Effect of simultaneous integrated boost concepts on photoneutron and distant out-of-field doses in VMAT for prostate cancer.

BACKGROUND: A simultaneous integrated boost (SIB) may result in increased out-of-field (DOOF) and photoneutron (HPN) doses in volumetric modulated arc therapy (VMAT) for prostate cancer (PCA). This work therefore aimed to compare DOOF and HPN in flattened (FLAT) and flattening filter-free (FFF) 6­MV and 10-MV VMAT treatment plans with and without SIB. METHODS: Eight groups of 30 VMAT plans for PCA with 6 MV or 10 MV, with or without FF and with uniform (2 Gy) or SIB target dose (2.5/3.0 Gy) prescriptions (CONV, SIB), were generated. All 240 plans were delivered on a slab-phantom and compared with respect to measured DOOF and HPN in 61.8 cm distance from the isocenter. The 6­ and 10-MV flattened VMAT plans with conventional fractionation (6- and 10-MV FLAT CONV) served as standard reference groups. Doses were analyzed as a function of delivered monitor units (MU) and weighted equivalent square field size Aeq. Pearson's correlation coefficients between the presented quantities were determined. RESULTS: The SIB plans resulted in decreased HPN over an entire prostate RT treatment course (10-MV SIB vs. CONV -38.2%). Omission of the flattening filter yielded less HPN (10-MV CONV -17.2%; 10-MV SIB -22.5%). The SIB decreased DOOF likewise by 39% for all given scenarios, while the FFF mode reduced DOOF on average by 60%. A strong Pearson correlation was found between MU and HPN (r > 0.9) as well as DOOF (0.7 < r < 0.9). CONCLUSION: For a complete treatment, SIB reduces both photoneutron and OOF doses to almost the same extent as FFF deliveries. It is recommended to apply moderately hypofractionated 6­MV SIB FFF-VMAT when considering photoneutron or OOF doses.

Radiosurgery for ventricular tachycardia (RAVENTA): interim analysis of a multicenter multiplatform feasibility trial.

BACKGROUND: Single-session cardiac stereotactic radiation therapy (SBRT) has demonstrated promising results for patients with refractory ventricular tachycardia (VT). However, the full safety profile of this novel treatment remains unknown and very limited data from prospective clinical multicenter trials are available. METHODS: The prospective multicenter multiplatform RAVENTA (radiosurgery for ventricular tachycardia) study assesses high-precision image-guided cardiac SBRT with 25 Gy delivered to the VT substrate determined by high-definition endocardial and/or epicardial electrophysiological mapping in patients with refractory VT ineligible for catheter ablation and an implanted cardioverter defibrillator (ICD). Primary endpoint is the feasibility of full-dose application and procedural safety (defined as an incidence of serious [grade ≥ 3] treatment-related complications ≤ 5% within 30 days after therapy). Secondary endpoints comprise VT burden, ICD interventions, treatment-related toxicity, and quality of life. We present the results of a protocol-defined interim analysis. RESULTS: Between 10/2019 and 12/2021, a total of five patients were included at three university medical centers. In all cases, the treatment was carried out without complications. There were no serious potentially treatment-related adverse events and no deterioration of left ventricular ejection fraction upon echocardiography. Three patients had a decrease in VT episodes during follow-up. One patient underwent subsequent catheter ablation for a new VT with different morphology. One patient with local VT recurrence died 6 weeks after treatment in cardiogenic shock. CONCLUSION: The interim analysis of the RAVENTA trial demonstrates early initial feasibility of this new treatment without serious complications within 30 days after treatment in five patients. Recruitment will continue as planned and the study has been expanded to further university medical centers. TRIAL REGISTRATION NUMBER: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. Study start: October 1, 2019.

Local dose rate effects in implantable cardioverter-defibrillators with flattening filter free and flattened photon radiation.

