Independent Monte Carlo dose calculation identifies single isocenter multi-target radiosurgery targets most likely to fail pre-treatment measurement.

PURPOSE: For individual targets of single isocenter multi-target (SIMT) Stereotactic radiosurgery (SRS), we assess dose difference between the treatment planning system (TPS) and independent Monte Carlo (MC), and demonstrate persistence into the pre-treatment Quality Assurance (QA) measurement. METHODS: Treatment plans from 31 SIMT SRS patients were recalculated in a series of scenarios designed to investigate sources of discrepancy between TPS and independent MC. Targets with > 5% discrepancy in DMean[Gy] after progressing through all scenarios were measured with SRS MapCHECK. A matched pair analysis was performed comparing SRS MapCHECK results for these targets with matched targets having similar characteristics (volume & distance from isocenter) but no such MC dose discrepancy. RESULTS: Of 217 targets analyzed, individual target mean dose (DMean[Gy]) fell outside a 5% threshold for 28 and 24 targets before and after removing tissue heterogeneity effects, respectively, while only 5 exceeded the threshold after removing effect of patient geometry (via calculation on StereoPHAN geometry). Significant factors affecting agreement between the TPS and MC included target distance from isocenter (0.83% decrease in DMean[Gy] per 2 cm), volume (0.15% increase per cc), and degree of plan modulation (0.37% increase per 0.01 increase in modulation complexity score). SRS MapCHECK measurement had better agreement with MC than with TPS (2%/1 mm / 10% threshold gamma pass rate (GPR) = 99.4 ± 1.9% vs. 93.1 ± 13.9%, respectively). In the matched pair analysis, targets exceeding 5% for MC versus TPS also had larger discrepancies between TPS and measurement with no GPR (2%/1 mm / 10% threshold) exceeding 90% (71.5% ± 16.1%); whereas GPR was high for matched targets with no such MC versus TPS difference (96.5% ± 3.3%, p = 0.01). CONCLUSIONS: Independent MC complements pre-treatment QA measurement for SIMT SRS by identifying problematic individual targets prior to pre-treatment measurement, thus enabling plan modifications earlier in the planning process and guiding selection of targets for pre-treatment QA measurement.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Quality assurance for on-table adaptive magnetic resonance guided radiation therapy: A software tool to complement secondary dose calculation and failure modes discovered in clinical routine.

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.

First prospective clinical evaluation of feasibility and patient acceptance of magnetic resonance-guided radiotherapy in Germany.

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 PRO­Q. Almost two thirds of patients (65%) complained about at least one item of the PRO­Q (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.

Target miss using PTV-based IMRT compared to robust optimization via coverage probability concept in prostate cancer.

Purpose: Cure- and toxicity rates of prostate IGRT can both be affected by ill-chosen planning target volume (PTV) margins. For dose-escalated prostate radiotherapy, we studied the potential for organ at risk (OAR) sparing and compensation of prostate motion with robust plan optimization using the coverage probability (CovP) concept compared to conventional PTV-based IMRT.Material and methods: We evaluated plan quality of CovP-plans for 27 intermediate risk prostate cancer patients treated in a prospective study (78 Gy/39 fractions). Clinical target volume (CTV) and OARs were contoured on three separate CTs to capture movement and deformation. To define the internal target volume (ITV), the union of CTV1-3 was encompassed by an isotropic margin of 7 mm for the planning process. CovP-dose distribution is optimized considering weight factors for IMRT constraints derived from probabilities of systematic organ displacement in the three CTs. CovP-dose volume histograms (DVHs) were compared with additionally calculated conventional PTV-based IMRT plans. PTV-based IMRT was planned on one-single CT with an isotropically expanded CTV to generate the PTV (i.e., CTV1 + 7mm) and was evaluated on the two other CTs.Results: The CovP-concept showed higher robustness in target volume coverage. Target miss was frequently observed with PTV-based IMRT, resulting in cold spots until 70 Gy with the CovP-concept. The target dose at 74 Gy was comparable, while further the dose-escalation (75-78 Gy) was improved with PTV-based IMRT. However, dose-escalation with PTV-based IMRT was associated with increased OAR-doses, especially in high-dose areas.Conclusions: Probabilistic dose-escalated IMRT was feasible in this prospective study. Comparison of the CovP-concept with PTV-based IMRT revealed superiority with regard to target-coverage and sparing of OARs. The CovP-concept implements a robust plan optimization strategy for organ deformation and motions and could, therefore, serve as a less demanding compromise on the way to adaptive IGRT avoiding daily time-consuming re-planning. SUMMARYWe evaluated the robustness of coverage probability (CovP)-based IMRT plans within a prospective study for prostate cancer radiotherapy. The treatment plans were compared with newly calculated conventional PTV-based IMRT plans. We were able to show that CovP led to a clearly more robust target coverage by avoiding hot spots at OARs compared to conventional PTV-based IMRT. In addition, negative consequences of an inflated PTV can be ameliorated by a more relaxed CovP-based dose prescription.

