MR-related complaints and complaints about uncomfortable immobilization. Prospective clinical studies are in development for further evaluation of MRgRT and for quantification of the benefit of MR-guided on-table adaptive radiotherapy.

Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood.We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54 Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years.Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) vs. children (5%; p = 0.0043). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status.These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.

Online adaption of treatment plans on a magnetic resonance (MR)-Linac enables the daily creation of new (adapted) treatment plans using current anatomical information of the patient as seen on MR images. Plan quality assurance (QA) relies on a secondary dose calculation (SDC) that is required because a pretreatment measurement is impossible during the adaptive workflow. However, failure mode and effect analysis of the adaptive planning process shows a large number of error sources, and not all of them are covered by SDC. As the complex multidisciplinary adaption process takes place under time pressure, additional software solutions for pretreatment per-fraction QA need to be used. It is essential to double-check SDC input to ensure a safe treatment delivery. Here, we present an automated treatment plan check tool for adaptive radiotherapy (APART) at a 0.35 T MR-Linac. It is designed to complement the manufacturer-provided adaptive QA tool comprising SDC. Checks performed by APART include contour analysis, electron density map examinations, and fluence modulation complexity controls. For nine of 362 adapted fractions (2.5%), irregularities regarding missing slices in target volumes and organs at risks as well as in margin expansion of target volumes have been found. This demonstrates that mistakes occur and can be detected by additional QA measures, especially contour analysis. Therefore, it is recommended to implement further QA tools additional to what the manufacturer provides to facilitate an informed decision about the quality of the treatment plan.

Tumor hypoxia is a major cause of resistance to radiochemotherapy in locally advanced head-and-neck cancer (LASCCHN). We present results of a randomized phase II trial on hypoxia dose escalation (DE) in LASCCHN based on dynamic [Patients with LASCCHN underwent baseline dynFMISO PET/CT. Hypoxic volumes (HV) were derived from dynFMISO data. Patients with hypoxic tumors (HV 0) were randomized into standard radiotherapy (ST: 70Gy/35fx) or dose escalation (DE: 77Gy/35fx) to the HV. Patients with non-hypoxic tumors were treated with ST. After a minimum follow-up of 2 years feasibility, acute/late toxicity and local control (LC) were analyzed.The study was closed prematurely due to slow accrual. Between 2009 and 2017, 53 patients were enrolled, 39 (74%) had hypoxic tumors and were randomized into ST or DE. For non-hypoxic patients, 100% 5-year LC was observed compared to 74% in patients with hypoxic tumors (p = 0.039). The difference in 5-year LC between DE (16/19) and ST (10/17) was 25%, p = 0.150. No relevant differences related to acute and late toxicities between the groups were observed.This study confirmed the prognostic value of hypoxia PET in LASCCHN for LC. Outcome after hypoxia DE appears promising and may support the concept of DE. Slow accrual and premature closure may partly be due to a high complexity of the study setup which needs to be considered for future multicenter trials.

Introduction: Tumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). Methods: In 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50–66 Gy/25–33 fractions, 2010–2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. Results: No significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). Conclusion: Tumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) versus children (5%) (p = 0.0043). Also, within the adult cohort, RICE risk increases with age (p = 0,00128). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.

