DART-bid for loco-regionally advanced NSCLC : Summary of acute and late toxicity with long-term follow-up; experiences with pulmonary dose constraints.

BACKGROUND: To report acute and late toxicity with long-term follow-up, and to describe our experiences with pulmonary dose constraints. METHODS: Between 2002 and 2009, 150 patients with 155 histologically/cytologically proven non-small cell lung cancer (NSCLC; tumor stages II, IIIA, IIIB in 6, 55 and 39%, respectively) received the following median doses: primary tumors 79.2 Gy (range 72.0-90.0 Gy), lymph node metastases 59.4 Gy (54.0-73.8 Gy), nodes electively 45 Gy; with fractional doses of 1.8 Gy twice daily (bid). In all, 86% of patients received 2 cycles of chemotherapy previously. RESULTS: Five treatment-related deaths occurred: pneumonitis, n = 1; progressive pulmonary fibrosis in patients with pre-existing pulmonary fibrosis, n = 2; haemorrhage, n = 2. In all, 8% of patients experienced grade 3 and 1.3% grade 4 pneumonitis; 11% showed late fibrotic alterations grade 2 in lung parenchyma. Clinically relevant acute esophagitis (grade 2 and 3) was seen in 33.3% of patients, 2 patients developed late esophageal stenosis (G3). Patients with upper lobe, middle lobe and central lower lobe tumours (n = 130) were treated with V20 (total lung) up to 50% and patients with peripheral lower lobe tumours (n = 14, basal lateral tumours excluded) up to 42%, without observing acute or late pulmonary toxicity >grade 3. Only patients with basal lateral lower lobe tumours (n = 5) experienced grade 4/5 pulmonary toxicity; V20 for this latter group ranged between 30 and 53%. The mean lung dose was below the QUANTEC recommendation of 20-23 Gy in all patients. The median follow-up time of all patients is 26.3 months (range 2.9-149.4) and of patients alive 80.2 months (range 63.9-149.4.). The median overall survival time of all patients is 26.3 months; the 2-, 5- and 8­year survival rates of 54, 21 and 15%, respectively. The local tumour control rate at 2 and 5 years is 70 and 64%, the regional control rate 90 and 88%, respectively. DISCUSSION AND CONCLUSION: Grade 4 or 5 toxicity occurred in 7/150 patients (4.7%), which can be partially avoided in the future (e.g. by excluding patients with pre-existing pulmonary fibrosis). Tolerance and oncologic outcome compare favourably to concomitant chemoradiation also in long-term follow-up.

DART-bid: dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily: high local control in early stage (I/II) non-small-cell lung cancer.

BACKGROUND: While surgery is considered standard of care for early stage (I/II), non-small-cell lung cancer (NSCLC), radiotherapy is a widely accepted alternative for medically unfit patients or those who refuse surgery. International guidelines recommend several treatment options, comprising stereotactic body radiation therapy (SBRT) for small tumors, conventional radiotherapy ≥ 60 Gy for larger sized especially centrally located lesions or continuous hyperfractionated accelerated RT (CHART). This study presents clinical outcome and toxicity for patients treated with a dose-differentiated accelerated schedule using 1.8 Gy bid (DART-bid). PATIENTS AND METHODS: Between April 2002 and December 2010, 54 patients (median age 71 years, median Karnofsky performance score 70%) were treated for early stage NSCLC. Total doses were applied according to tumor diameter: 73.8 Gy for < 2.5 cm, 79.2 Gy for 2.5-4.5 cm, 84.6 Gy for 4.5-6 cm, 90 Gy for > 6 cm. RESULTS: The median follow-up was 28.5 months (range 2-108 months); actuarial local control (LC) at 2 and 3 years was 88%, while regional control was 100%. There were 10 patients (19%) who died of the tumor, and 18 patients (33%) died due to cardiovascular or pulmonary causes. A total of 11 patients (20%) died intercurrently without evidence of progression or treatment-related toxicity at the last follow-up, while 15 patients (28%) are alive. Acute esophagitis ≤ grade 2 occurred in 7 cases, 2 patients developed grade 2 chronic pulmonary fibrosis. CONCLUSION: DART-bid yields high LC without significant toxicity. For centrally located and/or large (> 5 cm) early stage tumors, where SBRT is not feasible, this method might serve as radiotherapeutic alternative to present treatment recommendations, with the need of confirmation in larger cohorts.