Commissioning and clinical implementation of the first commercial independent Monte Carlo 3D dose calculation to replace CyberKnife M6™ patient-specific QA measurements.

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 patient-specific QA measurements in our clinic.

Automatic replanning of VMAT plans for different treatment machines: A template-based approach using constrained optimization.

PURPOSE: To investigate a new automatic template-based replanning approach combined with constrained optimization, which may be highly useful for a rapid plan transfer for planned or unplanned machine breakdowns. This approach was tested for prostate cancer (PC) and head-and-neck cancer (HNC) cases. METHODS: The constraints of a previously optimized volumetric modulated arc therapy (VMAT) plan were used as a template for automatic plan reoptimization for different accelerator head models. All plans were generated using the treatment planning system (TPS) Hyperion. Automatic replanning was performed for 16 PC cases, initially planned for MLC1 (4 mm MLC) and reoptimized for MLC2 (5 mm) and MLC3 (10 mm) and for 19 HNC cases, replanned from MLC2 to MLC3. EUD, Dmean, D2%, and D98% were evaluated for targets; for OARs EUD and D2% were analyzed. Replanning was considered successful if both plans fulfilled equal constraints. RESULTS: All prostate cases were successfully replanned. The mean relative target EUD deviation was -0.15% and -0.57% for replanning to MLC2 and MLC3, respectively. OAR sparing was successful in all cases. Replanning of HNC cases from MLC2 to MLC3 was successful in 16/19 patients with a mean decrease of -0.64% in PTV60 EUD. In three cases target doses were substantially decreased by up to -2.58% (PTV60) and -3.44% (PTV54), respectively. Nevertheless, OAR sparing was always achieved as planned. CONCLUSIONS: Automatic replanning of VMAT plans for a different treatment machine by using pre-existing constraints as a template for a reoptimization is feasible and successful in terms of equal constraints.

Early clinical outcome of coverage probability based treatment planning for simultaneous integrated boost of nodes in locally advanced cervical cancer.

INTRODUCTION: More than 50% of patients with locally advanced cervical cancer (LACC) have pathological nodes. Coverage probability (CovP) is a new planning technique allowing for relaxed dose at the boost periphery minimising collateral irradiation. The aim was to report the first early clinical outcome data for CovP based simultaneous integrated boost (SIB) in LACC. MATERIAL AND METHODS: Twenty-three consecutive node positive patients were analysed. FIGO stage IB2/IIB/IIIB/IVA/IVB was 1/14/3/1/4. Treatment was radio(chemo)therapy (RT) delivering 45 Gy/25 fx whole pelvis ± para-aortic region (PAN) using volumetric arc therapy (VMAT) followed by magnetic resonance imaging (MRI) guided brachytherapy. PAN RT (13 pts) was given if >2 nodes or if node(s) were present at the common iliac vessels or PAN. Nodal gross tumour volumes (GTV-N) were contoured on both PET-CT and MRI. Clinical target volume (CTV-N) was formed by fusion of GTV-NCT and GTV-NMRI. A 5-mm isotropic margin was used for planning target volume (PTV-N). Nodes in the small pelvis were boosted to 55.0 Gy/25 fx. Common iliac and para-aortic nodes received 57.5 Gy/25 fx. Planning aims for CovP were PTV-N D98 ≥ 90%, CTV-N D98 ≥ 100% and CTV-N D50 ≥ 101.5%. RESULTS: Seventy-four nodes were boosted. A consistent 5.0 ± 0.7 Gy dose reduction from CTV-N D98 to PTV-N D98 was obtained. In total, 73/74 nodes were in complete remission at 3 months PET-CT and MRI. Pelvic control was obtained in 21/23 patients. One patient (IB2, clear cell) had salvageable local disease, while another (IIB) failed in a boosted node. Two patients failed in un-irradiated PAN. One patient age 88 (IIIB) did not receive PAN RT, despite a common iliac node. The other (IIB) recurred above L1. Two further patients (IVB) failed systemically. CONCLUSION: Since complete remission at 3 months is predictive for favourable long-term nodal control, our study indicates that CovP for SIB is promising.