Purpose The need for four-dimensional (4D) treatment planning becomes indispensable when it comes to radiation therapy for moving tumors in the thoracic and abdominal regions. The primary purpose of this study is to combine the actual breathing trace during each individual treatment fraction with the Linac's log file information and Monte Carlo 4D dose calculations. We investigated this workflow on multiple computed tomography (CT) datasets in a clinical environment for stereotactic body radiation therapy (SBRT) treatment planning. Methods We have developed a workflow, which allows us to recalculate absorbed dose to a 4DCT dataset using Monte Carlo calculation methods and accumulate all 4D doses in order to compare them to the planned dose using the Linac's log file, a 4DCT dataset, and the patient's actual breathing curve for each individual fraction. For five lung patients, three-dimensional-conformal radiation therapy (3D-CRT) and volumetric modulated arc treatment (VMAT) treatment plans were generated on four different CT image datasets: a native free-breathing 3DCT, an average intensity projection (AIP) and a maximum intensity projection (MIP) CT both obtained from a 4DCT, and a 3DCT with density overrides based on the 3DCT (DO). The Monte Carlo 4D dose has been calculated on each 4DCT phase using the Linac's log file and the patient's breathing trace as a surrogate for tumor motion and dose was accumulated to the gross tumor volume (GTV) at the 50% breathing phase (end of exhale) using deformable image registration. Results Δ D 98 % and Δ D 2 % between 4D dose and planned dose differed largely for 3DCT-based planning and also for DO in three patients. Least dose differences between planned and recalculated dose have been found for AIP and MIP treatment planning which both tend to be superior to DO, but the results indicate a dependency on the breathing variability, tumor motion, and size. An interplay effect has not been observed in the small patient cohort. Conclusions We have developed a workflow which, to our best knowledge, is the first incorporation of the patient breathing trace over the course of all individual treatment fractions with the Linac's log file information and 4D Monte Carlo recalculations of the actual treated dose. Due to the small patient cohort, no clear recommendation on which CT can be used for SBRT treatment planning can be given, but the developed workflow, after adaption for clinical use, could be used to enhance a priori 4D Monte Carlo treatment planning in the future and help with the decision on which CT dataset treatment planning should be carried out.

Our purpose was to evaluate an imaging parameter–response relationship between the extent of tumor hypoxia quantified by dynamic 18F-fluoromisonidazole (18F-FMISO) PET/CT and the risk of relapse after radiotherapy in patients with head and neck cancer. Methods: Before a prospective cohort of 25 head and neck cancer patients started radiotherapy, they were examined with dynamic 18F-FMISO PET/CT 0–240 min after tracer injection. 18F-FMISO image parameters, including a hypoxia metric, MFMISO, derived from pharmacokinetic modeling of dynamic 18F-FMISO and maximum tumor-to-muscle ratio (TMRmax) at 4 h after injection, gross tumor volume (GTV), relative hypoxic volume based on MFMISO, and a logistic regression model combining GTV and TMRmax, were assessed and compared with a previous training cohort (n = 15). Dynamic 18F-FMISO was used to validate a tumor control probability model based on MFMISO. The prognostic potential with respect to local control of all potential parameters was validated using the concordance index for univariate Cox regression models determined from the training cohort, in addition to Kaplan–Meier analysis including the log-rank test. Results: The tumor control probability model was confirmed, indicating that dynamic 18F-FMISO allows stratification of patients into different risk groups according to radiotherapy outcome. In this study, MFMISO was the only parameter that was confirmed as prognostic in the independent validation cohort (concordance index, 0.71; P = 0.004). All other investigated parameters, such as TMRmax, GTV, relative hypoxic volume, and the combination of GTV and TMRmax, were not able to stratify patient groups according to outcome in this validation cohort (P = not statistically significant). Conclusion: In this study, the relationship between MFMISO and the risk of relapse was prospectively validated. The data support further evaluation and external validation of dynamic 18F-FMISO PET/CT as a promising method for patient stratification and hypoxia-based radiotherapy personalization, including dose painting.

SFUD strategies with one or two posterior proton beams and three target coverage strategies are compared with IMRT and tested for robustness towards anatomical changes by recalculation on surveillance CTs during treatment. We find posterior beam SFUD combining PTV coverage with robust optimization increases robustness towards anatomical changes compared to IMRT.

