"Primer shot" fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer.

PURPOSE: Radiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC). METHODS: Previously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP). RESULTS: Optimal schedules consistently favored a "primer shot" fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3). CONCLUSION: A validated simulation model clearly supports non-standard "primer shot" fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.

Technical feasibility and clinical evaluation of 4D-MRI guided liver SBRT on the MR-linac.

PURPOSE: Image-guided stereotactic body radiation therapy (SBRT) is an important local treatment for liver metastases. MRI-guidance enables direct tumor visualization, eliminating fiducial marker implantation. The purpose of this study was to test technical feasibility of our 4D-MRI guided liver SBRT workflow. Additionally, intra-fraction target motion and consequent target-coverage were studied. MATERIALS & METHODS: Patients with liver metastases were included in this sub-study of the prospective UMBRELLA-II clinical trial. Patients received mid-position (midP) SBRT. The daily adapt-to-position workflow included localization, verification and intra-fraction tumor midP monitoring using 4D-MRI. Technical feasibility was established based on persistence of the treatment protocol, treatment time ≤1 h, no geographical miss and no unexpected acute toxicity grade >3. All 4D-MRIs were registered to the planning midP-CT and tumor midP and amplitude were calculated. Additionally, delivered target dose was accumulated incorporating the 4D-MRI intra-fraction tumor motion and evaluated with Monte-Carlo error simulations. RESULTS: 20 patients with liver metastases were included and treated with 4D-MRI guided SBRT. Feasibility criteria were met in all-but-one patient. No grade ≥3 acute toxicity was observed. Group mean (M), systematic and random midP-drifts were 2.4 mm, 2.6 mm and 3.1 mm in CC-direction. 4D-MRI tumor CC-amplitudes were reduced compared to the simulation 4D-CT (M = -1.9 mm) and decreased during treatment (M = -1.4 mm). Dose accumulation showed adequate target-coverage on a population level. CONCLUSION: We successfully demonstrated technical feasibility of 4D-MRI guided SBRT in a cohort of 20 patients with liver metastases. However, substantial midposition drifts occurred which stress the need for intra-fraction motion management strategies to further increase the precision of treatment delivery.

The effect of eating on the uptake of PSMA ligands in the salivary glands.

RATIONALE: PSMA-directed therapy for metastatic prostate cancer is gaining adoption as a treatment option. However, accumulation of 177Lu/225Ac-PSMA in the salivary glands remains a problem, with risk of dose-limiting xerostomia and potentially severe effect on the quality of life. Gustatory stimulation is an approach that has commonly been used in radioactive iodine therapy to reduce accumulation in the salivary glands. However, based on theoretical differences in biodistribution, it was hypothesized that this could potentially lead to adverse increased toxicity for PSMA-ligand therapy. The primary objective of this work was to determine if gustatory stimulation by eating an assortment of sweet/fatty/acidic foods during the biodistribution phase of [18F]DCFPyl could result in a clinically relevant (> 30%) change in the uptake of the tracer in the salivary glands. METHODS: 10 patients who already received a whole-body [18F]DCFPyl PET/CT scan for evaluation of prostate cancer, underwent a repeat (intervention) PET/CT scan within a month of the first (control) scan. During the intervention scan, patients chose from an assortment of sweet/fatty/acidic foods, which they then chewed and swallowed for a period of time starting 1 min before tracer administration to 10 min thereafter. Data from both scans were analyzed by placing VOIs on the major salivary glands and segmenting them using relative thresholds. RESULTS: A slight increase in PSMA uptake in the parotid glands was observed on the intervention scan when compared to the baseline scan (+ 7.1% SULmean and + 9.2% SULmax, p < 0.05). No significant difference in PSMA uptake in the submandibular glands was seen. CONCLUSIONS: Eating only slightly increases uptake of [18F]DCFPyl in the parotid glands. We nonetheless recommend refraining from gustatory stimulation during the administration and early biodistribution phase of radionuclide therapy with PSMA-ligands to reduce the risk of avoidable additional toxicity.

Muscarinic inhibition of salivary glands with glycopyrronium bromide does not reduce the uptake of PSMA-ligands or radioiodine.

RATIONALE: Salivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium-iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands. METHODS: Ten patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared. RESULTS: No significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46). CONCLUSION: Muscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies.