Accuracy of software-assisted contour propagation from planning CT to cone beam CT in head and neck radiotherapy.

BACKGROUND: Autocontouring improves workflow in computed tomography (CT)-based dose planning, but could also potentially play a role for optimal use of daily cone beam CT (CBCT) in adaptive radiotherapy. This study aims to determine the accuracy of a deformable image registration (DIR) algorithm for organs at risk (OAR) in the neck region, when applied to CBCT. MATERIAL AND METHODS: For 30 head and neck cancer (HNC) patients 14 OARs including parotid glands, swallowing structures and spinal cord were delineated. Contours were propagated by DIR from CT to the CBCTs of the first and last treatment fraction. An indirect approach, propagating contours to the first CBCT and from there to the last CBCT was also tested. Propagated contours were compared to manually corrected contours by Dice similarity coefficient (DSC) and Hausdorff distance (HD). Dose was recalculated on CBCTs and dosimetric consequences of uncertainties in DIR were reviewed. RESULTS: Mean DSC values of ≥0.8 were considered adequate and were achieved in tongue base (0.91), esophagus (0.85), glottic (0.81) and supraglottic larynx (0.83), inferior pharyngeal constrictor muscle (0.84), spinal cord (0.89) and all salivary glands in the first CBCT. For the last CBCT by direct propagation, adequate DSC values were achieved for tongue base (0.85), esophagus (0.84), spinal cord (0.87) and all salivary glands. Using indirect propagation only tongue base (0.80) and parotid glands (0.87) were ≥0.8. Mean relative dose difference between automated and corrected contours was within ±2.5% of planed dose except for esophagus inlet (-4.5%) and esophagus (5.0%) for the last CBCT using indirect propagation. CONCLUSION: Compared to manually corrected contours, the DIR algorithm was accurate for use in CBCT images of HNC patients and the minor inaccuracies had little consequence for mean dose in most clinically relevant OAR. The method can thus enable a more automated segmentation of CBCT for use in adaptive radiotherapy.

Intrafraction organ movement in adaptive MR-guided radiotherapy of abdominal lesions - dosimetric impact and how to detect its extent in advance.