A novel risk model has recently been proposed for the occurrence of late contrast-enhancing brain lesions (CEBLs) after proton irradiation of low-grade glioma (LGG) patients. It predicts a strong dependence on dose-weighted linear-energy transfer (LETd effect) and an increased radiosensitivity of the ventricular proximity, a 4-mm fringe surrounding the ventricular system (VP4mm effect). On this basis, we investigated (A) how these two risk factors and patient-specific anatomical and treatment plan (TP) features contribute to normal tissue complication probability (NTCP) and (B) if conventional LETd -reduction techniques like multiple-field TP are able to reduce NTCP. (A) The LGG model cohort (N = 110) was stratified with respect to prescribed dose, tumor grade, and treatment field configuration. NTCP predictions and CEBL occurrence rates per strata were analyzed. (B) The effect of multiple-field TP was investigated in two patient groups: (i) nine high-risk subjects with extended lateral target volumes who had developed CEBLs after single-beam treatments were retrospectively replanned with a clinical standard two-field setting using almost orthogonal fields and strictly opposing fields, (ii) single-field treatments were simulated for seven low-risk patients with small central target volumes clinically treated with two strictly opposing fields. (A) In the model cohort, we identified the exposure of the radiosensitive VP4mm fringe with proton field components of increased biological effectiveness as dominant NTCP driving factor. We observed that larger target volumes and location lateral to the main ventricles, both being characteristic for WHO°II tumors, presented with the highest complication risks. Among subjects of an equal dose prescription of 54 Gy(RBE), the highest median NTCP was obtained for the WHO°II group treated with two fields using sharp angles. (B) Regarding the effect of multiple-field plans, we found that an NTCP reduction was only achievable in the low-risk group where the LETd effect dominates and the VP4mm effect is small. NTCP of the single-field plans was 23% higher compared to the clinical opposing field plan. In the high-risk group, where the VP4mm effect dominates the risk, both two-field scenarios yielded 44% higher NTCP predictions compared to the clinical single-field plans. The interplay of an increased radiosensitivity in the VP4mm fringe with proton field components of increased biological effectiveness creates a geometric complexity that can hardly be managed by current clinical TP. Our results underline that advanced biologically guided TP approaches become crucial for an effective risk minimization in proton therapy of LGG.

Understanding dose-dependent survival of irradiated cells is a pivotal goal in radiotherapy and radiobiology. To this end, the clonogenic assay is the standard in vitro method, classifying colonies into either clonogenic or non-clonogenic based on a size threshold at a fixed time. Here we developed a methodological framework for the automated analysis of time course live-cell image data to examine in detail the growth dynamics of large numbers of colonies that occur during such an experiment. We developed a segmentation procedure that exploits the characteristic composition of phase-contrast images to identify individual colonies. Colony tracking allowed us to characterize colony growth dynamics as a function of dose by extracting essential information: (a) colony size distributions across time; (b) fractions of differential growth behavior; and (c) distributions of colony growth rates across all tested doses. We analyzed three data sets from two cell lines (H3122 and RENCA) and made consistent observations in line with already published results: (i) colony growth rates are normally distributed with a large variance; (ii) with increasing dose, the fraction of exponentially growing colonies decreases, whereas the fraction of delayed abortive colonies increases; as a novel finding, we observed that (iii) mean exponential growth rates decrease linearly with increasing dose across the tested range (0–10 Gy). The presented method is a powerful tool to examine live colony growth on a large scale and will help to deepen our understanding of the dynamic, stochastic processes underlying the radiation response in vitro.

Highlights • No statistically significant difference between the high- and low dose arm in risk of RP. • Identified risk factors for RP: target volume, infection, dyspnea at baseline, and increase of cough during RT. • number of patients was too small to establish a statistically sound multivariable model., Purpose Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investigated. Methods Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo-radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A–59pts) and 66 Gy/33fx (B–58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP ≥ G2. Results Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5.8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP ≥ G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP ≥ G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP ≥ G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivariable logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. Conclusion No statistical difference between the high- and low dose arm was found in the risk of developing RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model.