Investigating focal spot position drift in a mobile imaging system equipped with a monobloc-based x-ray generator.

BACKGROUND: Misalignment or double-contouring artifacts can appear in high-resolution 3D cone beam computed tomography (CBCT) images, potentially indicating geometric accuracy issues in the projection data. Such artifacts may go unnoticed in low-resolution images and could be associated with changes in the focal spot (FS) position. PURPOSE: High-resolution 3D-CBCT imaging by a mobile imaging device with a large gantry clearance offers more versatility for clinical workflows in image-guided brachytherapy (IGBT), intraoperative radiation therapy (IORT), and spinal, as well as maxillofacial surgery. However, misalignment or double-contouring artifacts hinder workflow advancements in these domains. This paper introduces intrinsic calibration and geometrical correction methods as extensions to a well-established technique for addressing geometrical deviations resulting from factors such as gravity or mechanical inconsistencies. These extensions cover shifts and drifts of the FS depending on FS size selection, temperature, tube current, and tube potential. The proposed methods effectively mitigate artifacts in high-resolution CBCT images stemming from geometrical inaccuracies in projection data, without requiring additional equipment like a pinhole device. METHODS: Geometrical offsets and drifts of the x-ray tube FS were characterized on a mobile multi-purpose imaging system, the ImagingRing-m. A pinhole-like experiment was simulated by adjusting the movable collimation unit to a small rectangular aperture within the FS size range. The influence of filament selection, that is, FS size, temperature, the relatively low tube currents, as well as tube potential settings have been studied on two different monobloc types sharing the same x-ray tube insert. The Catphan 504 and an Alderson head phantom were used to assess resulting image artifacts. RESULTS: Switching the FS size to one different from what was used for geometrical (gravitation, mechanical variations) calibration induced the most notable position changes of the x-ray FS, resulting in double-contouring artifacts and blurring of high-resolution 3D-CBCT images. Incorporating these shifts into a geometrical correction method effectively minimized these artifacts. Thermal drifts exhibited the second largest geometrical changes, comparable to FS size shifts across the thermal operating conditions of the x-ray system. The proposed thermal drift compensation markedly reduced thermal drift effects. Tube current and potential had little impact within the range of available tube currents, eliminating the need for compensation in current applications. CONCLUSIONS: Augmenting the geometrical calibration pipeline with proposed FS drift compensations yielded significant enhancements in image quality for high-resolution reconstructions. While compensation for thermal effects posed challenges, it proved achievable. The roles of tube current and potential were found to be negligible.

Non-small cell lung cancer in stages I-IIIB: Long-term results of definitive radiotherapy with doses ≥ 80 Gy in standard fractionation.

PURPOSE: To investigate therapeutic outcome of dose escalation ≥ 80 Gy in nonresected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 124 consecutive patients with histologically/cytologically proven NSCLC were enrolled. Tumor stage I, II, IIIA, and IIIB was diagnosed in 30, eight, 39, and 47 patients, respectively. 38 patients (31%) had weight loss > 5% during the 3 months before diagnosis. A median dose of 88.2 Gy (range 80.0-96.0 Gy), 69.3 Gy (63.0-88.0 Gy) and 56.7 Gy was applied to primary lesions, involved lymph nodes, and elective nodes (within a region of about 6 cm cranial to macroscopically involved nodes), respectively. Daily fractional ICRU doses of 2.0-2.2 Gy were delivered by the conformal target-splitting technique. 58 patients (47%) received induction chemotherapy, in median two cycles prior to radiotherapy. RESULTS: Median follow-up time of all patients was 19 months, of patients alive 72.4 months (69-121 months). The cumulative actual overall survival rate at 2 and 5 years amounts to 39% and 11.3%, respectively, resulting in a median overall survival time of 19.6 months. According to stages I, II, IIIA, and IIIB, the median overall survival times are 31.8, 31.4, 19.0, and 14.5 months, respectively. The locoregional tumor control rate at 2 years is 49%. Apart from one treatment-related death (pneumonitis), acute toxicity according to EORTC/RTOG scores was moderate: lung grade 2 (n = 7), grade 3 (n = 3); esophagus grade 1 (n = 11); heart grade 3 (n = 1, pericarditis). No late toxicity grade > 1 has been observed. CONCLUSION: Sequential, conventionally fractionated high-dose radiotherapy by conformal target splitting is well tolerated. The results for survival and locoregional tumor control seem to at least equalize the outcome of simultaneous chemoradiation approaches, which, at present, are considered "state of the art" for patients with nonresected NSCLC. A higher potential of radiation therapy might be reached by accelerated fractionation regimens.