INTRODUCTION: Magnetic resonance guided radiotherapy (MRgRT) allows daily adaptation of treatment plans to compensate for positional changes of target volumes and organs at risk (OARs). However, current adaptation times are relatively long and organ movement occurring during the adaptation process might offset the benefit gained by adaptation. The aim of this study was to evaluate the dosimetric impact of these intrafractional changes. Additionally, a method to predict the extent of organ movement before the first treatment was evaluated in order to have the possibility to compensate for them, for example by adding additional margins to OARs. MATERIALS & METHODS: Twenty patients receiving adaptive MRgRT for treatment of abdominal lesions were retrospectively analyzed. Magnetic resonance (MR) images acquired at the start of adaptation and immediately before irradiation were used to calculate adapted and pre-irradiation dose in OARs directly next to the planning target volume. The extent of organ movement was determined on MR images acquired during simulation sessions and adaptive treatments, and their agreement was evaluated. Correlation between the magnitude of organ movement during simulation and the duration of simulation session was analyzed in order to assess whether organ movement might be relevant even if the adaptation process could be accelerated in the future. RESULTS: A significant increase in dose constraint violations was observed from adapted (6.9%) to pre-irradiation (30.2%) dose distributions. Overall, OAR dose increased significantly by 4.3% due to intrafractional organ movement. Median changes in organ position of 7.5 mm (range 1.5-10.5 mm) were detected within a median time of 17.1 min (range 1.6-28.7 min). Good agreement was found between the range of organ movement during simulation and adaptation (66.8%), especially if simulation sessions were longer and multiple MR images were acquired. No correlation was determined between duration of simulation sessions and magnitude of organ movement. CONCLUSION: Intrafractional organ movement can impact dose distributions and lead to violations of OAR tolerance doses, which impairs the benefit of daily on-table plan adaptation. By application of simulation images, the extent of intrafractional organ movement can be predicted, which possibly allows to compensate for them.

Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

Correlation between tumor oxygenation and 18F-fluoromisonidazole PET data simulated based on microvessel images.

BACKGROUND: Assessing hypoxia with oxygen probes provides a sparse sampling of tumor volumes only, bearing a risk of missing hypoxic regions. Full coverage is achieved with positron emission tomography (PET) using the tracer (18)F-fluoromisonidazole (FMISO). In this study, the correlation between different FMISO PET imaging parameters and the median voxel PO2 (medianPO2) was analyzed. A measure of the median PO2 characterizes the microenvironment in consistency with probe measurements. MATERIAL AND METHODS: Tissue oxygenations and FMISO diffusion-retention dynamics were simulated. Transport of FMISO and O2 molecules into and out of tissue was modeled by vessel maps derived from histology of head-and-neck squamous cell cancer xenograft tumor lines. Parameter sets were evaluated for 300 distinct 2 × 2 mm(2) vessel configurations, including medianPO2 and two FMISO PET parameters: FH denotes the sub-regional signal four hours post injection (pi) and FH/P denotes the ratio between FH and the time-averaged signal 0-15 min pi. Correlations between O2 and FMISO parameters were evaluated. A receiver operating characteristics (ROC) analysis was performed, regarding the accuracy of FH and FH/P in identifying voxels with medianPO2 < 2.5 mmHg. RESULTS: In hypoxic sub-regions, the correlation between FH and medianPO2 is low (R(2) = 0.37), while the correlation between FH/P and median PO2 is high (R(2) = 0.99). The ROC analysis showed that hypoxic regions can be identified using FH/P with a higher diagnostic accuracy (YI = sensitivity+ specificity-1 = 1.0), than using FH alone (YI = 0.83). Both FMISO parameters are moderately effective in identifying hypoxia on the microscopic length scale (YI = 0.63 and 0.60). CONCLUSIONS: A combination of two FMISO PET scans acquired 0-15 min and four hours pi may yield an accurate measure of the medianPO2 in a voxel (FH/P). This measure is comparable to averaged oxygen probe measurements and has the advantage of covering the entire tumor volume. Therefore, it may improve the prediction of radiotherapy outcome and facilitate individualized dose prescriptions.

Sensitivity and specificity of Monte Carlo based independent secondary dose computation for detecting modulation-related dose errors in intensity modulated radiotherapy.

