Correlations between the shifts in prompt gamma emission profiles and the changes in daily target coverage during simulated pencil beam scanning proton therapy.

The aim of this study was to investigate the feasibility of using prompt gamma (PG) ray emission profiles to monitor changes in dose to the planning target volume (PTV) during pencil beam scanning (PBS) proton therapy as a result of day-to-day variation in patient anatomy. For 11 prostate patients, we simulated treatment plan delivery using the patients' daily anatomy as observed in the planning CT and 7-9 control CT scans, including the detected PG profiles resulting from the 5%, 10%, and 20% most intense proton pencil beams. For each patient, we determined the changes in dosimetric parameters for the high- and low-dose PTVs between the simulations performed using the planning CT scan and the different control CT scans and correlated these to changes in the PG emission profiles. Changes in coverage of the high- and low-dose PTV correlated most strongly with the median and mean absolute PG emission profile shifts of the 5% most intense pencil beams, respectively. With a mean Pearson correlation coefficient of -0.76 (SD: 0.17) for the high-dose PTV and of -0.60 (SD: 0.51) for the low-dose PTV. We showed, as a proof of principle, that PG emission profiles obtained during PBS proton therapy could be used to detect changes in PTV coverage due to day-to-day anatomical variation.

Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer : The dummy run.

BACKGROUND: The Dutch Pancreatic Cancer Group initiated the national, multicentre, controlled PREOPANC trial, randomising between preoperative radiochemotherapy and direct explorative laparotomy for patients with (borderline) resectable pancreatic cancer. The aim of this dummy run is to evaluate compliance with the radiotherapy protocol of this trial, and the quality of delineation and radiation plans. METHODS: Eleven radiation oncology departments open for accrual of patients in the PREOPANC trial were provided with all necessary information of a selected 'dummy' patient. Each institute was asked to delineate the target volumes, including gross tumour volume, internal gross tumour volume (iGTV), internal clinical target volume, and planning target volume. The institutions were also asked to provide a radiation treatment plan in accordance with the PREOPANC trial protocol. RESULTS: The range of the iGTV was 19.3-77.2 cm3 with a mean iGTV of 41.5 cm3 (standard deviation 14.8 cm3). Nine institutions made a treatment plan using an arc technique for treatment delivery, one an intensity modulated technique and one a 3-field conformal technique. All institutions reached the prescribed target coverage, without exceeding the organs at risk constraints. The institution with the 3­field conformal technique was advised to use a more sophisticated technique (e. g. volumetric modulated arc therapy) to reduce the dose to the spinal cord. CONCLUSION: All institutions showed acceptable deviations from the PREOPANC trial protocol and achieved an acceptable quality of delineation and radiation technique. All institutions were allowed to continue participation in the PREOPANC trial.

Addition of MRI for CT-based pancreatic tumor delineation: a feasibility study.

PURPOSE: To assess the effect of additional magnetic resonance imaging (MRI) alongside the planning computed tomography (CT) scan on target volume delineation in pancreatic cancer patients. MATERIAL AND METHODS: Eight observers (radiation oncologists) from six institutions delineated the gross tumor volume (GTV) on 3DCT, and internal GTV (iGTV) on 4DCT of four pancreatic cancer patients, while MRI was available in a second window (CT + MRI). Variations in volume, generalized conformity index (CIgen), and overall observer variation, expressed as standard deviation (SD) of the distances between delineated surfaces, were analyzed. CIgen is a measure of overlap of the delineated iGTVs (1 = full overlap, 0 = no overlap). Results were compared with those from an earlier study that assessed the interobserver variation by the same observers on the same patients on CT without MRI (CT-only). RESULTS: The maximum ratios between delineated volumes within a patient were 6.1 and 22.4 for the GTV (3DCT) and iGTV (4DCT), respectively. The average (root-mean-square) overall observer variations were SD = 0.41 cm (GTV) and SD = 0.73 cm (iGTV). The mean CIgen was 0.36 for GTV and 0.37 for iGTV. When compared to the iGTV delineated on CT-only, the mean volumes of the iGTV on CT + MRI were significantly smaller (32%, Wilcoxon signed-rank, p < .0005). The median volumes of the iGTV on CT + MRI were included for 97% and 92% in the median volumes of the iGTV on CT. Furthermore, CT + MRI showed smaller overall observer variations (root-mean-square SD = 0.59 cm) in six out of eight delineated structures compared to CT-only (root-mean-square SD = 0.72 cm). However, large local observer variations remained close to biliary stents and pathological lymph nodes, indicating issues with instructions and instruction compliance. CONCLUSIONS: The availability of MRI images during target delineation of pancreatic cancer on 3DCT and 4DCT resulted in smaller target volumes and reduced the interobserver variation in six out of eight delineated structures.