Background This work addresses a basic inconsistency in the way dose is accumulated in radiotherapy when predicting the biological effect based on the linear quadratic model (LQM). To overcome this inconsistency, we introduce and evaluate the concept of the total biological dose, bEQDd. Methods Daily computed tomography imaging of nine patients treated for prostate carcinoma with intensity-modulated radiotherapy was used to compute the delivered deformed dose on the basis of deformable image registration (DIR). We compared conventional dose accumulation (DA) with the newly introduced bEQDd, a new method of accumulating biological dose that considers each fraction dose and tissue radiobiology. We investigated the impact of the applied fractionation scheme (conventional/hypofractionated), uncertainties induced by the DIR and by the assigned α/β-value. Results bEQDd was systematically higher than the conventionally accumulated dose with difference hot spots of 3.3–4.9 Gy detected in six out of nine patients in regions of high dose gradient in the bladder and rectum. For hypofractionation, differences are up to 8.4 Gy. The difference amplitude was found to be in a similar range to worst-case uncertainties induced by DIR and was higher than that induced by α/β. Conclusion Using bEQDd for dose accumulation overcomes a potential systematic inaccuracy in biological effect prediction based on accumulated dose. Highest impact is found for serial-type late responding organs at risk in dose gradient regions and for hypofractionation. Although hot spot differences are in the order of several Gray, in dose-volume parameters there is little difference compared with using conventional or biological DA. However, when local dose information is used, e.g. dose surface maps, difference hot spots can potentially change outcomes of dose-response modelling and adaptive treatment strategies.

Purpose: To report on the commissioning and clinical validation of the first commercially available independent Monte Carlo (MC) three-dimensional (3D) dose calculation for CyberKnife robotic radiosurgery system® (Accuray, Sunnyvale, CA). Methods: The independent dose calculation (IDC) by SciMoCa® (Scientific RT, Munich, Germany) was validated based on water measurements of output factors and dose profiles (unshielded diode, field-size dependent corrections). A set of 84 patient-specific quality assurance (QA) measurements for multi-leaf collimator (MLC) plans, using an Octavius two-dimensional SRS1000 array (PTW, Freiburg, Germany), was compared to results of respective calculations. Statistical process control (SPC) was used to detect plans outside action levels. Results: Of all output factors for the three collimator systems of the CyberKnife, 99% agreed within 2% and 81% within 1%, with a maximum deviation of 3.2% for a 5-mm fixed cone. The profiles were compared using a one-dimensional gamma evaluation with 2% dose difference and 0.5 mm distance-to-agreement (Γ(2,0.5)). The off-centre ratios showed an average pass rate >99% (92–100%). The agreement of the depth dose profiles depended on field size, with lowest pass rates for the smallest MLC field sizes. The average depth dose pass rate was 88% (35–99%). The IDCs showed a Γ(2,1) pass rate of 98%. Statistical process control detected six plans outside tolerance levels in the measurements, all of which could be attributed the measurement setup. Independent dose calculations showed problems in five plans, all due to differences in the algorithm between TPS and IDC. Based on these results changes were made in the class solution for treatment plans. Conclusion: The first commercially available MC 3D dose IDC was successfully commissioned and validated for the CyberKnife and replaced all routine patientspecific QA measurements in our clinic.