The increasing potential of nuclear medicine imaging for the evaluation and reduction of normal tissue toxicity from radiation treatments.

Radiation therapy is an effective treatment modality for a variety of cancers. Despite several advances in delivery techniques, its main drawback remains the deposition of dose in normal tissues which can result in toxicity. Common practices of evaluating toxicity, using questionnaires and grading systems, provide little underlying information beyond subjective scores, and this can limit further optimization of treatment strategies. Nuclear medicine imaging techniques can be utilised to directly measure regional baseline function and function loss from internal/external radiation therapy within normal tissues in an in vivo setting with high spatial resolution. This can be correlated with dose delivered by radiotherapy techniques to establish objective dose-effect relationships, and can also be used in the treatment planning step to spare normal tissues more efficiently. Toxicity in radionuclide therapy typically occurs due to undesired off-target uptake in normal tissues. Molecular imaging using diagnostic analogues of therapeutic radionuclides can be used to test various interventional protective strategies that can potentially reduce this normal tissue uptake without compromising tumour uptake. We provide an overview of the existing literature on these applications of nuclear medicine imaging in diverse normal tissue types utilising various tracers, and discuss its future potential.

MRI-guided mid-position liver radiotherapy: Validation of image processing and registration steps.

BACKGROUND & PURPOSE: To propose a novel mid-position (midP) workflow for MRI-guided liver SBRT and provide a validation of the required midP-MRI generation and registration steps. MATERIALS & METHODS: The first step of the midP workflow is the generation of a simulation midP-MRI from a 4D-MRI scan using deformable image registration. Next, a planning midP-CT is warped to the midP-MRI to enable planning in the midP-MRI anatomy. For daily MRI-guidance, three different registration methods to the simulation midP-MRI are proposed; (1) 4D rigid registration of all phases of the daily 4D-MRI, (2) 3D rigid registration of the daily midP-MRI, and (3) 3D deformable registration of the daily midP-MRI. The midP-MRI image quality was assessed with respect to 4D-MRI acquisition time, which is related to over-sampling of the data acquisition (i.e. number of dynamics). The deformable registration precision for the midP-MRI generation was validated using the distance discordance metric (DDM). The deformable CT-MRI and daily MRI-MRI registration accuracies were quantified using the 'full circle method'. RESULTS: The DDM was 1.5 mm (median) within the liver, independent of the number of dynamics. The root-mean-squared difference between midP-MRIs based on 10 and 60 dynamics was only 5.2%. The full circle CT-MRI deformable registration error had a median 3D vector length of 1.8 mm in the liver. The daily MRI-MRI registration error was submillimeter for all three evaluated methods. CONCLUSION: The feasibility of an MRI-guided mid-position workflow for liver SBRT is supported by the demonstrated high precision of all image processing and registration steps.

Micro cone beam computed tomography for sensitive assessment of radiation-induced late lung toxicity in preclinical models.

BACKGROUND AND PURPOSE: Preclinical models are much needed to assess the effect of novel radio-sensitizers or mitigators on radiation dose limiting lung toxicity. Albeit showing radiation-induced lung pathologies, current mouse models lack the sensitivity to do so. Using micro image-guided radiotherapy (µIGRT) techniques, we aimed to establish murine models which enable the sensitive detection of lung damage aggravation and characterized functional, radiological and histological responses. MATERIALS AND METHODS: Right lungs of C57Bl/6J mice were irradiated using µIGRT with doses from 15 to 27 Gy and with 21 Gy and cisplatin as a radio-sensitizer in a second study. Mice were sacrificed for histological and pathological assessment at different time-points post-IR. Lung density was determined using the integrated micro cone-beam CT (µCBCT). Lung function was measured by double-chamber-plethysmography. RESULTS: µIGRT resulted in accurate deposition of the radiation dose in the right lung only as determined by É£H2AX staining. Lung fibrosis was confirmed by pathological assessments and increased significantly at 21 Gy as determined by automated quantification of histochemical analyses. Lung function was affected in a dose-dependent manner. µCBCT-determined lung densities increased significantly over time in the irradiated lungs and showed a strong radiation dose-dependence. Importantly, the µCBCT analyses allowed the detection of additional lung damage caused by 3 Gy dose increments or by the combination with cisplatin. CONCLUSION: µCBCT after right lung µIGRT enables the sensitive detection of effects inflicted by relative small dose increments or radio-sensitizers. Our preclinical model therefore facilitates the determination of lung damage exacerbation for the safety assessment of novel RT-drug combinations.