BACKGROUND: The recent availability of Monte Carlo based independent secondary dose calculation (ISDC) for patient-specific quality assurance (QA) of modulated radiotherapy requires the definition of appropriate, more sensitive action levels, since contemporary recommendations were defined for less accurate ISDC dose algorithms. PURPOSE: The objective is to establish an optimum action level and measure the efficacy of a Monte Carlo ISDC software for pre-treatment QA of intensity modulated radiotherapy treatments. METHODS: The treatment planning system and the ISDC were commissioned by their vendors from independent base data sets, replicating a typical real-world scenario. In order to apply Receiver-Operator-Characteristics (ROC), a set of treatment plans for various case classes was created that consisted of 190 clinical treatment plans and 190 manipulated treatment plans with dose errors in the range of 1.5-2.5%. All 380 treatment plans were evaluated with ISDC in the patient geometry. ROC analysis was performed for a number of Gamma (dose-difference/distance-to-agreement) criteria. QA methods were ranked according to Area under the ROC curve (AUC) and optimum action levels were derived via Youden's J statistics. RESULTS: Overall, for original treatment plans, the mean Gamma pass rate (GPR) for Gamma(1%, 1 mm) was close to 90%, although with some variation across case classes. The best QA criterion was Gamma(2%, 1 mm) with GPR > 90% and an AUC of 0.928. Gamma criteria with small distance-to-agreement had consistently higher AUC. GPR of original treatment plans depended on their modulation degree. An action level in terms of Gamma(1%, 1 mm) GPR that decreases with modulation degree was the most efficient criterion with sensitivity = 0.91 and specificity = 0.95, compared with Gamma(3%, 3 mm) GPR > 99%, sensitivity = 0.73 and specificity = 0.91 as a commonly used action level. CONCLUSIONS: ISDC with Monte Carlo proves highly efficient to catch errors in the treatment planning process. For a Monte Carlo based TPS, dose-difference criteria of 2% or less, and distance-to-agreement criteria of 1 mm, achieve the largest AUC in ROC analysis.

A time-resolved clonogenic assay for improved cell survival and RBE measurements.

Purpose: The in vitro clonogenic assay (IVCA) is the mainstay of quantitative radiobiology. Here, we investigate the benefit of a time-resolved IVCA version (trIVCA) to improve the quantification of clonogenic survival and relative biological effectiveness (RBE) by analyzing cell colony growth behavior. Materials & Methods: In the IVCA, clonogenicity classification of cell colonies is performed based on a fixed colony size threshold after incubation. In contrast, using trIVCA, we acquire time-lapse microscopy images during incubation and track the growth of each colony using neural-net-based image segmentation. Attributes of the resulting growth curves are then used as predictors for a decision tree classifier to determine clonogenicity of each colony. The method was applied to three cell lines, each irradiated with 250 kV X-rays in the range 0-8 Gy and carbon ions of high LET (100 keV/µm, dose-averaged) in the range 0-2 Gy. We compared the cell survival curves determined by trIVCA to those from the classical IVCA across different size thresholds and incubation times. Further, we investigated the impact of the assaying method on RBE determination. Results: Size distributions of abortive and clonogenic colonies overlap consistently, rendering perfect separation via size threshold unfeasible at any readout time. This effect is dose-dependent, systematically inflating the steepness and curvature of cell survival curves. Consequently, resulting cell survival estimates show variability between 3% and 105%. This uncertainty propagates into RBE calculation with variability between 8% and 25% at 2 Gy.Determining clonogenicity based on growth curves has an accuracy of 95% on average. Conclusion: The IVCA suffers from substantial uncertainty caused by the overlap of size distributions of delayed abortive and clonogenic colonies. This impairs precise quantification of cell survival and RBE. By considering colony growth over time, our method improves assaying clonogenicity.

Generation, validation, and benchmarking of a commercial independent Monte Carlo calculation beam model for multi-target SRS.