Modelling of the focal spot intensity distribution and the off-focal spot radiation in kilovoltage x-ray tubes for imaging.

X-ray tubes for medical applications typically generate x-rays by accelerating electrons, emitted from a cathode, with an interelectrode electric field, towards an anode target. X-rays are not emitted from one point, but from an irregularly shaped area on the anode, the focal spot. Focal spot intensity distributions and off-focal radiation negatively affect the imaging spatial resolution and broadens the beam penumbra. In this study, a Monte Carlo simulation model of an x-ray tube was developed to evaluate the spectral and spatial characteristics of off-focal radiation for multiple photon energies. Slit camera measurements were used to determine the horizontal and vertical intensity profiles of the small and the large focal spot of a diagnostic x-ray tube. First, electron beamlet weighting factors were obtained via an iterative optimization method to represent both focal spot sizes. These weighting factors were then used to extract off-focal spot radiation characteristics for the small and large focal spot sizes at 80, 100, and 120 kV. Finally, 120 kV simulations of a steel sphere (d = 4 mm) were performed to investigate image blurring with a point source, the small focal spot, and the large focal spot. The magnitude of off-focal radiation strongly depends on the anode size and the electric field coverage, and only minimally on the tube potential and the primary focal spot size. In conclusion, an x-ray tube Monte Carlo simulation model was developed to simulate focal spot intensity distributions and to evaluate off-focal radiation characteristics at several energies. This model can be further employed to investigate focal spot correction methods and to improve cone-beam CT image quality.

A Monte Carlo based scatter removal method for non-isocentric cone-beam CT acquisitions using a deep convolutional autoencoder.

The primary cone-beam computed tomography (CBCT) imaging beam scatters inside the patient and produces a contaminating photon fluence that is registered by the detector. Scattered photons cause artifacts in the image reconstruction, and are partially responsible for the inferior image quality compared to diagnostic fan-beam CT. In this work, a deep convolutional autoencoder (DCAE) and projection-based scatter removal algorithm were constructed for the ImagingRingTM system on rails (IRr), which allows for non-isocentric acquisitions around virtual rotation centers with its independently rotatable source and detector arms. A Monte Carlo model was developed to simulate (i) a non-isocentric training dataset of ≈1200 projection pairs (primary + scatter) from 27 digital head-and-neck cancer patients around five different virtual rotation centers (DCAENONISO), and (ii) an isocentric dataset existing of ≈1200 projection pairs around the physical rotation center (DCAEISO). The scatter removal performance of both DCAE networks was investigated in two digital anthropomorphic phantom simulations and due to superior performance only the DCAENONISO was applied on eight real patient acquisitions. Measures for the quantitative error, the signal-to-noise ratio, and the similarity were evaluated for two simulated digital head-and-neck patients, and the contrast-to-noise ratio (CNR) was investigated between muscle and adipose tissue in the real patient image reconstructions. Image quality metrics were compared between the uncorrected data, the currently implemented heuristic scatter correction data, and the DCAE corrected image reconstruction. The DCAENONISO corrected image reconstructions of two digital patient simulations showed superior image quality metrics compared to the uncorrected and corrected image reconstructions using a heuristic scatter removal. The proposed DCAENONISO scatter correction in this study was successfully demonstrated in real non-isocentric patient CBCT acquisitions and achieved statistically significant higher CNRs compared to the uncorrected or the heuristic corrected image data. This paper presents for the first time a projection-based scatter removal algorithm for isocentric and non-isocentric CBCT imaging using a deep convolutional autoencoder trained on Monte Carlo composed datasets. The algorithm was successfully applied to real patient data.

"Augmented reality" in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

BACKGROUND AND PURPOSE: In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time. PATIENTS AND METHODS: Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters. RESULTS: Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66). CONCLUSION: The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.