PURPOSE: In the beam penumbra of stereotactic body radiotherapy volumes, dose rate effects in implantable cardioverter-defibrillators (ICDs) may be the predominant cause for failures in the absence of neutron-generating photon energies. We investigate such dose rate effects in ICDs and provide evidence for safe use of lung tumor stereotactic radioablation with flattening filter free (FFF) and flattened 6 Megavolt (MV) beams in ICD-bearing patients. METHODS: Sixty-two ICDs were subjected to scatter radiation in 1.0, 2.5, and 7.0 cm distance to 100 Gy within a 5â€¯× 5 cm2 radiation field. Radiation was applied with 6 MV FFF beams (constant dose rate of 1400 cGy/min) and flattened (FLAT) 6 MV beams (430 cGy/min). Local dose rates (LDR) at the position of all ICDs were measured. All ICDs were monitored continuously. RESULTS: With 6 MV FFF beams, ICD errors occurred at distances of 1.0 cm (LDR 46.8 cGy/min; maximum ICD dose 3.4 Gy) and 2.5 cm (LDR 15.6 cGy/min; 1.1 Gy). With 6 MV FLAT beams, ICD errors occurred only at 1 cm distance (LDR 16.8 cGy/min; 3.9 Gy). No errors occurred at an LDR below 7 cGy/min, translating to a safe distance of 2.5 cm (1.5 Gy) in flattened and 7 cm (0.4 Gy) in 6 MV FFF beams. CONCLUSION: A LDR in ICDs larger than 7 cGy/min may cause ICD malfunction. At identical LDR, differences between 6 MV FFF and 6 MV FLAT beams do not yield different rates of malfunction. The dominant reason for ICD failures could be the LDR and not the total dose to the ICD. For most stereotactic treatments, it is recommended to generate a planning risk volume around the ICD in which LDR larger than 7 cGy/min are avoided.

Technological quality requirements for stereotactic radiotherapy : Expert review group consensus from the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy.

This review details and discusses the technological quality requirements to ensure the desired quality for stereotactic radiotherapy using photon external beam radiotherapy as defined by the DEGRO Working Group Radiosurgery and Stereotactic Radiotherapy and the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The covered aspects of this review are 1) imaging for target volume definition, 2) patient positioning and target volume localization, 3) motion management, 4) collimation of the irradiation and beam directions, 5) dose calculation, 6) treatment unit accuracy, and 7) dedicated quality assurance measures. For each part, an expert review for current state-of-the-art techniques and their particular technological quality requirement to reach the necessary accuracy for stereotactic radiotherapy divided into intracranial stereotactic radiosurgery in one single fraction (SRS), intracranial fractionated stereotactic radiotherapy (FSRT), and extracranial stereotactic body radiotherapy (SBRT) is presented. All recommendations and suggestions for all mentioned aspects of stereotactic radiotherapy are formulated and related uncertainties and potential sources of error discussed. Additionally, further research and development needs in terms of insufficient data and unsolved problems for stereotactic radiotherapy are identified, which will serve as a basis for the future assignments of the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The review was group peer-reviewed, and consensus was obtained through multiple working group meetings.

Irradiation Delays Tissue Growth but Enhances Osteogenic Differentiation in Vascularized Constructs.

BACKGROUND: Regenerative medicine is still deficient in the reconstruction after cancer due to impaired vascularization after radiotherapy and due to the need to substitute larger defects after tumor excision. Aiming at introducing regenerative medicine for reconstruction after cancer, we tested an axially vascularized bone construct in an experimental setting that mimics the clinical situation after tumor resection and adjuvant radiotherapy. METHODS: Twenty bone constructs were axially vascularized using microsurgically created arteriovenous loops and were implanted subcutaneously in Lewis rats. After 2 weeks, the animals were randomly allocated either to receive a clinically relevant single dose of external beam irradiation or not (n = 10 for each group). The animals were sacrificed either after 1 week or 10 weeks after irradiation (n = 5 for each time point). The constructs were tested for vascularization, tissue growth, cellular proliferation, cellular apoptosis, and osteogenic differentiation via histomorphometric, immunohistochemical, and polymerase chain reaction (PCR) analysis. One construct per group was subjected at 10 weeks to qualitative micro-computed tomography (CT) imaging. RESULTS: Tissue generation and cellular proliferation were significantly reduced at 1 week after irradiation, but no longer significantly different after 10 weeks.No significant differences in vascularization were detected at any time point. Apoptosis did not show any statistically significant differences between both groups at both time points. At the late time point, mature bone was considerably more in the irradiated group, but the results were not statistically significant. PCR analysis showed a significantly enhanced expression of osteocalcin in the irradiated group at 1 week. Micro-CT imaging showed that both constructs were adequately vascularized with no evident morphologic differences regarding vascular density or vascular distribution. CONCLUSIONS: Axially vascularized bone constructs can withstand clinically relevant doses of irradiation and retain their angiogenic and osteogenic potential in the long term. Irradiation led to a delayed tissue generation with a comparatively enhanced osteogenic differentiation within the constructs.

Non-coplanar VMAT combined with non-uniform dose prescription markedly reduces lung dose in breath-hold lung SBRT.