BACKGROUND: Dosimetric validation of single isocenter multi-target radiosurgery plans is difficult due to conditions of electronic disequilibrium and the simultaneous irradiation of multiple off-axis lesions dispersed throughout the volume. Here we report the benchmarking of a customizable Monte Carlo secondary dose calculation algorithm specific for multi-target radiosurgery which future users may use to guide their commissioning and clinical implementation. PURPOSE: To report the generation, validation, and clinical benchmarking of a volumetric Monte Carlo (MC) dose calculation beam model for single isocenter radiosurgery of intracranial multi-focal disease. METHODS: The beam model was prepared within SciMoCa (ScientificRT, Munich Germany), a commercial independent dose calculation software, with the aim of broad availability via the commercial software for use with single isocenter radiosurgery. The process included (1) definition & acquisition of measurement data required for beam modeling, (2) tuning model parameters to match measurements, (3) validation of the beam model via independent measurements and end-to-end testing, and finally, (4) clinical benchmarking and validation of beam model utility in a patient specific QA setting. We utilized a 6X Flattening-Filter-Free photon beam from a TrueBeam STX linear accelerator (Siemens Healthineers, Munich Germany). RESULTS: In addition to the measured data required for standard IMRT/VMAT (depth dose, central axis profiles & output factors, leaf gap), beam modeling and validation for single-isocenter SRS required central axis and off axis (5 cm & 9 cm) small field output factors and comparison between measurement and simulation of backscatter with aperture for jaw much greater than MLCs. Validation end-to-end measurements included SRS MapCHECK in StereoPHAN geometry (2%/1 mm Gamma = 99.2% ±â€¯2.2%), and OSL & scintillator measurements in anthropomorphic STEEV phantom (6 targets, volume = 0.1-4.1cc, distance from isocenter = 1.2-7.9 cm) for which mean difference was -1.9% ±â€¯2.2%. For 10 patient cases, MC for individual PTVs was -0.8% ±â€¯1.5%, -1.3% ±â€¯1.7%, and -0.5% ±â€¯1.8% for mean dose, D95%, and D1%, respectively. This corresponded to custom passing rates action limits per AAPM TG-218 guidelines of ±5.2%, ±6.4%, and ±6.3%, respectively. CONCLUSIONS: The beam modeling, validation, and clinical action criteria outlined here serves as a benchmark for future users of the customized beam model within SciMoCa for single isocenter radiosurgery of multi-focal disease.

A body mass index-based method for "MR-only" abdominal MR-guided adaptive radiotherapy.

PURPOSE: Dose calculation for MR-guided radiotherapy (MRgRT) at the 0.35 T MR-Linac is currently based on deformation of planning CTs (defCT) acquired for each patient. We present a simple and robust bulk density overwrite synthetic CT (sCT) method for abdominal treatments in order to streamline clinical workflows. METHOD: Fifty-six abdominal patient treatment plans were retrospectively evaluated. All patients had been treated at the MR-Linac using MR datasets for treatment planning and plan adaption and defCT for dose calculation. Bulk density CTs (4M-sCT) were generated from MR images with four material compartments (bone, lung, air, soft tissue). The relative electron densities (RED) for bone and lung were extracted from contoured CT structure average REDs. For soft tissue, a correlation between BMI and RED was evaluated. Dose was recalculated on 4M-sCT and compared to dose distributions on defCTs assessing dose differences in the PTV and organs at risk (OAR). RESULTS: Mean RED of bone was 1.17 ±â€¯0.02, mean RED of lung 0.17 ±â€¯0.05. The correlation between BMI and RED for soft tissue was statistically significant (p < 0.01). PTV dose differences between 4M-sCT and defCT were Dmean: -0.4 ±â€¯1.0%, D1%: -0.3 ±â€¯1.1% and D95%: -0.5 ±â€¯1.0%. OARs showed D2%: -0.3 ±â€¯1.9% and Dmean: -0.1 ±â€¯1.4% differences. Local 3D gamma index pass rates (2%/2mm) between dose calculated using 4M-sCT and defCT were 96.8 ±â€¯2.6% (range 89.9-99.6%). CONCLUSION: The presented method for sCT generation enables precise dose calculation for MR-only abdominal MRgRT.

Leaf-individual calibration for a double stack multileaf collimator in photon radiotherapy.