Cerebral cortex dose sparing for glioblastoma patients: IMRT versus robust treatment planning.

BACKGROUND: To date, patients with glioblastoma still have a bad median overall survival rate despite radiation dose-escalation and combined modality treatment. Neurocognitive decline is a crucial adverse event which may be linked to high doses to the cortex. In a planning study, we investigated the impact of dose constraints to the cerebral cortex and its relation to the organs at risk for glioblastoma patients. METHODS: Cortical sparing was implemented into the optimization process for two planning approaches: classical intensity-modulated radiotherapy (IMRT) and robust treatment planning. The plans with and without objectives for cortex sparing where compared based on dose-volume histograms (DVH) data of the main organs at risk. Additionally the cortex volume above a critical threshold of 28.6 Gy was elaborated. Furthermore, IMRT plans were compared with robust treatment plans regarding potential cortex sparing. RESULTS: Cortical dose constraints result in a statistically significant reduced cerebral cortex volume above 28.6 Gy without negative effects to the surrounding organs at risk independently of the optimization technique. For IMRT we found a mean volume reduction of doses beyond the threshold of 19%, and 16% for robust treatment planning, respectively. Robust plans delivered sharper dose gradients around the target volume in an order of 3 - 6%. Aside from that the integration of cortical sparing into the optimization process has the potential to reduce the dose around the target volume (4 - 8%). CONCLUSIONS: We were able to show that dose to the cerebral cortex can be significantly reduced both with robust treatment planning and IMRT while maintaining clinically adequate target coverage and without corrupting any organ at risk. Robust treatment plans delivered more conformal plans compared to IMRT and were superior in regards to cortical sparing.

The technological basis for adaptive ion beam therapy at MedAustron: Status and outlook.

The ratio of patients who need a treatment adaptation due to anatomical variations at least once during the treatment course is significantly higher in light ion beam therapy (LIBT) than in photon therapy. The ballistic behaviour of ion beams makes them more sensitive to changes. Hence, the delivery of LIBT has always been supported by state of art image guidance. On the contrary CBCT technology was adapted for LIBT quite late. Adaptive concepts are being implemented more frequently in photon therapy and also efficient workflows are needed for LIBT. The MedAustron Ion Beam Therapy Centre was designed to allow the clinical implementation of adaptive image-guided concepts. The aim of this paper is to describe the current status and the potential future use of the technology installed at MedAustron. Specifically addressed is the beam delivery system, the patient alignment system, the treatment planning system as well as the Record & Verify system. Finally, an outlook is given on how high quality X-ray imaging, MR image guidance, fast and automated treatment planning as well as in vivo range verification methods could be integrated.

Nine-degrees-of-freedom flexmap for a cone-beam computed tomography imaging device with independently movable source and detector.