Impact of setup and range uncertainties on TCP and NTCP following VMAT or IMPT of oropharyngeal cancer patients.

Setup and range uncertainties compromise radiotherapy plan robustness. We introduce a method to evaluate the clinical effect of these uncertainties on the population using tumor control probability (TCP) and normal tissue complication probability (NTCP) models. Eighteen oropharyngeal cancer patients treated with curative intent were retrospectively included. Both photon (VMAT) and proton (IMPT) plans were created using a planning target volume as planning objective. Plans were recalculated for uncertainty scenarios: two for range over/undershoot (IMPT) or CT-density scaling (VMAT), six for shifts. An average shift scenario ([Formula: see text]) was calculated to assess random errors. Dose differences between nominal and scenarios were translated to TCP (2 models) and NTCP (15 models). A weighted average (W_Avg) of the TCP\NTCP based on Gaussian distribution over the variance scenarios was calculated to assess the clinical effect of systematic errors on the population. TCP/NTCP uncertainties were larger in IMPT compared to VMAT. Although individual perturbations showed risks of plan deterioration, the [Formula: see text] scenario did not show a substantial decrease in any of the TCP endpoints suggesting evaluated plans in this cohort were robust for random errors. Evaluation of the W_Avg scenario to assess systematic errors showed in VMAT no substantial decrease in TCP endpoints and in IMPT a limited decrease. In IMPT, the W_Avg scenario had a mean TCP loss of 0%-2% depending on plan type and primary or nodal control. The W_Avg for NTCP endpoints was around 0%, except for mandible necrosis in IMPT (W_Avg: 3%). The estimated population impact of setup and range uncertainties on TCP/NTCP following VMAT or IMPT of oropharyngeal cancer patients was small for both treatment modalities. The use of TCP/NTCP models allows for clinical interpretation of the population effect and could be considered for incorporation in robust evaluation methods. Highlights: - TCP/NTCP models allow for a clinical evaluation of uncertainty scenarios. - For this cohort, in silico-PTV based IMPT plans and VMAT plans were robust for random setup errors. - Effect of systematic errors on the population was limited: mean TCP loss was 0%-2%.

A back-projection algorithm in the presence of an extra attenuating medium: towards EPID dosimetry for the MR-Linac.

In external beam radiotherapy, electronic portal imaging devices (EPIDs) are frequently used for pre-treatment and for in vivo dose verification. Currently, various MR-guided radiotherapy systems are being developed and clinically implemented. Independent dosimetric verification is highly desirable. For this purpose we adapted our EPID-based dose verification system for use with the MR-Linac combination developed by Elekta in cooperation with UMC Utrecht and Philips. In this study we extended our back-projection method to cope with the presence of an extra attenuating medium between the patient and the EPID. Experiments were performed at a conventional linac, using an aluminum mock-up of the MRI scanner housing between the phantom and the EPID. For a 10 cm square field, the attenuation by the mock-up was 72%, while 16% of the remaining EPID signal resulted from scattered radiation. 58 IMRT fields were delivered to a 20 cm slab phantom with and without the mock-up. EPID reconstructed dose distributions were compared to planned dose distributions using the [Formula: see text]-evaluation method (global, 3%, 3 mm). In our adapted back-projection algorithm the averaged [Formula: see text] was [Formula: see text], while in the conventional it was [Formula: see text]. Dose profiles of several square fields reconstructed with our adapted algorithm showed excellent agreement when compared to TPS.

Recurrent oropharyngeal cancer after organ preserving treatment: pattern of failure and survival.