BACKGROUND AND PURPOSE: In this retrospective treatment planning study, the effect of a uniform and non-uniform planning target volume (PTV) dose coverage as well as a coplanar and non-coplanar volumetric modulated arc therapy (VMAT) delivery approach for lung stereotactic body radiation therapy (SBRT) in deep inspiration breath-hold (DIBH) were compared. MATERIALS AND METHODS: For 46 patients with lesions in the peripheral lungs, three different treatment plans were generated: First, a coplanar 220° VMAT sequence with a uniform PTV dose prescription (UC). Second, a coplanar 220° VMAT treatment plan with a non-uniform dose distribution in the PTV (nUC). Third, a non-coplanar VMAT dose delivery with four couch angles (0°, ±35°, 90°) and a non-uniform prescription (nUnC) was used. All treatment plans were optimized for pareto-optimality with respect to PTV coverage and ipsilateral lung dose. Treatment sequences were delivered on a flattening-filter-free linear accelerator and beam-on times were recorded. Dosimetric comparison between the three techniques was performed. RESULTS: For the three scenarios (UC, nUC, nUnC), median gross tumor volume (GTV) doses were 63.4 ± 2.5, 74.4 ± 3.6, and 77.9 ± 3.8 Gy, and ipsilateral V10Gy lung volumes were 15.7 ± 6.1, 13.9 ± 4.7, and 12.0 ± 5.1%, respectively. Normal tissue complication probability of the ipsilateral lung was 3.9, 3.1, and 2.8%, respectively. The number of monitor units were 5141 ± 1174, 4104 ± 786, and 3657 ± 710 MU and the corresponding beam-on times were 177 ± 54, 143 ± 29, and 148 ± 26 s. CONCLUSION: For SBRT treatments in DIBH, a non-uniform dose prescription in the PTV, combined with a non-coplanar VMAT arc arrangement, significantly spares the ipsilateral lung while increasing dose to the GTV without major treatment time increase.

Small bowel protection in IMRT for rectal cancer : A dosimetric study on supine vs. prone position.

BACKGROUND: This treatment planning study analyzes dose coverage and dose to organs at risk (OAR) in intensity-modulated radiotherapy (IMRT) of rectal cancer and compares prone vs. supine positioning as well as the effect of dose optimization for the small bowel (SB) by additional dose constraints in the inverse planning process. PATIENTS AND METHODS: Based on the CT datasets of ten male patients in both prone and supine position, a total of four different IMRT plans were created for each patient. OAR were defined as the SB, bladder, and femoral heads. In half of the plans, two additional SB cost functions were used in the inverse planning process. RESULTS: There was a statistically significant dose reduction for the SB in prone position of up to 41% in the high and intermediate dose region, compared with the supine position. Furthermore, the femoral heads showed a significant dose reduction in prone position in the low dose region. Regarding the additional active SB constraints, the dose in the high dose region of the SB was significantly reduced by up to 14% with the additional cost functions. There were no significant differences in the dose distribution of the planning target volume (PTV) and the bladder. CONCLUSION: Prone positioning can significantly reduce dose to the SB in IMRT for rectal cancer and therefore should not only be used in 3D conformal radiotherapy but also in IMRT of rectal cancer. Further protection of the SB can be achieved by additional dose constraints in inverse planning without jeopardizing the homogeneity of the PTV.

Towards clinical implementation of ultrafast combined kV-MV CBCT for IGRT of lung cancer : Evaluation of registration accuracy based on phantom study.

PURPOSE: Combined kV-MV cone-beam CT (CBCT) is a promising approach to accelerate imaging for patients with lung tumors treated with deep inspiration breath-hold. During a single breath-hold (15 s), a 3D kV-MV CBCT can be acquired, thus minimizing motion artifacts and increasing patient comfort. Prior to clinical implementation, positioning accuracy was evaluated and compared to clinically established imaging techniques. METHODS AND MATERIALS: An inhomogeneous thorax phantom with four tumor-mimicking inlays was imaged in 10 predefined positions and registered to a planning CT. Novel kV-MV CBCT imaging (90° arc) was compared to clinically established kV-chest CBCT (360°) as well as nonclinical kV-CBCT and low-dose MV-CBCT (each 180°). Manual registration, automatic registration provided by the manufacturer and an additional in-house developed manufacturer-independent framework based on the MATLAB registration toolkit were applied. RESULTS: Systematic setup error was reduced to 0.05 mm by high-precision phantom positioning with optical tracking. Stochastic mean displacement errors were 0.5 ± 0.3 mm in right-left, 0.4 ± 0.4 mm in anteroposterior and 0.0 ± 0.4 mm in craniocaudal directions for kV-MV CBCT with manual registration (maximum errors of no more than 1.4 mm). Clinical kV-chest CBCT resulted in mean errors of 0.2 mm (other modalities: 0.4-0.8 mm). Similar results were achieved with both automatic registration methods. CONCLUSION: The comparison study of repositioning accuracy between novel kV-MV CBCT and clinically established volume imaging demonstrated that registration accuracy is maintained below 1 mm. Since imaging time is reduced to one breath-hold, kV-MV CBCT is ideal for image guidance, e.g., in lung stereotactic ablative radiotherapy.