Background and Purpose: In online adaptive stereotactic body radiotherapy treatments, linear accelerator delivery accuracy is essential. Recently introduced double stack multileaf collimators (MLCs) have new facets in their calibration. We established a radiation-based leaf-individual calibration (LIMCA) method for double stack MLCs. Materials and Methods: MLC leaf positions were evaluated from four cardinal angles with test patterns at measurement positions throughout the radiation field on EBT3 radiochromic film for each single stack. The accuracy of the method and repeatability of the results were assessed. The effect of MLC positioning errors was characterized for a measured output factor curve and a clinical patient plan. Results: All positions in the motor step - position calibration file were optimized in the established LIMCA method. The resulting double stack mean accuracy for all angles was 0.2 ± 0.1 mm for X1 (left bank) and 0.2 ± 0.2 mm for X2 (right bank). The accuracy of the leaf position evaluation was 0.2 mm (95% confidence level). The MLC calibration remained stable over four months. Small MLC leaf position errors (e.g. 1.2 mm field size reduction) resulted in important dose errors (-5.8 %) for small quadratic fields of 0.83 × 0.83 cm2. Single stack position accuracy was essential for highly modulated treatment plans. Conclusions: LIMCA is a new double stack MLC calibration method that increases treatment accuracy from four angles and for all moving leaves.

Validation of a virtual source model for Monte Carlo dose calculations of a flattening filter free linac.

PURPOSE: A linac delivering intensity-modulated radiotherapy (IMRT) can benefit from a flattening filter free (FFF) design which offers higher dose rates and reduced accelerator head scatter than for conventional (flattened) delivery. This reduction in scatter simplifies beam modeling, and combining a Monte Carlo dose engine with a FFF accelerator could potentially increase dose calculation accuracy. The objective of this work was to model a FFF machine using an adapted version of a previously published virtual source model (VSM) for Monte Carlo calculations and to verify its accuracy. METHODS: An Elekta Synergy linear accelerator operating at 6 MV has been modified to enable irradiation both with and without the flattening filter (FF). The VSM has been incorporated into a commercially available treatment planning system (Monaco™ v 3.1) as VSM 1.6. Dosimetric data were measured to commission the treatment planning system (TPS) and the VSM adapted to account for the lack of angular differential absorption and general beam hardening. The model was then tested using standard water phantom measurements and also by creating IMRT plans for a range of clinical cases. RESULTS: The results show that the VSM implementation handles the FFF beams very well, with an uncertainty between measurement and calculation of <1% which is comparable to conventional flattened beams. All IMRT beams passed standard quality assurance tests with >95% of all points passing gamma analysis (γ < 1) using a 3%/3 mm tolerance. CONCLUSIONS: The virtual source model for flattened beams was successfully adapted to a flattening filter free beam production. Water phantom and patient specific QA measurements show excellent results, and comparisons of IMRT plans generated in conventional and FFF mode are underway to assess dosimetric uncertainties and possible improvements in dose calculation and delivery.

The use and QA of biologically related models for treatment planning: short report of the TG-166 of the therapy physics committee of the AAPM.

Treatment planning tools that use biologically related models for plan optimization and/or evaluation are being introduced for clinical use. A variety of dose-response models and quantities along with a series of organ-specific model parameters are included in these tools. However, due to various limitations, such as the limitations of models and available model parameters, the incomplete understanding of dose responses, and the inadequate clinical data, the use of biologically based treatment planning system (BBTPS) represents a paradigm shift and can be potentially dangerous. There will be a steep learning curve for most planners. The purpose of this task group is to address some of these relevant issues before the use of BBTPS becomes widely spread. In this report, the authors (1) discuss strategies, limitations, conditions, and cautions for using biologically based models and parameters in clinical treatment planning; (2) demonstrate the practical use of the three most commonly used commercially available BBTPS and potential dosimetric differences between biologically model based and dose-volume based treatment plan optimization and evaluation; (3) identify the desirable features and future directions in developing BBTPS; and (4) provide general guidelines and methodology for the acceptance testing, commissioning, and routine quality assurance (QA) of BBTPS.

Dose escalation to hypoxic subvolumes in head and neck cancer: A randomized phase II study using dynamic [18F]FMISO PET/CT.

BACKGROUND AND PURPOSE: 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 [18F]FMISO (dynFMISO) positron emission tomography (PET). The purpose was to confirm the prognostic value of hypoxia PET and assess feasibility, toxicity and efficacy of hypoxia-DE. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.