The objectives is to thoroughly analyze the pattern of failure and oncologic outcome in recurrent oropharyngeal cancer (OPC) after (chemo)radiotherapy and correlate the site of failure to the planned radiation dose. Between January 2010 and April 2014, 57 patients with recurrent OPC after (chemo)radiotherapy were analyzed. Endpoints were pattern of failure and overall survival (OS). Local (LF) and regional failure (RF) were classified as in-field [>50% within gross tumor volume (GTV)], marginal [<50% within GTV but >50% within clinical target volume (CTV)], or out-of-field (>50% outside CTV) recurrences. In the whole group, 70 recurrences were reported. Of the 31 LF, 29 (93.5%) were in-field and 2 (6.5%) were marginal. No out-field LF was reported. Of the 21 RF, 13 RF (62%) were in-field, 6 (28.5%) marginal, and 2 (9.5%) out-of-field recurrences. Forty-three percent of RF was developed in an electively treated neck level, and 2 of them were contralateral. OS at 2 years in recurrent HPV positive, compared to HPV-negative OPC, were 66 and 18%, respectively (p = 0.011). OS was also significantly better in patients that were salvage treatment which was possible (70 vs. 6%, p < 0.001). Median survival after distant failure was 3.6 months. The great majority of LFs were located within the GTV and 43% of RFs developed in an electively treated neck level. The currently used margins and dose recipe and the indication for bilateral nodal irradiation need to be reevaluated. OS was significantly better in recurrent HPV-positive OPC and in patients, where salvage treatment was possible.

Radioactive seed localization in breast cancer treatment.

BACKGROUND: Breast cancer screening, improved imaging and neoadjuvant systemic therapy (NST) have led to increased numbers of non-palpable tumours suitable for breast-conserving surgery (BCS). Accurate tumour localization is essential to achieve a complete resection in these patients. This study evaluated the role of radioactive seed localization (RSL) in improving breast- and axilla-conserving surgery in patients with breast cancer with or without NST. METHODS: Patients who underwent RSL between 2007 and 2014 were included. Learning curves were analysed by the rates of minimally involved (in situ/invasive tumour cells on a length of 0-4 mm on ink) and positive resection margins (over 4 mm on ink) after BCS, and the median resection volume over time. RESULTS: A total of 367 patients with in situ carcinomas and 199 with non-palpable invasive breast cancer underwent RSL before primary surgery. A further 697 patients had RSL before NST, of whom 206 also underwent RSL of a histologically verified axillary lymph node metastasis. BCS was performed in 93·2 and 87·9 per cent of patients undergoing primary surgery for in situ and invasive tumours respectively, and 57·5 per cent of those in the NST group. The rate of BCS with positive resection margins was low and stable over time in the three groups (9·1, 9·7 and 11·2 per cent respectively). The median resection volume decreased significantly with time in the invasive cancer and NST groups. CONCLUSION: In the present study of more than 1200 patients and 7 years of experience, RSL was shown to facilitate breast- and axilla-conserving surgery in a diverse patient population. There was a significant reduction in resection volume while maintaining low positive resection margin rates after BCS.

Automatic detection system for multiple region of interest registration to account for posture changes in head and neck radiotherapy.

Despite immobilization of head and neck (H and N) cancer patients, considerable posture changes occur over the course of radiotherapy (RT). To account for the posture changes, we previously implemented a multiple regions of interest (mROIs) registration system tailored to the H and N region for image-guided RT correction strategies. This paper is focused on the automatic segmentation of the ROIs in the H and N region. We developed a fast and robust automatic detection system suitable for an online image-guided application and quantified its performance. The system was developed to segment nine high contrast structures from the planning CT including cervical vertebrae, mandible, hyoid, manubrium of sternum, larynx and occipital bone. It generates nine 3D rectangular-shaped ROIs and informs the user in case of ambiguities. Two observers evaluated the robustness of the segmentation on 188 H and N cancer patients. Bland-Altman analysis was applied to a sub-group of 50 patients to compare the registration results using only the automatically generated ROIs and those manually set by two independent experts. Finally the time performance and workload were evaluated. Automatic detection of individual anatomical ROIs had a success rate of 97%/53% with/without user notifications respectively. Following the notifications, for 38% of the patients one or more structures were manually adjusted. The processing time was on average 5 s. The limits of agreement between the local registrations of manually and automatically set ROIs was comprised between ±1.4 mm, except for the manubrium of sternum (-1.71 mm and 1.67 mm), and were similar to the limits agreement between the two experts. The workload to place the nine ROIs was reduced from 141 s (±20 s) by the manual procedure to 59 s (±17 s) using the automatic method. An efficient detection system to segment multiple ROIs was developed for Cone-Beam CT image-guided applications in the H and N region and is clinically implemented in our department.

Multi-institutional dosimetric and geometric commissioning of image-guided small animal irradiators.