PURPOSE: The two distinct dose computation paradigms of Boltzmann equation solvers and Monte Carlo simulation both promise in principle maximum accuracy. In practice, clinically acceptable calculation times demand approximations and numerical short-cuts on one hand, and modeling the beam characteristics of a real linear accelerator to the required accuracy on the other. A thorough benchmark of both algorithm types therefore needs to start with beam modeling, and needs to include a number of clinically challenging treatment plans.METHODS: The Acuros XB (v 13.7, Varian Medical Systems) and SciMoCa (v 1.0, Scientific RT) algorithms were commissioned for the same Varian Clinac accelerator for beam qualities 6 and 15 MV. Beam models were established with water phantom measurements and MLC calibration protocols. In total, 25 patients of five case classes (lung/three-dimensional (3D) conformal, lung/IMRT, head and neck/VMAT, cervix/IMRT, and rectum/VMAT) were randomly selected from the clinical database and computed with both algorithms. Statistics of 3D gamma analysis for various dose/distance-to-agreement (DTA) criteria and differences in selected DVH parameters were analyzed.RESULTS: The percentage of points fulfilling a gamma evaluation was scored as the gamma agreement index (GAI), denoted as G(ΔD, DTA). G(3,3), G(2,2), and G(1,1) were evaluated for the full body, PTV, and selected organs at risk (OARs). For all patients, G(3,3) ≥ 99.9% and G(2,2) > 97% for the body. G(1,1) varied among the patients. However, for all patients, G(1,1) > 70% and G(1,1) > 80% for 68% of the patients. For each patient, the mean dose deviation was ΔD < 1% for the body, PTV, and all evaluated OARs, respectively. In dense bone and at off-axis distance > 10 cm, the Acuros algorithm yielded slightly higher doses. In the first layer of voxels of the patient surface, the calculated doses deviated between the algorithms. However, at the second voxel, good agreement was observed. The differences in D(98%PTV) were CONCLUSIONS: Overall, an outstanding agreement was found between the Boltzmann equation solver and Monte Carlo. High-accuracy dose computation algorithms have matured to a level that their differences are below common experimental detection thresholds for clinical treatment plans. Aside from residual differences which could be traced back to implementation details and fundamental cross-section data, both algorithms arrive at identical dose distributions.

PURPOSE: In image-guided adaptive brachytherapy (IGABT), dose distributions are optimized for each fraction. Optimum fractional dose can be constant or adapted to previous fractions and a conjecture about the future ones. We evaluate the efficacy of different fraction size schemes, derived from total IGABT dose constraints, against constant per-fraction constraints.METHODS AND MATERIALS: This retrospective planning study included 20 IGABT patients where four different fractionation schedules were compared based on modern planning recommendations. A total high-risk clinical target volume D-90 (minimum dose in 90% of the volume) dose aim of 90.0 Gy with constant per-fraction organs at risk (OARs) dose constraint planning (CONST) was compared with conservative and aggressive fractionation compensation (COMP) techniques. COMP allows variations in the per-fraction dose constraints. Dose accumulation was performed through dose summation at a given volume and equivalent uniform dose (EUD) worst-case dose estimates.RESULTS: No significant differences were identifiable between dose metrics of CONST and COMP in the total patient population. However, a subgroup of patients with alternating dose limiting OARs had significant benefit from COMP. Median high-risk clinical target volume dose escalation ranged from 5% to 12%, whereas OAR dose increases were lower and ranged from 3% to 8%. EUD-based planning delivered similar tumor doses, although slightly lower OAR doses. By distributing the treatment aim over an increased number of treatment fractions, median tumor dose could be increased by a further 8% per additional treatment fraction at the same OAR dose levels for both CONST and COMP.CONCLUSIONS: COMP is effective in patients with alternating dose-limiting OARs and is enhanced using more treatment fractions and EUD constraints. (C) 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Dose volume histogram points (DVHPs) frequently serve as dose constraints in radiotherapy treatment planning. An experiment was designed to investigate the reliability of DVHP inference from clinical data for multiple cohort sizes and complication incidence rates. The experimental background was radiation pneumonitis in non-small cell lung cancer and the DVHP inference method was based on logistic regression. From 102 NSCLC real-life dose distributions and a postulated DVHP model, an 'ideal' cohort was generated where the most predictive model was equal to the postulated model. A bootstrap and a Cohort Replication Monte Carlo (CoRepMC) approach were applied to create 1000 equally sized populations each. The cohorts were then analyzed to establish inference frequency distributions. This was applied to nine scenarios for cohort sizes of 102 (1), 500 (2) to 2000 (3) patients (by sampling with replacement) and three postulated DVHP models. The Bootstrap was repeated for a 'non-ideal' cohort, where the most predictive model did not coincide with the postulated model. The Bootstrap produced chaotic results for all models of cohort size 1 for both the ideal and non-ideal cohorts. For cohort size 2 and 3, the distributions for all populations were more concentrated around the postulated DVHP. For the CoRepMC, the inference frequency increased with cohort size and incidence rate. Correct inference rates >[Formula: see text] were only achieved by cohorts with more than 500 patients. Both Bootstrap and CoRepMC indicate that inference of the correct or approximate DVHP for typical cohort sizes is highly uncertain. CoRepMC results were less spurious than Bootstrap results, demonstrating the large influence that randomness in dose-response has on the statistical analysis. Dose volume histogram points (DVHPs) frequently serve as dose constraints in radiotherapy treatment planning. An experiment was designed to investigate the reliability of DVHP inference from clinical data for multiple cohort sizes and complication incidence rates. The experimental background was radiation pneumonitis in non-small cell lung cancer and the DVHP inference method was based on logistic regression. From 102 NSCLC real-life dose distributions and a postulated DVHP model, an 'ideal' cohort was generated where the most predictive model was equal to the postulated model. A bootstrap and a Cohort Replication Monte Carlo (CoRepMC) approach were applied to create 1000 equally sized populations each. The cohorts were then analyzed to establish inference frequency distributions. This was applied to nine scenarios for cohort sizes of 102 (1), 500 (2) to 2000 (3) patients (by sampling with replacement) and three postulated DVHP models. The Bootstrap was repeated for a 'non-ideal' cohort, where the most predictive model did not coincide with the postulated model. The Bootstrap produced chaotic results for all models of cohort size 1 for both the ideal and non-ideal cohorts. For cohort size 2 and 3, the distributions for all populations were more concentrated around the postulated DVHP. For the CoRepMC, the inference frequency increased with cohort size and incidence rate. Correct inference rates >[Formula: see text] were only achieved by cohorts with more than 500 patients. Both Bootstrap and CoRepMC indicate that inference of the correct or approximate DVHP for typical cohort sizes is highly uncertain. CoRepMC results were less spurious than Bootstrap results, demonstrating the large influence that randomness in dose-response has on the statistical analysis.