Considerable interobserver variation in delineation of pancreatic cancer on 3DCT and 4DCT: a multi-institutional study.

BACKGROUND: The delineation of pancreatic tumors on CT is challenging. In this study, we quantified the interobserver variation for pancreatic tumor delineation on 3DCT as well as on 4DCT. METHODS: Eight observers (radiation oncologists) from six institutions delineated pancreatic tumors of four patients with (borderline) resectable pancreatic cancer. The study consisted of two stages. In the 3DCT-stage, the gross tumor volume (GTV) was delineated on a contrast-enhanced scan. In the 4DCT-stage, the internal GTV (iGTV) was delineated, accounting for the respiratory motion. We calculated the volumes of the (i)GTV, the overlap of the delineated volumes (expressed as generalized conformity index: CIgen), the local observer variation (local standard deviation: SD) and the overall observer variation (overall SD). We compared these results between GTVs and iGTVs. Additionally, observers were asked to fill out a questionnaire concerning the difficulty of the delineation and their experience in delineating pancreatic tumors. RESULTS: The ratios of the largest to the smallest delineated GTV and iGTV within the same patient were 6.8 and 16.5, respectively. As the iGTV incorporates the GTV during all respiratory phases, the mean volumes of the iGTV (40.07 cm3) were larger than those of the GTV (29.91 cm3). For all patients, CIgen was larger for the iGTV than for the GTV. The mean overall observer variation (root-mean-square of all local SDs over four patients) was 0.63 cm and 0.80 cm for GTV and iGTV, respectively. The largest local observer variations were seen close to biliary stents and suspicious pathological enlarged lymph nodes, as some observers included them and some did not. This variation was more pronounced for the iGTV than for the GTV. The observers rated the 3DCT-stage and 4DCT-stage equally difficult and treated on average three to four pancreatic cancer patients per year. CONCLUSIONS: A considerable interobserver variation in delineation of pancreatic tumors was observed. This variation was larger for 4D than for 3D delineation. The largest local observer variation was found around biliary stents and suspicious pathological enlarged lymph nodes.

Probabilistic treatment planning for pancreatic cancer treatment: prospective incorporation of respiratory motion shows only limited dosimetric benefit.

BACKGROUND: We introduced a probabilistic treatment planning approach that prospectively incorporates respiratory-induced motion in the treatment plan optimization. The aim of this study was to determine the potential dosimetric benefit by comparing this approach to the use of an internal target volume (ITV). MATERIAL AND METHOD: We retrospectively compared the probabilistic respiratory motion-incorporated (RMI) approach to the ITV approach for 18 pancreatic cancer patients, for seven simulated respiratory amplitudes from 5 to 50 mm in the superior-inferior (SI) direction. For each plan, we assessed the target coverage (required: D98%≥95% of 50 Gy prescribed dose). For the RMI plans, we investigated whether target coverage was robust against daily variations in respiratory amplitude. We determined the distance between the clinical target volume and the 30 Gy isodose line (i.e. dose gradient steepness) in the SI direction. To investigate the clinical benefit of the RMI approach, we created for each patient an ITV and RMI treatment plan for the three-dimensional (3D) respiratory amplitudes observed on their pretreatment 4D computed tomography (4DCT). We determined Dmean, V30Gy, V40Gy and V50Gy for the duodenum. RESULTS: All treatment plans yielded good target coverage. The RMI plans were robust against respiratory amplitude variations up to 10 mm, as D98% remained ≥95%. We observed steeper dose gradients compared to the ITV approach, with a mean decrease from 25.9 to 19.2 mm for a motion amplitude of 50 mm. For the 4DCT motion amplitudes, the RMI approach resulted in a mean decrease of 0.43 Gy, 1.1 cm3, 1.4 cm3 and 0.9 cm3 for the Dmean, V30Gy, V40Gy and V50Gy of the duodenum, respectively. CONCLUSION: The probabilistic treatment planning approach yielded significantly steeper dose gradients and therefore significantly lower dose to surrounding healthy tissues than the ITV approach. However, the observed dosimetric gain for clinically observed respiratory motion amplitudes for this patient group was limited.