PURPOSE: Couch-mounted cone-beam computed tomography (CBCT) imaging devices with independently rotatable x-ray source and flat-panel detector arms for acquisitions of arbitrary regions of interest (ROI) have recently been introduced in image-guided radiotherapy (IGRT). This work analyzes mechanical limitations and gravity-induced effects influencing the geometric accuracy of images acquired with arbitrary angular constellations of source and detector in nonisocentric trajectories, which is considered essential for IGRT. In order to compensate for geometric inaccuracies of this modality, a 9-degrees-of-freedom (9-DOF) flexmap correction approach is presented, focusing especially on the separability of the flexmap parameters of the independently movable components of the device. METHODS: The 9-DOF comprise a 3D translation of the x-ray source focal spot, a 3D translation of the flat-panel's active area center and three Euler-rotations of the detector's row and column vectors. The flexmap parameters are expressed with respect to the angular position of each of the devices arms. Estimation of the parameters is performed, using a CT-based structure set of a table-mounted, cylindrical ball-bearing phantom. Digitally reconstructed radiograph (DRR) patches are derived from the structure set followed by local 2D in-plane registration and subsequent 3D transform estimation by nonlinear regression with outlier detection. RESULTS: Flexmap parameter evaluations for the factory-calibrated system in clockwise and counter-clockwise rotation direction have shown only minor differences for the overall set of flexmap parameters. High short-term reproducibility of the flexmap parameters has been confirmed by experiments over 10 acquisitions for both directions, resulting in standard deviation values of ≤0.183 mm for translational components and ≤0.0219 deg for rotational components, respectively. A comparison of isocentric and nonisocentric flexmap evaluations showed that the mean differences of the parameter curves reside within their standard deviations, confirming the ability of the proposed calibration method to handle both types of trajectories equally well. Reconstructions of 0.1 mm and 0.25 mm steel wires showed similar results for the isocentric and nonisocentric cases. The full-width at half maximum (FWHM) measure indicates an average improvement of the calibrated reconstruction of 85% over the uncalibrated reconstruction. The contrast of the point spread function (PSF) improved by 310% on average over all experiments. Moreover, a reduced amount of artifacts visible in nonisocentric reconstructions of a head phantom and a line-pair phantom has been achieved by separate application of the 9-DOF flexmap on the geometry described by the independently moving source arm and detector arm. CONCLUSIONS: Using a 9-DOF flexmap approach for correcting the geometry of projections acquired with a device capable of independent movements of the source and panel arms has been shown to be essential for IGRT use cases such as CBCT reconstruction and 2D/3D registration tasks. The proposed pipeline is able to create flexmap curves which are easy to interpret, useful for mechanical description of the device and repetitive quality assurance as well as system-level preventive maintenance. Application of the flexmap has shown improvements of image quality for planar imaging and volumetric imaging which is crucial for patient alignment accuracy.

Intraoperative radiotherapy (IORT) as boost in breast cancer.

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show huge differences in dose delivery and coverage of the tissue at risk. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments (IOERT) with single doses around 10 Gy. At median follow-up periods at 6 years, outstandingly low local recurrence rates of less than 1% are observed. Higher local relapse rates were described for G3 tumors and triple negative breast cancers as well as for IORT following primary systemic treatment for locally advanced tumors. Even there, long term (>5y) local tumor control rates mostly beyond 95% were maintained. Compared to other boost methods, an intraoperative treatment has evident advantages in terms of precision (by avoiding a "spatial and/or temporal miss"), cosmetic outcome and patient comfort. Direct visualisation of a tumor bed during surgery guarantees for an accurate dose delivery, which has additionally gained importance in times of primary reconstruction techniques after lumpectomy, since IORT is performed before breast tissue including parts of the tumor bed is mobilized for plastic purposes. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with external beam radiotherapy to the whole breast (WBI) is currently tested in two multicentric prospective trials: as kV-IORT in the multicentric TARGIT-B (oost) study, and as IOERT in the HIOB trial (3 weeks hypofractionated WBI preceded by IORT electron boost).

A dosimetric comparison of IORT techniques in limited-stage breast cancer.

BACKGROUND AND PURPOSE: For intraoperative radiotherapy (IORT) during breast-conserving treatment four different techniques have been addressed: interstitial brachytherapy, an inflatable balloon with a central high-dose-rate source (MammoSite), a miniature orthovolt system (Intrabeam), and linac-based electron radiotherapy (IOERT). The dosimetric properties of these methods are compared. MATERIAL AND METHODS: Planning target volumes (PTVs) of the same size but of different shapes are assumed, corresponding to the technique's specific situs. Dose distributions for the PTVs and for surrounding tissues are demonstrated by dose-volume histograms and a list of physical parameters. A dose inhomogeneity index (DII) is introduced to describe the deviation of a delivered from the prescribed dose, reaching its minimal value 0 in case of perfect homogeneity. RESULTS: In terms of DII, IOERT reaches the lowest value followed by the MammoSite, the Intrabeam and interstitial implants. The surrounding tissues receive the smallest average dose with IOERT, closely followed by the orthovolt system. CONCLUSION: When comparing simplified geometric figures, IOERT delivers the most homogeneous dose distributions. However, in clinical reality PTVs often present asymmetric shapes instead of ideal geometries. Due to a strictly centric dose fall-off, any system with a round central applicator will have technical limits. During IOERT margin-directed applicator guidance is possible and interstitial brachytherapy allows for polygonal dose shaping. These techniques seem to be superior for asymmetric PTV irradiation.

Hsa-miR-375 is a predictor of local control in early stage breast cancer.