Background and purpose Plasticity of the intestinal stem cell compartment in response to radiation injury is regulated by a stem cell niche. We present here the first experimental observations of a dose-volume effect of the intestinal stem cell niche and of the solitary intestinal lymphoid tissues (SILT). Materials and methods Regeneration of intestinal crypts in mice was studied following irradiation of millimetre-size jejunal sections with single doses of 6 to 24 Gy and compared to total body irradiation (TBI). The statistical distribution of cells per crypt was scored and regressed to a biomathematical model. The number of SILTs was scored for different doses and field sizes and crypt regeneration was correlated with SILT proximity. Results We observed a differential dose–response of the intestinal stem cell niche at the centres of the irradiated sections, but only for field sizes below 10 mm. Irradiation of 5 mm jejunum results in an increase in crypt survival by up to an order of magnitude, compared to TBI. Distributions of cell-per-crypt numbers and comparison to biomathematical modelling suggest that these observations stem from a field size-dependent regeneration rate. The density of SILTs also exhibits a volume-dependent dose–response and increased crypt survival correlates with a proximity to SILTs. Conclusion Our findings present the first observation of a field-size dependent dose–response of the intestinal stem cell niche. Its regeneration process does apparently not rely on distant radiation-sensitive resources of the organism, such as the bone marrow. Yet, our observations suggest that the niche interacts with intact tissue in millimetres distance, leading to faster crypt regeneration. The field-size dependent dose–response of SILTs posits a role of the immune system on the dose-volume effect.