Impact of flattening-filter-free radiation on the clonogenic survival of astrocytic cell lines.

BACKGROUND AND PURPOSE: Flattening-filter-free (FFF) beams are increasingly used in radiotherapy as delivery times can be substantially reduced. However, the relative biologic effectiveness (RBE) of FFF may be increased relative to conventional flattened (FLAT) beams due to differences in energy spectra. Therefore, we investigated the effects of FFF and FLAT beams on the clonogenic survival of astrocytoma cells. MATERIAL AND METHODS: Three cell lines (U251, U251-MGMT, and U87) were irradiated with 6-MV and 10-MV X-rays from a linear accelerator in FFF- or FLAT-beam modes at dose rates in the range of 0.5-24 Gy/min. The surviving fraction (SF) as function of dose (2-12 Gy) was determined by the colony formation assay and fitted by the linear-quadratic model. For both beams (FFF or FLAT), the cells were pelleted in conical 15-ml centrifuge tubes and irradiated at 2-cm depth in a 1 × 1-cm(2) area on the central axis of a 30 × 30-cm(2) field. Dosimetry was performed with a 0.3-cm(3) rigid ionization chamber. RBE was determined for FFF versus FLAT irradiation. RESULTS: The RBE of FFF at 7.3-11.3 Gy was 1.027 ± 0.013 and 1.063 ± 0.018 relative to FLAT beams for 6- and 10-MV beams, respectively, and was only significantly higher than 1 for 10 MV. Significantly increased survival rates were seen for lower dose rates (0.5 Gy/min FLAT vs. 5 Gy/min FLAT) at higher doses (11.9 Gy), while no differences were seen at dose rates ≥ 1.4 Gy/min (1.4 Gy/min FFF vs. 14 Gy/min FFF and 2.4 Gy/min FFF vs. 24 Gy/min FFF). CONCLUSIONS: FFF beams showed only a slightly increased RBE relative to FLAT beams in this experimental set-up, which is unlikely to result in clinically relevant differences in outcome.

Homogenous dose prescription in Gamma Knife Radiotherapy: Combining the best of both worlds.

PURPOSE: Stereotactic radiosurgery with linear accelerators (LINACs) or Leksell Gamma Knife® (LGK, Elekta AB) is an established treatment option for intracranial tumors. When those are involving/abutting organs at risk (OAR), homogenous and normofractionated treatments outmatch single fraction deliveries. In such situations, it would be desirable to balance LINAC's homogeneity benefits with LGK's dose gradient attributes. In this study, we determined homogeneity and OAR sparing ranges using a non-clinical, homogenous prototype version of LGK Lightning. METHODS: We retrospectively analyzed thirty fractionated LGK Icon in-house patients with acoustic neuromas, pituitary adenomas and meningiomas. Four treatment plans were generated (54 Gy,1.8 Gy/fx) per patient: one LINAC plan, one clinical Lightning plan ("LGK") and two prototype Lightning plans ("LGK Hom" and "LGK OAR"). We analyzed Dmean and D2% for different OAR, Gradient Index (GI), Paddick Conformity Index (PCI), Homogeneity Index (HI) and beam-on-time (BOT). RESULTS: While the LINAC vs. Lightning plans (LGK Hom|LGK OAR|LGK) boast better homogeneity (median: 1.08 vs. 1.18|1.24|1.35) and shorter BOT (median: 137 s vs. 432 s|510 s|510 s), Lightning plans show improved GI (median: 6.68 vs. 3.86|3.50|3.19), similar PCI (median: 0.75 vs. 0.76|0.75|0.82) and significantly reduced OAR doses. For in-tumor OAR, LGK Hom and LINAC plans achieves similar OAR sparing with improved GI for LGK Hom. CONCLUSIONS: This study is a preliminary attempt to combine the dosimetric advantages of LINAC and LGK treatment planning. We observed that LGK plan homogeneity can be improved toward LINAC standards while maintaining the LGK advantage of favorable OAR doses and GI. Additionally, in-tumor OAR hotspots can be considerably reduced.

Hypoxia as a stimulus for tissue formation: The concept of organogenesis in microsurgically vascularized tissue engineering constructs.