BACKGROUND: A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer. RESULTS: Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value = 0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p = 0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value = 0.000195 HR = 0.76, 95 % CI 0.66-0.88; corrected p value = 0.005). CONCLUSIONS: Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor α (ER-α)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted.

Technical Note: Procedure for the calibration and validation of kilo-voltage cone-beam CT models.

PURPOSE: The aim of this work is to propose a general and simple procedure for the calibration and validation of kilo-voltage cone-beam CT (kV CBCT) models against experimental data. METHODS: The calibration and validation of the CT model is a two-step procedure: the source model then the detector model. The source is described by the direction dependent photon energy spectrum at each voltage while the detector is described by the pixel intensity value as a function of the direction and the energy of incident photons. The measurements for the source consist of a series of dose measurements in air performed at each voltage with varying filter thicknesses and materials in front of the x-ray tube. The measurements for the detector are acquisitions of projection images using the same filters and several tube voltages. The proposed procedure has been applied to calibrate and assess the accuracy of simple models of the source and the detector of three commercial kV CBCT units. If the CBCT system models had been calibrated differently, the current procedure would have been exclusively used to validate the models. Several high-purity attenuation filters of aluminum, copper, and silver combined with a dosimeter which is sensitive to the range of voltages of interest were used. A sensitivity analysis of the model has also been conducted for each parameter of the source and the detector models. RESULTS: Average deviations between experimental and theoretical dose values are below 1.5% after calibration for the three x-ray sources. The predicted energy deposited in the detector agrees with experimental data within 4% for all imaging systems. CONCLUSIONS: The authors developed and applied an experimental procedure to calibrate and validate any model of the source and the detector of a CBCT unit. The present protocol has been successfully applied to three x-ray imaging systems. The minimum requirements in terms of material and equipment would make its implementation suitable in most clinical environments.

Radiotherapy planning for lung cancer: slow CTs allow the drawing of tighter margins.

BACKGROUND AND PURPOSE: Evaluation of the use of planning CTs with slow revolution time (4s/slice; 'slow CTs') in the planning procedure of radiotherapy for lung cancer patients in comparison to commonly used 'fast' planning CTs; impact on margin assessment of planning target volume (PTV) design. PATIENTS AND METHODS: Eighteen lung cancer patients (six upper, lower lobe and central tumors, respectively) have been scanned each by three series of slow CTs and one fast CT (spiral CT). Patients have been freely breathing. The largest transversal tumor diameters in slow and fast CTs have been measured. Tumor edge positions have been determined for six spatial directions in all slices of the three slow CT series. RESULTS: Slow CTs show larger dimensions of the visible tumor than fast CTs. The median difference of the diameter for all tumors is 2mm (range 0-4mm). Slow CTs deliver constant depictions of lung tumors within a range of 1.6mm in all directions. This margin is considered to be sufficient to compensate for tumor movements by respiration and cardiovascular motions (internal margin). A margin of 7 mm added to the GTV of a single slow CT series to draw the PTV is proposed. CONCLUSIONS: Slow planning CTs show larger, but highly constant depictions of lung tumors in comparison to conventional fast CT scanning, yielding an integral delineation of almost all positions of the moving tumors. Thus the use of slow planning CTs enables the drawing of tighter margins in external beam treatment planning of lung cancer.

Comparison of two different rectal spacers in prostate cancer external beam radiotherapy in terms of rectal sparing and volume consistency.

BACKGROUND AND PURPOSE: In external beam radiation (EBRT) of the prostate, the rectum is the dose-limiting organ at risk, and sparing of the anterior rectal wall is a prerequisite for safe delivery of doses beyond 70 Gy. Spatial sparing of the rectum can be achieved by introducing a spacer material into the retroprostatic space, thus separating the anterior rectal wall from the PTV. MATERIALS AND METHODS: Two spacer technologies, Spacer OAR, a polyethylene glycol gel and ProSpace, a saline inflated balloon, were compared in terms of spacer volume, stability, and dose reduction to the anterior rectum wall in 78 patients. RESULTS: Both spacer systems significantly reduced the rectum surface encompassed by the 95% isodose (gel: -35%, p<0.01; balloon -63.4%, p<0.001) compared to a control group. The balloon spacer was superior in reducing rectum dose (-27.7%, p=0.034), but exhibited an average volume loss of >50% during the full course of treatment of 37-40 fractions, while the volume of gel spacers remained fairly constant. CONCLUSIONS: In choosing between the two spacer technologies, the advantageous dose reduction of the balloon needs to be weighed up against the better volume consistency of the gel spacer with respect to the duration of hypofractionated vs normofractionated regimens.