PURPOSE: To compare the dosimetric and geometric properties of a commercial x-ray based image-guided small animal irradiation system, installed at three institutions and to establish a complete and broadly accessible commissioning procedure. METHODS: The system consists of a 225 kVp x-ray tube with fixed field size collimators ranging from 1 to 44 mm equivalent diameter. The x-ray tube is mounted opposite a flat-panel imaging detector, on a C-arm gantry with 360° coplanar rotation. Each institution performed a full commissioning of their system, including half-value layer, absolute dosimetry, relative dosimetry (profiles, percent depth dose, and relative output factors), and characterization of the system geometry and mechanical flex of the x-ray tube and detector. Dosimetric measurements were made using Farmer-type ionization chambers, small volume air and liquid ionization chambers, and radiochromic film. The results between the three institutions were compared. RESULTS: At 225 kVp, with 0.3 mm Cu added filtration, the first half value layer ranged from 0.9 to 1.0 mm Cu. The dose-rate in-air for a 40 × 40 mm(2) field size, at a source-to-axis distance of 30 cm, ranged from 3.5 to 3.9 Gy/min between the three institutions. For field sizes between 2.5 mm diameter and 40 × 40 mm(2), the differences between percent depth dose curves up to depths of 3.5 cm were between 1% and 4% on average, with the maximum difference being 7%. The profiles agreed very well for fields >5 mm diameter. The relative output factors differed by up to 6% for fields larger than 10 mm diameter, but differed by up to 49% for fields ≤5 mm diameter. The mechanical characteristics of the system (source-to-axis and source-to-detector distances) were consistent between all three institutions. There were substantial differences in the flex of each system. CONCLUSIONS: With the exception of the half-value layer, and mechanical properties, there were significant differences between the dosimetric and geometric properties of the three systems. This underscores the need for careful commissioning of each individual system for use in radiobiological experiments.

Validation of deformable registration in head and neck cancer using analysis of variance.

PURPOSE: Deformable image registration (DIR) is often validated based on a distance-to-agreement (DTA) criterion of automatically propagated anatomical landmarks that were manually identified. Due to human observer variability, however, the performance of the registration method is diluted. The purpose of this study was to evaluate an analysis of variance (ANOVA) based validation to account for such observer variation. METHODS: Weekly cone beam CTs (CBCTs) of ten head and neck cancer patients undergoing five weeks of radiotherapy were used. An expert identified 23 anatomical features (landmarks) on the planning CT. The landmarks were automatically propagated to the CBCT using multiregion-of-interest (mROI) registration. Additionally, two human observers independently localized these landmarks on the CBCTs. Subsequently, ANOVA was used to compute the variance of each observer on the pairwise distance (PWD). RESULTS: ANOVA based analysis demonstrated that a classical DTA approach underestimated the precision for the mROI due to human observer variation by about 25%. The systematic error (accuracy) of mROI ranged from 0.13 to 0.17 mm; the variability (1 SD) (precision) ranged from 1.3 to 1.5 mm demonstrating that its performance is dominated by the precision. CONCLUSIONS: The PWD-ANOVA method accounts for human observer variation allowing a better estimation of the of DIR errors.

Catching errors with in vivo EPID dosimetry.

The potential for detrimental incidents and the ever increasing complexity of patient treatments emphasize the need for accurate dosimetric verification in radiotherapy. For this reason, all curative treatments are verified, either pretreatment or in vivo, by electronic portal imaging device (EPID) dosimetry in the Radiation Oncology Department of The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands. Since the clinical introduction of the method in January 2005 until August 2009, treatment plans of 4337 patients have been verified. Among these plans, 17 serious errors were detected that led to intervention. Due to their origin, nine of these errors would not have been detected with pretreatment verification. The method is illustrated in detail by the case of a plan transfer error detected in a 5 x 5 Gy intensity-modulated radiotherapy (IMRT) rectum treatment. The EPID reconstructed dose at the isocenter was 6.3% below the planned value. Investigation of the plan transfer chain revealed that due to a network transfer error, the plan was corrupted. 3D analysis of the acquired EPID data revealed serious underdosage of the planning target volume: On average 11.6%, locally up to 20%. This report shows the importance of in vivo (EPID) dosimetry for all treatment plans as well as the ability of the method to assess the dosimetric impact of deviations found.

Reconstruction of a time-averaged midposition CT scan for radiotherapy planning of lung cancer patients using deformable registration.