Quantitative assessment of biliary stent artifacts on MR images: Potential implications for target delineation in radiotherapy.

PURPOSE: Biliary stents may cause susceptibility artifacts, gradient-induced artifacts, and radio frequency (RF) induced artifacts on magnetic resonance images, which can hinder accurate target volume delineation in radiotherapy. In this study, the authors investigated and quantified the magnitude of these artifacts for stents of different materials. METHODS: Eight biliary stents made of nitinol, platinum-cored nitinol, stainless steel, or polyethylene from seven vendors, with different lengths (57-98 mm) and diameters (3.0-11.7 mm), were placed in a phantom. To quantify the susceptibility artifacts sequence-independently, ΔB0-maps and T2∗-maps were acquired at 1.5 and 3 T. To study the effect of the gradient-induced artifacts at 3 T, signal decay in images obtained with maximum readout gradient-induced artifacts was compared to signal decay in reference scans. To quantify the RF induced artifacts at 3 T, B1-maps were acquired. Finally, ΔB0-maps and T2∗-maps were acquired at 3 T of two pancreatic cancer patients who had received platinum-cored nitinol biliary stents. RESULTS: Outside the stent, susceptibility artifacts dominated the other artifacts. The stainless steel stent produced the largest susceptibility artifacts. The other stents caused decreased T2∗ up to 5.1 mm (1.5 T) and 8.5 mm (3 T) from the edge of the stent. For sequences with a higher bandwidth per voxel (1.5 T: BWvox > 275 Hz/voxel; 3 T: BWvox > 500 Hz/voxel), the B0-related susceptibility artifacts were negligible (<0.2 voxels). The polyethylene stent showed no artifacts. In vivo, the changes in B0 and T2∗ induced by the stent were larger than typical variations in B0 and T2∗ induced by anatomy when the stent was at an angle of 30° with the main magnetic field. CONCLUSIONS: Susceptibility artifacts were dominating over the other artifacts. The magnitudes of the susceptibility artifacts were determined sequence-independently. This method allows to include additional safety margins that ensure target irradiation.

Abdominal organ motion during inhalation and exhalation breath-holds: pancreatic motion at different lung volumes compared.

PURPOSE: Contrary to what is commonly assumed, organs continue to move during breath-holding. We investigated the influence of lung volume on motion magnitude during breath-holding and changes in velocity over the duration of breath-holding. MATERIALS AND METHODS: Sixteen healthy subjects performed 60-second inhalation breath-holds in room-air, with lung volumes of ∼100% and ∼70% of the inspiratory capacity, and exhalation breath-holds, with lung volumes of ∼30% and ∼0% of the inspiratory capacity. During breath-holding, we obtained dynamic single-slice magnetic-resonance images with a time-resolution of 0.6s. We used 2-dimensional image correlation to obtain the diaphragmatic and pancreatic velocity and displacement during breath-holding. RESULTS: Organ velocity was largest in the inferior-superior direction and was greatest during the first 10s of breath-holding, with diaphragm velocities of 0.41mm/s, 0.29mm/s, 0.16mm/s and 0.15mm/s during BH100%, BH70%, BH30% and BH0%, respectively. Organ motion magnitudes were larger during inhalation breath-holds (diaphragm moved 9.8 and 9.0mm during BH100% and BH70%, respectively) than during exhalation breath-holds (5.6 and 4.3mm during BH30% and BH0%, respectively). CONCLUSION: Using exhalation breath-holds rather than inhalation breath-holds and delaying irradiation until after the first 10s of breath-holding may be advantageous for irradiation of abdominal tumors.

Considerable pancreatic tumor motion during breath-holding.