Normal tissue complication models for clinically relevant acute esophagitis (≥ grade 2) in patients treated with dose differentiated accelerated radiotherapy (DART-bid).

BACKGROUND: One of the primary dose-limiting toxicities during thoracic irradiation is acute esophagitis (AE). The aim of this study is to investigate dosimetric and clinical predictors for AE grade ≥ 2 in patients treated with accelerated radiotherapy for locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 66 NSCLC patients were included in the present analysis: 4 stage II, 44 stage IIIA and 18 stage IIIB. All patients received induction chemotherapy followed by dose differentiated accelerated radiotherapy (DART-bid). Depending on size (mean of three perpendicular diameters) tumors were binned in four dose groups: <2.5 cm 73.8 Gy, 2.5-4.5 cm 79.2 Gy, 4.5-6 cm 84.6 Gy, >6 cm 90 Gy. Patients were treated in 3D target splitting technique. In order to estimate the normal tissue complication probability (NTCP), two Lyman models and the cutoff-logistic regression model were fitted to the data with AE ≥ grade 2 as statistical endpoint. Inter-model comparison was performed with the corrected Akaike information criterion (AICc), which calculates the model's quality of fit (likelihood value) in relation to its complexity (i.e. number of variables in the model) corrected by the number of patients in the dataset. Toxicity was documented prospectively according to RTOG. RESULTS: The median follow up was 686 days (range 84-2921 days), 23/66 patients (35 %) experienced AE ≥ grade 2. The actuarial local control rates were 72.6 % and 59.4 % at 2 and 3 years, regional control was 91 % at both time points. The Lyman-MED model (D50 = 32.8 Gy, m = 0.48) and the cutoff dose model (Dc = 38 Gy) provide the most efficient fit to the current dataset. On multivariate analysis V38 (volume of the esophagus that receives 38 Gy or above, 95 %-CI 28.2-57.3) was the most significant predictor of AE ≥ grade 2 (HR = 1.05, CI 1.01-1.09, p = 0.007). CONCLUSION: Following high-dose accelerated radiotherapy the rate of AE ≥ grade 2 is slightly lower than reported for concomitant radio-chemotherapy with the additional benefit of markedly increased loco-regional tumor control. In the current patient cohort the most significant predictor of AE was found to be V38. A second clinically useful parameter in treatment planning may be MED (mean esophageal dose).

Boost IORT in Breast Cancer: Body of Evidence.

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show decisive differences in dose delivery. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments with single doses around 10 Gy, providing outstandingly low local recurrence rates in any risk constellation also at long term analyses. Compared to other boost methods, an intraoperative treatment has evident advantages as follows. Precision. Direct visualisation of the tumour bed during surgery guarantees an accurate dose delivery. This fact has additionally gained importance in times of primary reconstruction techniques after lumpectomy to optimise cosmetic outcome. IORT is performed before breast tissue is mobilised for plastic purposes. Cosmesis. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Patient Comfort. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with a 3-week hypofractionated external beam radiotherapy to the whole breast (WBI) is presently tested in the HIOB trial (hypofractionated WBI preceded by IORT electron boost), a prospective multicenter trial of the International Society of Intraoperative Radiotherapy (ISIORT).

Analysis of a free-running synchronization artifact correction for MV-imaging with aSi:H flat panels.