Purpose Late radiation-induced contrast-enhancing brain lesions (CEBLs) on magnetic resonance imaging (MRI) after proton therapy of brain tumors have been observed to occur frequently in regions of high linear energy transfer (LET) and in proximity to the ventricular system. We analyzed 110 patients with low-grade glioma treated with proton therapy to determine whether the risk for CEBLs is increased in proximity to the ventricular system and if there is a relationship between relative biological effectiveness (RBE) and LET. Methods and Materials We contoured CEBLs identified on follow-up T1-MRI scans and computed dose and dose-averaged LET (LETd) distributions for all patients using the Monte Carlo method. We then performed cross-validated voxel-level logistic regression to predict local risks for image change and to extract model parameters, such as the RBE. From the voxel-level model, we derived a model for patient-level risk prediction based on the treatment plan. Results Of 110 patients, 23 exhibited 1 or several CEBLs on follow-up MRI scans. The voxel-level logistic model has an accuracy as follows: area under the curve of 0.94 and Brier score of 2.6 × 10-5. Model predictions are a 3-fold increased risk in the 4 mm region around the ventricular system and an LETd-dependent RBE of, for example, 1.20 for LETd = 2 keV/μm and 1.50 for LETd = 5 keV/μm. The patient-level risk model has an accuracy as follows: area under the curve of 0.78 and Brier score of 0.13. Conclusions Our findings present clinical evidence for an increased risk in ventricular proximity and for a proton RBE that increases significantly with increasing LET. We present a voxel-level model that accurately predicts the localization of late MRI contrast change and extrapolate a patient-level model that allows treatment plan–based risk prediction.

Purpose To assess the efficacy of individual sentinel node (SN)-guided pelvic intensity modulated radiation therapy (IMRT) by determining nodal clearance rate [(n expected nodal involvement − n observed regional recurrences)/n expected nodal involvement] in comparison with surgically staged patients. Methods and Materials Data on 475 high-risk prostate cancer patients were examined. Sixty-one consecutive patients received pelvic SN-based IMRT (5 × 1.8 Gy/wk to 50.4 Gy [pelvic nodes + individual SN] and an integrated boost with 5 × 2.0 Gy/wk to 70.0 Gy to prostate + [base of] seminal vesicles) and neo-/adjuvant long-term androgen deprivation therapy; 414 patients after SN–pelvic lymph node dissection were used to calculate the expected nodal involvement rate for the radiation therapy sample. Biochemical control and overall survival were estimated for the SN-IMRT patients using the Kaplan-Meier method. The expected frequency of nodal involvement in the radiation therapy group was estimated by imputing frequencies of node-positive patients in the surgical sample to the pattern of Gleason, prostate-specific antigen, and T category in the radiation therapy sample. Results After a median follow-up of 61 months, 5-year OS after SN-guided IMRT reached 84.4%. Biochemical control according to the Phoenix definition was 73.8%. The nodal clearance rate of SN-IMRT reached 94%. Retrospective follow-up evaluation is the main limitation. Conclusions Radiation treatment of pelvic nodes individualized by inclusion of SNs is an effective regional treatment modality in high-risk prostate cancer patients. The pattern of relapse indicates that the SN-based target volume concept correctly covers individual pelvic nodes. Thus, this SN-based approach justifies further evaluation, including current dose-escalation strategies to the prostate in a larger prospective series.

Motion and uncertainty in radiotherapy is traditionally handled via margins. The clinical target volume (CTV) is expanded to a larger planning target volume (PTV), which is irradiated to the prescribed dose. However, the PTV concept has several limitations, especially in proton therapy. Therefore, robust and probabilistic optimization methods have been developed that directly incorporate motion and uncertainty into treatment plan optimization for intensity modulated radiotherapy (IMRT) and intensity modulated proton therapy (IMPT). Thereby, the explicit definition of a PTV becomes obsolete and treatment plan optimization is directly based on the CTV. Initial work focused on random and systematic setup errors in IMRT. Later, inter-fraction prostate motion and intra-fraction lung motion became a research focus. Over the past ten years, IMPT has emerged as a new application for robust planning methods. In proton therapy, range or setup errors may lead to dose degradation and misalignment of dose contributions from different beams - a problem that cannot generally be addressed by margins. Therefore, IMPT has led to the first implementations of robust planning methods in commercial planning systems, making these methods available for clinical use. This paper first summarizes the limitations of the PTV concept. Subsequently, robust optimization methods are introduced and their applications in IMRT and IMPT planning are reviewed.