Axial vascularization of tissue constructs is essential to maintain an adequate blood supply for a stable regeneration of a clinically relevant tissue size. The versatility of the arterio-venous loop (AVL) has been previously shown in various small and large animal models as well as in clinical reports for bone regeneration. We have previously demonstrated the capability of the AVL to induce axial vascularization and to support the nourishment of tissue constructs in small animal models after applying high doses of ionizing radiation comparable to those applied for adjuvant radiotherapy after head and neck cancer. We hypothesize that this robust ability to induce regeneration after irradiation could be related to a state of hypoxia inside the constructs that triggers the HIF1 (hypoxia induced factor 1) - SDF1 (stromal derived factor 1) axis leading to chemotaxis of progenitor cells and induction of tissue regeneration and vascularization. We analyzed the expression of HIF1 and SDF1 via immunofluorescence in axially vascularized bone tissue engineering constructs in Lewis rats 2 and 5 weeks after local irradiation with 9Gy or 15Gy. We also analyzed the expression of various genes for osteogenic differentiation (collagen 1, RUNX, alkaline phosphatase and osteonectin) via real time PCR analysis. The expression of HIF1 and SDF1 was enhanced two weeks after irradiation with 15Gy in comparison to non-irradiated constructs. The expression of osteogenic markers was enhanced at the 5-weeks time point with significant results regarding collagen, alkaline phosphatase and osteonectin. These results indicate that the hypoxia within the AVL constructs together with an enhanced SDF1 expression probably play a role in promoting tissue differentiation. The process of tissue generation triggered by hypoxia in the vicinity of a definite vascular axis with enhanced tissue differentiation over time resembles hereby the well-known concept of organogenesis in fetal life.

Dosimetric benefits of adaptive radiation therapy for patients with stage III non-small cell lung cancer.

BACKGROUND: Daily adaptive radiation therapy (ART) of patients with non-small cell lung cancer (NSCLC) lowers organs at risk exposure while maintaining the planning target volume (PTV) coverage. Thus, ART allows an isotoxic approach with increased doses to the PTV that could improve local tumor control. Herein we evaluate daily online ART strategies regarding their impact on relevant dose-volume metrics. METHODS: Daily cone-beam CTs (1 × n = 28, 1 × n = 29, 11 × n = 30) of 13 stage III NSCLC patients were converted into synthetic CTs (sCTs). Treatment plans (TPs) were created retrospectively on the first-fraction sCTs (sCT1) and subsequently transferred unaltered to the sCTs of the remaining fractions of each patient (sCT2-n) (IGRT scenario). Two additional TPs were generated on sCT2-n: one minimizing the lung-dose while preserving the D95%(PTV) (isoeffective scenario), the other escalating the D95%(PTV) with a constant V20Gy(lungipsilateral) (isotoxic scenario). RESULTS: Compared to the original TPs predicted dose, the median D95%(PTV) in the IGRT scenario decreased by 1.6 Gy ± 4.2 Gy while the V20Gy(lungipsilateral) increased in median by 1.1% ± 4.4%. The isoeffective scenario preserved the PTV coverage and reduced the median V20Gy(lungipsilateral) by 3.1% ± 3.6%. Furthermore, the median V5%(heart) decreased by 2.9% ± 6.4%. With an isotoxic prescription, a median dose-escalation to the gross target volume of 10.0 Gy ± 8.1 Gy without increasing the V20Gy(lungipsilateral) and V5%(heart) was feasible. CONCLUSIONS: We demonstrated that even without reducing safety margins, ART can reduce lung-doses, while still reaching adequate target coverage or escalate target doses without increasing ipsilateral lung exposure. Clinical benefits by means of toxicity and local control of both strategies should be evaluated in prospective clinical trials.

Surface guidance compared with ultrasound-based monitoring and diaphragm position in cone-beam computed tomography during abdominal stereotactic radiotherapy in breath-hold.