BACKGROUND: Breath-holding (BH) is often used to reduce abdominal organ motion during radiotherapy. However, for inhale BH, abdominal tumor motion during BH has not yet been investigated. The aim of this study was to quantify tumor motion during inhale BH and tumor position variations between consecutive inhale BHs in pancreatic cancer patients. MATERIAL AND METHODS: Twelve patients with intratumoral fiducials were included and asked to perform three consecutive 30-second inhale BHs on each of three measurement days. During BH, lateral fluoroscopic movies were obtained and a two-dimensional (2D) image correlation algorithm was used to track the fiducials and the diaphragm, yielding the tumor and diaphragm motion during each BH. The tumor position variation between consecutive BHs was obtained from the difference in initial tumor position between consecutive BHs on a single measurement day. RESULTS: We observed tumor motion during BH with a mean absolute maximum displacement over all BHs of 4.2 mm (range 1.0-11.0 mm) in inferior-superior (IS) direction and 2.7 mm (range 0.5-8.0 mm) in anterior-posterior (AP) direction. We found only a moderate correlation between tumor and diaphragm motion in the IS direction (Pearson's correlation coefficient |r|>0.6 in 45 of 76 BHs). The mean tumor position variation between consecutive BHs was 0.2 [standard deviation (SD) 1.7] mm in the inferior direction and 0.5 (SD 0.8) mm in the anterior direction. CONCLUSION: We observed substantial pancreatic tumor motion during BH as well as considerable position variation between consecutive BHs on a single day. We recommend further quantifying these uncertainties before introducing breath-hold during radiation treatment of pancreatic cancer patients. Also, the diaphragm cannot be used as a surrogate for pancreatic tumor motion.

Visibility and artifacts of gold fiducial markers used for image guided radiation therapy of pancreatic cancer on MRI.

PURPOSE: In radiation therapy of pancreatic cancer, tumor alignment prior to each treatment fraction is improved when intratumoral gold fiducial markers (from here onwards: markers), which are visible on computed tomography (CT) and cone beam CT, are used. Visibility of these markers on magnetic resonance imaging (MRI) might improve image registration between CT and magnetic resonance (MR) images for tumor delineation purposes. However, concomitant image artifacts induced by markers are undesirable. The extent of visibility and artifact size depend on MRI-sequence parameters. The authors' goal was to determine for various markers their potential to be visible and to generate artifacts, using measures that are independent of the MRI-sequence parameters. METHODS: The authors selected ten different markers suitable for endoscopic placement in the pancreas and placed them into a phantom. The markers varied in diameter (0.28-0.6 mm), shape, and iron content (0%-0.5%). For each marker, the authors calculated T2 (∗)-maps and ΔB0-maps using MRI measurements. A decrease in relaxation time T2 (∗) can cause signal voids, associated with visibility, while a change in the magnetic field B0 can cause signal shifts, which are associated with artifacts. These shifts inhibit accurate tumor delineation. As a measure for potential visibility, the authors used the volume of low T2 (∗), i.e., the volume for which T2 (∗) differed from the background by >15 ms. As a measure for potential artifacts, the authors used the volume for which |ΔB0| > 9.4 × 10(-8) T (4 Hz). To test whether there is a correlation between visibility and artifact size, the authors calculated the Spearman's correlation coefficient (Rs) between the volume of low T2 (∗) and the volume of high |ΔB0|. The authors compared the maps with images obtained using a clinical MR-sequence. Finally, for the best visible marker as well as the marker that showed the smallest artifact, the authors compared the phantom data with in vivo MR-images in four pancreatic cancer patients. RESULTS: The authors found a strong correlation (Rs = 1.00, p < 0.01) between the volume of low T2 (∗) and the volume with high |ΔB0|. Visibility in clinical MR-images increased with lower T2 (∗). Signal shift artifacts became worse for markers with high |ΔB0|. The marker that was best visible in the phantom, a folded marker with 0.5% iron content, was also visible in vivo, but showed artifacts on diffusion weighted images. The marker with the smallest artifact in the phantom, a small, stretched, ironless marker, was indiscernible on in vivo MR-images. CONCLUSIONS: Changes in T2 (∗) and ΔB0 are sequence-independent measures for potential visibility and artifact size, respectively. Improved visibility of markers correlates strongly to signal shift artifacts; therefore, marker choice will depend on the clinical purpose. When visibility of the markers is most important, markers that contain iron are optimal, preferably in a folded configuration. For artifact sensitive imaging, small ironless markers are best, preferably in a stretched configuration.

Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer.

PURPOSE: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. METHODS AND MATERIALS: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V95% >98%. In addition, the change in PTV size and the changes in V10Gy, V20Gy, V30Gy, V40Gy, Dmean and D2cc for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. RESULTS: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D2cc of the duodenum, improved significantly (P≤.002). CONCLUSIONS: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors.

Limited role for biliary stent as surrogate fiducial marker in pancreatic cancer: stent and intratumoral fiducials compared.

PURPOSE: Because of low soft-tissue contrast of cone beam computed tomography (CBCT), fiducial markers are often used for radiation therapy patient setup verification. For pancreatic cancer patients, biliary stents have been suggested as surrogate fiducials. Using intratumoral fiducials as standard for tumor position, this study aims to quantify the suitability of biliary stents for measuring interfractional and respiratory-induced position variations of pancreatic tumors. METHODS AND MATERIALS: Eleven pancreatic cancer patients with intratumoral fiducials and a biliary stent were included in this study. Daily CBCT scans (243 in total) were registered with a reference CT scan, based on bony anatomy, on fiducial markers, and on the biliary stent, respectively. We analyzed the differences in tumor position (ie, markers center-of-mass position) among these 3 registrations. In addition, we measured for 9 patients the magnitude of respiratory-induced motion (MM) of the markers and of the stent on 4-dimensional CT (4DCT) and determined the difference between these 2 magnitudes (ΔMM). RESULTS: The stent indicated tumor position better than bony anatomy in 67% of fractions; the absolute difference between the markers and stent registration was >5 mm in 46% of fractions and >10 mm in 20% of fractions. Large PTV margins (superior-inferior direction, >19 mm) would be needed to account for this interfractional position variability. On 4DCT, we found in superior-inferior direction a mean ΔMM of 0.5 mm (range, -2.6 to 4.2 mm). CONCLUSIONS: For respiratory-induced motion, the mean ΔMM is small, but for individual patients the absolute difference can be >4 mm. For interfractional position variations, a stent is, on average, a better surrogate fiducial than bony anatomy, but large PTV margins would still be required. Therefore, intratumoral fiducials are recommended for online setup verification for all pancreatic patients scheduled for radiation therapy, including patients with a biliary stent.

Differences in respiratory-induced pancreatic tumor motion between 4D treatment planning CT and daily cone beam CT, measured using intratumoral fiducials.

BACKGROUND: In radiotherapy, the magnitude of respiratory-induced tumor motion is often measured using a single four-dimensional computed tomography (4DCT). This magnitude is required to determine the internal target volume. The aim of this study was to compare the magnitude of respiratory-induced motion of pancreatic tumors on a single 4DCT with the motion on daily cone beam CT (CBCT) scans during a 3-5-week fractionated radiotherapy scheme. In addition, we investigated changes in the respiratory motion during the treatment course. MATERIAL AND METHODS: The mean peak-to-peak motion (i.e. magnitude of motion) of pancreatic tumors was measured for 18 patients using intratumoral gold fiducials visible on CBCT scans made prior to each treatment fraction (10-27 CBCTs per patient; 401 CBCTs in total). For each patient, these magnitudes were compared to the magnitude measured on 4DCT. Possible time trends were investigated by applying linear fits to the tumor motion determined from daily CBCTs as a function of treatment day. RESULTS: We found a significant (p ≤ 0.01) difference between motion magnitude on 4DCT and on CBCT in superior-inferior, anterior-posterior and left-right direction, in 13, 9 and 12 of 18 patients, respectively. In the anterior- posterior and left-right direction no fractions had a difference ≥ 5 mm. In the superior-inferior direction the difference was ≥ 5 mm for 17% of the 401 fractions. In this direction, a significant (p ≤ 0.05) time trend in tumor motion was observed in 4 of 18 patients, but all trends were small (- 0.17-0.10 mm/day) and did not explain the large differences in motion magnitude between 4DCT and CBCT. CONCLUSION: A single measurement of the respiratory-induced motion magnitude of pancreatic tumors using 4DCT is often not representative for the magnitude during daily treatment over a 3-5-week radiotherapy scheme. For this patient group it may be beneficial to introduce breath-hold to eliminate respiratory-induced tumor motion.