PURPOSE: lower lobe lung tumors move with amplitudes of up to 2 cm due to respiration. To reduce respiration imaging artifacts in planning CT scans, 4D imaging techniques are used. Currently, we use a single (midventilation) frame of the 4D data set for clinical delineation of structures and radiotherapy planning. A single frame, however, often contains artifacts due to breathing irregularities, and is noisier than a conventional CT scan since the exposure per frame is lower. Moreover, the tumor may be displaced from the mean tumor position due to hysteresis. The aim of this work is to develop a framework for the acquisition of a good quality scan representing all scanned anatomy in the mean position by averaging transformed (deformed) CT frames, i.e., canceling out motion. A nonrigid registration method is necessary since motion varies over the lung. METHODS AND MATERIALS: 4D and inspiration breath-hold (BH) CT scans were acquired for 13 patients. An iterative multiscale motion estimation technique was applied to the 4D CT scan, similar to optical flow but using image phase (gray-value transitions from bright to dark and vice versa) instead. From the (4D) deformation vector field (DVF) derived, the local mean position in the respiratory cycle was computed and the 4D DVF was modified to deform all structures of the original 4D CT scan to this mean position. A 3D midposition (MidP) CT scan was then obtained by (arithmetic or median) averaging of the deformed 4D CT scan. Image registration accuracy, tumor shape deviation with respect to the BH CT scan, and noise were determined to evaluate the image fidelity of the MidP CT scan and the performance of the technique. RESULTS: Accuracy of the used deformable image registration method was comparable to established automated locally rigid registration and to manual landmark registration (average difference to both methods < 0.5 mm for all directions) for the tumor region. From visual assessment, the registration was good for the clearly visible features (e.g., tumor and diaphragm). The shape of the tumor, with respect to that of the BH CT scan, was better represented by the MidP reconstructions than any of the 4D CT frames (including MidV; reduction of "shape differences" was 66%). The MidP scans contained about one-third the noise of individual 4D CT scan frames. CONCLUSIONS: We implemented an accurate method to estimate the motion of structures in a 4D CT scan. Subsequently, a novel method to create a midposition CT scan (time-weighted average of the anatomy) for treatment planning with reduced noise and artifacts was introduced. Tumor shape and position in the MidP CT scan represents that of the BH CT scan better than MidV CT scan and, therefore, was found to be appropriate for treatment planning.

Clinical experience with EPID dosimetry for prostate IMRT pre-treatment dose verification.

The aim of this study was to demonstrate how dosimetry with an amorphous silicon electronic portal imaging device (a-Si EPID) replaced film and ionization chamber measurements for routine pre-treatment dosimetry in our clinic. Furthermore, we described how EPID dosimetry was used to solve a clinical problem. IMRT prostate plans were delivered to a homogeneous slab phantom. EPID transit images were acquired for each segment. A previously developed in-house back-projection algorithm was used to reconstruct the dose distribution in the phantom mid-plane (intersecting the isocenter). Segment dose images were summed to obtain an EPID mid-plane dose image for each field. Fields were compared using profiles and in two dimensions with the y evaluation (criteria: 3%/3 mm). To quantify results, the average gamma (gamma avg), maximum gamma (gamma max), and the percentage of points with gamma < 1(P gamma < 1) were calculated within the 20% isodose line of each field. For 10 patient plans, all fields were measured with EPID and film at gantry set to 0 degrees. The film was located in the phantom coronal mid-plane (10 cm depth), and compared with the back-projected EPID mid-plane absolute dose. EPID and film measurements agreed well for all 50 fields, with (gamma avg) =0.16, (gamma max)=1.00, and (P gamma < 1)= 100%. Based on these results, film measurements were discontinued for verification of prostate IMRT plans. For 20 patient plans, the dose distribution was re-calculated with the phantom CT scan and delivered to the phantom with the original gantry angles. The planned isocenter dose (plan(iso)) was verified with the EPID (EPID(iso)) and an ionization chamber (IC(iso)). The average ratio, (EPID(iso)/IC(iso)), was 1.00 (0.01 SD). Both measurements were systematically lower than planned, with (EPID(iso)/plan(iso)) and (IC(iso)/plan(iso))=0.99 (0.01 SD). EPID mid-plane dose images for each field were also compared with the corresponding plane derived from the three dimensional (3D) dose grid calculated with the phantom CT scan. Comparisons of 100 fields yielded (gamma avg)=0.39, gamma max=2.52, and (P gamma < 1)=98.7%. Seven plans revealed under-dosage in individual fields ranging from 5% to 16%, occurring at small regions of overlapping segments or along the junction of abutting segments (tongue-and-groove side). Test fields were designed to simulate errors and gave similar results. The agreement was improved after adjusting an incorrectly set tongue-and-groove width parameter in the treatment planning system (TPS), reducing (gamma max) from 2.19 to 0.80 for the test field. Mid-plane dose distributions determined with the EPID were consistent with film measurements in a slab phantom for all IMRT fields. Isocenter doses of the total plan measured with an EPID and an ionization chamber also agreed. The EPID can therefore replace these dosimetry devices for field-by-field and isocenter IMRT pre-treatment verification. Systematic errors were detected using EPID dosimetry, resulting in the adjustment of a TPS parameter and alteration of two clinical patient plans. One set of EPID measurements (i.e., one open and transit image acquired for each segment of the plan) is sufficient to check each IMRT plan field-by-field and at the isocenter, making it a useful, efficient, and accurate dosimetric tool.