Background and purpose: Spirometry induced deep-inspiration-breath-hold (DIBH) reduces intrafractional motion during upper abdominal stereotactic body radiotherapy (SBRT). The aim of this prospective study was to evaluate whether surface scanning (SGRT) is an adequate surrogate for monitoring residual internal motion during DIBH. Residual motion detected by SGRT was compared with experimental 4D-ultrasound (US) and an internal motion detection benchmark (diaphragm-dome-position in kV cone-beam computed tomography (CBCT) projections). Materials and methods: Intrafractional monitoring was performed with SGRT and US in 460 DIBHs of 12 patients. Residual motion detected by all modalities (SGRT (anterior-posterior (AP)), US (AP, craniocaudal (CC)) and CBCT (CC)) was analyzed. Agreement analysis included Wilcoxon signed rank test, Maloney and Rastogi's test, Pearson's correlation coefficient (PCC) and interclass correlation coefficient (ICC). Results: Interquartile range was 0.7 mm (US(AP)), 0.8 mm (US(CC)), 0.9 mm (SGRT) and 0.8 mm (CBCT). SGRT(AP) vs. CBCT(CC) and US(CC) vs. CBCT(CC) showed comparable agreement (PCCs 0.53 and 0.52, ICCs 0.51 and 0.49) with slightly higher precision of CBCT(CC). Most agreement was observed for SGRT(AP) vs. US(AP) with largest PCC (0.61) and ICC (0.60), least agreement for SGRT(AP) vs. US(CC) with smallest PCC (0.44) and ICC (0.42). Conclusions: Residual motion detected during spirometry induced DIBH is small. SGRT alone is no sufficient surrogate for residual internal motion in all patients as some high velocity motion could not be detected. Observed patient-specific residual errors may require individualized PTV-margins.

Modulation of PD­L1 expression by standard therapy in head and neck cancer cell lines and exosomes.

Although checkpoint inhibitors (CPI) have recently extended the treatment options and improved clinical response of advanced stage head and neck squamous cell carcinoma (HNSCC), treatment success remains unpredictable. Programmed cell death ligand­1 (PD­L1) is a key player in immunotherapy. Tumor cells, and exosomes derived therefrom, are carriers of PD­L1 and efficiently suppress immune responses. The aim of the present study was to analyze the influence of established therapies on PD­L1 expression of HNSCC cell lines and their exosomes. The HNSCC cell lines, UM­SCC­11B, UM­SCC­14C and UM­SCC­22C were treated with fractionated radiotherapy (RT; 5x2 Gy), cisplatin (CT) and cetuximab (Cetux) as monotherapy, or combined therapy, chemoradiotherapy (CRT; RT and CT) or radioimmunotherapy (RT and Cetux). The expression of PD­L1 and phosphorylated (p)ERK1/2 as a mediator of radioresistance were assessed using western blotting, immunohistochemistry and an ex vivo vital tissue culture model. Additionally, exosomes were isolated from concentrated supernatants of the (un­)treated HNSCC cell lines by size exclusion chromatography. Exosomal protein expression levels of PD­L1 were detected using western blotting and semi­quantitative levels were calculated. The functional impact of exosomes from the (un­)treated HNSCC cell lines on the proliferation (MTS assay) and apoptosis (Caspase 3/7 assay) of the untreated HNSCC cell lines were measured and compared. The HNSCC cell lines UM­SCC­11B and UM­SCC­22B showed strong expression of pERK1/2 and PD­L1, respectively. RT upregulated the PD­L1 expression in UM­SCC­11B and UM­SCC­14C and in exosomes from all three cell lines. CT alone induced PD­L1 expression in all cell lines. CRT induced the expression of PD­L1 in all HNSCC cell lines and exosomes from UM­SCC­14C and UM­SCC­22B. The data indicated a potential co­regulation of PD­L1 and activated ERK1/2, most evident in UM­SCC­14C. Exosomes from irradiated UM­SCC­14C cells protected the unirradiated cells from apoptosis by Caspase 3/7 downregulation. The present study suggested a tumor cell­mediated regulation of PD­L1 upon platinum­based CRT in HNSCC and in exosomes. A co­regulation of PD­L1 and MAPK signaling response was hypothesized.

Quality assurance process within the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial for the fusion of electroanatomical mapping and radiotherapy planning imaging data in cardiac radioablation.

A novel quality assurance process for electroanatomical mapping (EAM)-to-radiotherapy planning imaging (RTPI) target transport was assessed within the multi-center multi-platform framework of the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial. A stand-alone software (CARDIO-RT) was developed to enable platform independent registration of EAM and RTPI of the left ventricle (LV), based on pre-generated radiotherapy contours (RTC). LV-RTC were automatically segmented into the American-Heart-Association 17-segment-model and a manual 3D-3D method based on EAM 3D-geometry data and a semi-automated 2D-3D method based on EAM screenshot projections were developed. The quality of substrate transfer was evaluated in five clinical cases and the structural analyses showed substantial differences between manual target transfer and target transport using CARDIO-RT.

A novel end-to-end test for combined dosimetric and geometric treatment verification using a 3D-printed phantom.