PURPOSE: When treating lung cancer patients with intensity-modulated proton therapy (IMPT), target coverage can only be guaranteed when utilizing motion mitigation. The three motion mitigation techniques, gating, breath-hold, and dose repainting, all benefit from a more rapid application of the treatment plan. A lower limit for the ungated treatment time is defined by the number of energy layers in the IMPT plan. By limiting this number during treatment planning, IMPT could become more viable for lung cancer patients. We investigate to what extend the number of layers can be reduced in single-field optimization (SFO) and multifield optimization (MFO) plans and which implications it has on the plan quality and robustness.METHODS: We have implemented three distinct layer-reducing strategies in the treatment planning system Hyperion; constant energy steps, exponential energy steps, and an adaptive strategy, where the spot weights are exposed to a group sparsity penalty in combination with layer exclusion during optimization. Four levels of increasing layer removal are planned for each strategy. SFO and MFO plans with three treatment fields are created for eleven locally advanced NSCLC patients on the midventilation 4DCT phase to simulate a breath-hold. A minimum dose to the target is ensured for each degree of layer reduction, reflecting the plan quality in the homogeneity index (HI). Plan quality was also assessed by a robustness evaluation, where the patient setup was shifted 2 mm or 4 mm in six directions.RESULTS: The three strategies result in very similar target coverages and robustness levels as a function of removed layers. The HI increases unacceptably for all the SFO plans after 50% layer removal as compared to the reference plan, while all the MFO plans are clinically acceptable with up to a highest removed percentage of 75%. The robustness level is constant as a function of removed layers. The SFO plans are significantly more robust than the MFO plans with all P-values below 0.001 (Wilcoxon signed-rank). The overall mean D98% CTV dose difference is at 2-mm setup error amplitude: 0.7 Gy (SFO) and 1.9 Gy (MFO), and at 4 mm: 3.2 Gy (SFO) and 5.4 Gy (MFO), respectively.CONCLUSIONS: The number of layers in MFO plans can be reduced substantially more than in SFO plans without compromising plan quality. Furthermore, as the robustness is independent of the number of layers, it follows that if the level of robustness is acceptable or enforced via robust optimization, MFO plans could be candidates for treatment time reductions via energy layer reductions.

Background and purpose The high plasticity of the intestinal epithelium is maintained by a resilient reserve stem cell population, whose extent and biology are a matter of ongoing debate. The in vivo clonogenic assay (IVCA), presents a well established and efficient analysis of radiation insult to the intestinal crypts. However, we found that inadequate mathematical analysis over the last four decades led to systematic errors and contradictory results in estimates of radio-sensitivity and size of the reserve stem cell pool. Material and methods We devised a refinement of the IVCA via development of a biomathematical model that delivers a full statistical dynamic description of epithelial radiation injury and subsequent regeneration. We validated the model against cellular and crypt distribution statistics obtained from IVCA experiments and through systematic re-analysis of experimental data from 27 publications. Results A full dynamic description of the evolution of stem cell niche population statistics is obtained. A systematic re-analysis reveals a consistent clonogenic content of the crypt of 31 ± 6 cells. The stem cell reserve manifests to be, contrary to prior predictions, radio-resistant: α = ( 0.22 ± 0.04 ) Gy−1. Conclusion We established a precision tool for the quantitative analysis of radiation insult to the intestinal crypts, which we employ to show that the reserve stem cell population is small, radio-resistant, and remarkably immutable against a large variety of interventions. The increased resolution of the model allows not only a reduction of the number of animals by about 75%, but also to quantify experimentally the influence of additional agents on damage and on regeneration of the stem cell niche.