Comparison of ghosting effects for three commercial a-Si EPIDs.

Many studies have reported dosimetric characteristics of amorphous silicon electronic portal imaging devices (EPIDs). Some studies ascribed a non-linear signal to gain ghosting and image lag. Other reports, however, state the effect is negligible. This study compares the signal-to-monitor unit (MU) ratio for three different brands of EPID systems. The signal was measured for a wide range of monitor units (5-1000), dose-rates, and beam energies. All EPIDs exhibited a relative under-response for beams of few MUs; giving 4 to 10% lower signal-to-MU ratios relative to that of 1000 MUs. This under-response is consistent with ghosting effects due to charge trapping.

The long-term stability of amorphous silicon flat panel imaging devices for dosimetry purposes.

This study was carried out to determine the stability of the response of amorphous silicon (a-Si)-flat panel imagers for dosimetry applications. Measurements of the imager's response under reference conditions were performed on a regular basis for four detectors of the same manufacturer. We found that the ambient temperature influenced the dark-field, while the gain of the imager signal was unaffected. Therefore, temperature fluctuations were corrected for by applying a "dynamic" darkfield correction. This correction method also removed the influence of a small, irreversible increase of the dark-field current, which was equal to 0.5% of the dynamic range of the imager per year and was probably caused by mild radiation damage to the a-Si array. By applying a dynamic dark-field correction, excellent stability of the response over the entire panel of all imagers of 0.5% (1 SD) was obtained over an observation period up to 23 months. However, two imagers had to be replaced after several months. For one imager, an image segment stopped functioning, while the image quality of the other imager degraded significantly. We conclude that the tested a-Si EPIDs have a very stable response and are therefore well suited for dosimetry. We recommend, however, applying quality assurance tests dedicated to both imaging and dosimetry.

Dose-response and ghosting effects of an amorphous silicon electronic portal imaging device.

The purpose of this study was to investigate the dose-response characteristics, including ghosting effects, of an amorphous silicon-based electronic portal imaging device (a-Si EPID) under clinical conditions. EPID measurements were performed using one prototype and two commercial a-Si detectors on two linear accelerators: one with 4 and 6 MV and the other with 8 and 18 MV x-ray beams. First, the EPID signal and ionization chamber measurements in a mini-phantom were compared to determine the amount of buildup required for EPID dosimetry. Subsequently, EPID signal characteristics were studied as a function of dose per pulse, pulse repetition frequency (PRF) and total dose, as well as the effects of ghosting. There was an over-response of the EPID signal compared to the ionization chamber of up to 18%, with no additional buildup layer over an air gap range of 10 to 60 cm. The addition of a 2.5 mm thick copper plate sufficiently reduced this over-response to within 1% at clinically relevant patient-detector air gaps (> 40 cm). The response of the EPIDs varied by up to 8% over a large range of dose per pulse values, PRF values and number of monitor units. The EPID response showed an under-response at shorter beam times due to ghosting effects, which depended on the number of exposure frames for a fixed frame acquisition rate. With an appropriate build-up layer and corrections for dose per pulse, PRF and ghosting, the variation in the a-Si EPID response can be reduced to well within +/- 1%.