The dosimetric and geometric accuracy are important components to ensure safe patient treatment in radiation therapy. Therefore, these components must be checked during quality control. This work presents a possible solution for the determination of the geometric isocenter deviation in the entire treatment chain. Additionally, the dose measurement of the established end-to-end test workflow measured in the same procedure as the geometric deviation is described. An in-house designed end-to-end test phantom went through the entire procedure of a standard patient treatment and the dosimetric and geometric accuracy were determined. At 3 linear accelerators (linac), the phantom was positioned either with cone beam computed tomography or with surface guidance. In this position, a Winston-Lutz test was performed and the deviations of the gantry, collimator and couch isocenter measurements to the phantom position were determined. Additionally, a dose measurement in the phantom was performed and compared to the dose predicted in the treatment planning system. To validate the results obtained with the in-house designed phantom, comparative measurements with commercial phantoms were performed. According to the performed end-to-end test, 2 out of the 3 linacs showed isocenter variations larger than 1 mm for collimator and gantry rotations and larger than 2 mm for couch rotations. With an isocenter variation of less than 1 mm for collimator and gantry rotations, 1 linac fulfilled the tolerance for stereotactic treatments without couch rotation. With couch rotation, an isocenter variation of less than 2 mm was detected at this linac, which fulfilled the tolerance for IMRT treatments. The mean dose deviation between measurement and treatment planning system was 1.82% ± 1.03%. The results acquired with the UMM phantom did not show statistically significant deviations to those acquired with relevant other commercial phantoms. The novel end-to-end test procedure allows for a combined dosimetric and geometric treatment evaluation. Besides the commonly performed dose end-to-end test the geometric isocenter deviation within a patient treatment workflow was evaluated and categorized for IMRT or SBRT.

Treatment Planning for Cardiac Radioablation: Multicenter Multiplatform Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

PURPOSE: Cardiac radioablation is a novel treatment option for patients with refractory ventricular tachycardia unsuitable for catheter ablation. The quality of treatment planning depends on dose specifications, platform capabilities, and experience of the treating staff. To harmonize the treatment planning, benchmarking of this process is necessary for multicenter clinical studies such as the RAdiosurgery for VENtricular TAchycardia trial. METHODS AND MATERIALS: Planning computed tomography data and consensus structures from 3 patients were sent to 5 academic centers for independent plan development using a variety of platforms and techniques with the RAdiosurgery for VENtricular TAchycardia study protocol serving as guideline. Three-dimensional dose distributions and treatment plan details were collected and analyzed. In addition, an objective relative plan quality ranking system for ventricular tachycardia treatments was established. RESULTS: For each case, 3 coplanar volumetric modulated arc (VMAT) plans for C-arm linear accelerators (LINAC) and 3 noncoplanar treatment plans for robotic arm LINAC were generated. All plans were suitable for clinical applications with minor deviations from study guidelines in most centers. Eleven of 18 treatment plans showed maximal one minor deviation each for target and cardiac substructures. However, dose-volume histograms showed substantial differences: in one case, the planning target volume ≥30 Gy ranged from 0.0% to 79.9% and the ramus interventricularis anterior V14Gy ranged from 4.0% to 45.4%. Overall, the VMAT plans had steeper dose gradients in the high-dose region, while the plans for the robotic arm LINAC had smaller low-dose regions. Thereby, VMAT plans required only about half as many monitor units, resulting in shorter delivery times, possibly an important factor in treatment outcome. CONCLUSIONS: Cardiac radioablation is feasible with robotic arm and C-arm LINAC systems with comparable plan quality. Although cross-center training and best practice guidelines have been provided, further recommendations, especially for cardiac substructures, and ranking of dose guidelines will be helpful to optimize cardiac radioablation outcomes.

Planning Benchmark Study for Stereotactic Body Radiation Therapy of Liver Metastases: Results of the DEGRO/DGMP Working Group on Stereotactic Radiation Therapy and Radiosurgery.