PURPOSE: Solid state flat panel electronic portal imaging devices (EPIDs) are widely used for megavolt (MV) photon imaging applications in radiotherapy. In addition to their original purpose in patient position verification, they are convenient to use in quality assurance and dosimetry to verify beam geometry and dose deposition or to perform linear accelerator (linac) calibration procedures. However, native image frames from amorphous silicon (aSi:H) detectors show a range of artifacts which have to be eliminated by proper correction algorithms. When a panel is operated in free-running frame acquisition mode, moving vertical stripes (periodic synchronization artifacts) are a disturbing feature in image frames. Especially for applications in volumetric intensity modulated arc therapy (VMAT) or motion tracking, the synchronization (sync) artifacts are the limiting factor for potential and accuracy since they become even worse at higher frame rates and at lower dose rates, i.e., linac pulse repetition frequencies (PRFs). METHODS: The authors introduced a synchronization correction method which is based on a theoretical model describing the interferences of the panel's readout clocking with the linac's dose pulsing. Depending on the applied PRF, a certain number of dose pulses is captured per frame which is readout columnwise, sequentially. The interference of the PRF with the panel readout is responsible for the period and the different gray value levels of the sync stripes, which can be calculated analytically. Sync artifacts can then be eliminated multiplicatively in precorrected frames without additional information about radiation pulse timing. RESULTS: For the analysis, three aSi:H EPIDs of various types were investigated with 6 and 15 MV photon beams at varying PRFs of 25, 50, 100, 200, and 400 pulses per second. Applying the sync correction at panels with gadolinium oxysulfide scintillators improved single frame flood field image quality drastically [improvement of the signal-to-noise ratio (SNR) up to 66.1 dB for 6 MV and 66.0 dB for 15 MV]. Also for the EPID with a caesium iodide scintillator, the noise for the lower PRFs could be reduced (SNR at 6 MV of up to 56.3 dB and at 15 MV up to 46.7 dB). However, the simplistic readout interference model fails at higher PRFs, where image lag and ghosting effects due to trapped charges in the thin film transistor and scintillator postglowing require additional corrections. CONCLUSIONS: The presented free-running sync correction method improves SNR of single frames and enables imaging applications, like low-dose rate imaging at increased image frame rates (e.g., to track moving gold fiducials in the lung). Adaptive image guided radiotherapy protocols become even feasible in VMAT plans. Also simultaneous kilovolt and MV imaging applications can benefit from new possibilities of MV scatter removal in x-ray images.

DART-bid (Dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily)--a novel approach for non-resected NSCLC: final results of a prospective study, correlating radiation dose to tumor volume.

BACKGROUND: Sequential chemo-radiotherapies with intensive radiation components deliver promising results in non-resected non-small cell lung cancer (NSCLC). In general, radiation doses are determined by dose constraints for normal tissues, not by features relevant for tumor control. DART-bid targets directly the doses required for tumor control, correlating doses to tumor volume in a differentiated mode. MATERIALS/METHODS: Radiation doses to primary tumors were aligned along increasing tumor size within 4 groups (<2.5 cm/2.5-4.5 cm/4.5-6.0 cm/>6.0 cm; mean number of three perpendicular diameters). ICRU-doses of 73.8 Gy/79.2 Gy/84.6 Gy/90.0 Gy, respectively, were applied. Macroscopically involved nodes were treated with a median dose of 59.4 Gy, nodal sites about 6 cm cranial to involved nodes electively with 45 Gy. Fractional doses were 1.8 Gy twice daily (bid).2 cycles chemotherapy were given before radiotherapy.Between 2004 and 2009, 160 not selected patients with 164 histologically/cytologically proven NSCLC were enrolled; Stage I: 38 patients; II: 6 pts.; IIIA: 69 pts.; IIIB: 47 pts. Weight loss >5%/3 months: 38 patients (24%).Primary endpoints are local and regional tumor control rates at 2 years (as >90% of locoregional failures occur within 2 years). Secondary endpoints are survival and toxicity. With a minimum follow-up time of 2 years for patients alive, the final results are presented. RESULTS: 32 local and 10 regional recurrences occurred. The local and regional tumor control rates at 2 years are 77% and 93%, respectively.The median overall survival (OS) time is 28.0 months, the 2- and 5-year OS rates are 57% and 19%, respectively. For stage III patients, median OS amounts to 24.3 months, 2- /5-year OS rates to 51% and 18%, respectively.2 treatment-related deaths (progressive pulmonary fibrosis) occurred in patients with pre-existing pulmonary fibrosis. Further acute and late toxicity was mild. CONCLUSIONS: This novel approach yields a high level of locoregional tumor control and survival times. In general it is well tolerated. In all outcome parameters it seems to compare favourably with simultaneous chemo-radiotherapies, at present considered 'state of the art'; and is additionally amenable for an unselected patient population.