PURPOSE: Our purpose was to investigate whether liver stereotactic body radiation therapy treatment planning can be harmonized across different treatment planning systems, delivery techniques, and institutions by using a specific prescription method and to minimize the knowledge gap concerning intersystem and interuser differences. We provide best practice guidelines for all used techniques. METHODS AND MATERIALS: A multiparametric specification of target dose (gross target volume [GTV]D50%, GTVD0.1cc, GTVV90%, planning target volume [PTV]V70%) with a prescription dose of GTVD50% = 3 × 20 Gy and organ-at-risk (OAR) limits were distributed with computed tomography and structure sets from 3 patients with liver metastases. Thirty-five institutions provided 132 treatment plans using different irradiation techniques. These plans were first analyzed for target and OAR doses. Four different renormalization methods were performed (PTVDmin, PTVD98%, PTVD2%, PTVDmax). The resulting 660 treatments plans were evaluated regarding target doses to study the effect of dose renormalization to different prescription methods. A relative scoring system was used for comparisons. RESULTS: GTVD50% prescription can be performed in all systems. Treatment plan harmonization was overall successful, with standard deviations for Dmax, PTVD98%, GTVD98%, and PTVDmean of 1.6, 3.3, 1.9, and 1.5 Gy, respectively. Primary analysis showed 55 major deviations from clinical goals in 132 plans, whereas in only <20% of deviations GTV/PTV dose was traded for meeting OAR limits. GTVD50% prescription produced the smallest deviation from target planning objectives and between techniques, followed by the PTVDmax, PTVD98%, PTVD2%, and PTVDmin prescription. Deviations were significant for all combinations but for the PTVDmax prescription compared with GTVD50% and PTVD98%. Based on the various dose prescription methods, all systems significantly differed from each other, whereas GTVD50% and PTVD98% prescription showed the least difference between the systems. CONCLUSIONS: This study showed the feasibility of harmonizing liver stereotactic body radiation therapy treatment plans across different treatment planning systems and delivery techniques when a sufficient set of clinical goals is given.

A novel lateral disequilibrium inclusive (LDI) pencil-beam based dose calculation algorithm: evaluation in inhomogeneous phantoms and comparison with Monte Carlo calculations.

PURPOSE: Pencil-beam (PB) based dose calculation for treatment planning is limited by inaccuracies in regions of tissue inhomogeneities, particularly in situations with lateral electron disequilibrium as is present at tissue/lung interfaces. To overcome these limitations, a new "lateral disequilibrium inclusive" (LDI) PB based calculation algorithm was introduced. In this study, the authors evaluated the accuracy of the new model by film and ionization chamber measurements and Monte Carlo simulations. METHODS: To validate the performance of the new LDI algorithm implemented in Corvus 09, eight test plans were generated on inhomogeneous thorax and pelvis phantoms. In addition, three plans were calculated with a simple effective path length (EPL) algorithm on the inhomogeneous thorax phantom. To simulate homogeneous tissues, four test plans were evaluated in homogeneous phantoms (homogeneous dose calculation). RESULTS: The mean pixel pass rates and standard deviations of the gamma 4%/4 mm test for the film measurements were (96 +/- 3)% for the plans calculated with LDI, (70 +/- 5)% for the plans calculated with EPL, and (99 +/- 1)% for the homogeneous plans. Ionization chamber measurements and Monte Carlo simulations confirmed the high accuracy of the new algorithm (dose deviations < or = 4%; gamma 3%/3 mm > or = 96%). CONCLUSIONS: LDI represents an accurate and fast dose calculation algorithm for treatment planning.

Dosimetric benefits of daily treatment plan adaptation for prostate cancer stereotactic body radiotherapy.

BACKGROUND: Hypofractionation is increasingly being applied in radiotherapy for prostate cancer, requiring higher accuracy of daily treatment deliveries than in conventional image-guided radiotherapy (IGRT). Different adaptive radiotherapy (ART) strategies were evaluated with regard to dosimetric benefits. METHODS: Treatments plans for 32 patients were retrospectively generated and analyzed according to the PACE-C trial treatment scheme (40 Gy in 5 fractions). Using a previously trained cycle-generative adversarial network algorithm, synthetic CT (sCT) were generated out of five daily cone-beam CT. Dose calculation on sCT was performed for four different adaptation approaches: IGRT without adaptation, adaptation via segment aperture morphing (SAM) and segment weight optimization (ART1) or additional shape optimization (ART2) as well as a full re-optimization (ART3). Dose distributions were evaluated regarding dose-volume parameters and a penalty score. RESULTS: Compared to the IGRT approach, the ART1, ART2 and ART3 approaches substantially reduced the V37Gy(bladder) and V36Gy(rectum) from a mean of 7.4cm3 and 2.0cm3 to (5.9cm3, 6.1cm3, 5.2cm3) as well as to (1.4cm3, 1.4cm3, 1.0cm3), respectively. Plan adaptation required on average 2.6 min for the ART1 approach and yielded doses to the rectum being insignificantly different from the ART2 approach. Based on an accumulation over the total patient collective, a penalty score revealed dosimetric violations reduced by 79.2%, 75.7% and 93.2% through adaptation. CONCLUSION: Treatment plan adaptation was demonstrated to adequately restore relevant dose criteria on a daily basis. While for SAM adaptation approaches dosimetric benefits were realized through ensuring sufficient target coverage, a full re-optimization mainly improved OAR sparing which helps to guide the decision of when to apply which adaptation strategy.