Predicting Treatment Response From Extracellular Volume Fraction for Chemoradiation Therapy of Pancreatic Cancer.

PURPOSE: Dual-energy computed tomography (DECT) data can be used to calculate the extracellular volume fraction (ECVf) in tumors, which has been correlated with treatment outcome. This study sought to find a correlation between ECVf and treatment response as measured by the change in cancer antigen (CA) 19 to 9 during chemoradiation therapy (CRT) for pancreatic cancer. METHODS AND MATERIALS: Dual-energy CT data acquired during the late arterial contrast phase in the standard radiation therapy simulation on a dual-source DECT simulator for 25 patients with pancreatic cancer, along with their CA19-9 and hematocrit data, were analyzed. Each patient underwent preoperative CRT with a prescription of 50.4 Gy in 28 fractions. The patients were chosen based on the presence of a solid tumor in the pancreas that could be clearly delineated. A region of interest (ROI) was placed in the tumor and in the aorta. From the ratio of the iodine density calculated from the DECT in the ROI and the hematocrit taken at the time of simulation, the ECVf was calculated. The ECVf was then compared with the change in CA19-9 before and after the CRT. Distant metastases as the cause of CA19-9 elevation were ruled out on subsequent restaging images before surgery. The DECT-derived iodine ratio was validated using a phantom study. RESULTS: The DECT-derived iodine concentration agreed with the phantom measurements (R2, 1.0). The average hematocrit, ECVf, and change in CA19-9 during the treatment for the 25 patients was 35.6 ± 5.4%, 7.3 ± 4.9%, and -4.6 ± 21.8 respectively. A linear correlation was found between the ECVf and the change in CA19-9, with an R2 of 0.7: ΔCA19-9 = 3.63 × ECVf - 31.1. The correlation was statistically significant (P = .006). CONCLUSIONS: The calculated ECV fraction based on iodine maps from dual-source DECT may be used to predict treatment response after neoadjuvant chemoradiation therapy for pancreatic cancer.

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

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

A planning and delivery study of a rotational IMRT technique with burst delivery.

PURPOSE: A novel rotational IMRT (rIMRT) technique using burst delivery (continuous gantry rotation with beam off during MLC repositioning) is investigated. The authors evaluate the plan quality and delivery efficiency and accuracy of this dynamic technique with a conventional flat 6 MV photon beam. METHODS: Burst-delivery rIMRT was implemented in a planning system and delivered with a 160-MLC linac. Ten rIMRT plans were generated for five anonymized patient cases encompassing head and neck, brain, prostate, and prone breast. All plans were analyzed retrospectively and not used for treatment. Among the varied plan parameters were the number of optimization points, number of arcs, gantry speed, and gantry angle range (alpha) over which the beam is turned on at each optimization point. Combined rotational/step-and-shoot rIMRT plans were also created by superimposing multiple-segment static fields at several optimization points. The rIMRT trial plans were compared with each other and with plans generated using helical tomotherapy and VMAT. Burst-mode rotational IMRT plans were delivered and verified using a diode array, ionization chambers, thermoluminescent dosimeters, and film. RESULTS: Burst-mode rIMRT can achieve plan quality comparable to helical tomotherapy, while the former may lead to slightly better OAR sparing for certain cases and the latter generally achieves slightly lower hot spots. Few instances were found in which increasing the number of optimization points above 36, or superimposing step-and-shoot IMRT segments, led to statistically significant improvements in OAR sparing. Using an additional rIMRT partial arc yielded substantial OAR dose improvements for the brain case. Measured doses from the rIMRT plan delivery were within 4% of the plan calculation in low dose gradient regions. Delivery time range was 228-375 s for single-arc rIMRT 200-cGy prescription with a 300 MU/min dose rate, comparable to tomotherapy and VMAT. CONCLUSIONS: Rotational IMRT with burst delivery, whether combined with static fields or not, yields clinically acceptable and deliverable treatment plans.

Automated air region delineation on MRI for synthetic CT creation.

Automatically and accurately separating air from other low signal regions (especially bone, liver, etc) in an MRI is difficult because these tissues produce similar MR intensities, resulting in errors in synthetic CT generation for MRI-based radiation therapy planning. This work aims to develop a technique to accurately and automatically determine air-regions for MR-guided adaptive radiation therapy. CT and MRI scans (T2-weighted) of phantoms with fabricated air-cavities and abdominal cancer patients were used to establish an MR intensity threshold for air delineation. From the phantom data, air/tissue boundaries in MRI were identified by CT-MRI registration. A formula relating the MRI intensities of air and surrounding materials was established to auto-threshold air-regions. The air-regions were further refined by using quantitative image texture features. A naive Bayesian classifier was trained using the extracted features with a leave-one-out cross validation technique to differentiate air from non-air voxels. The multi-step air auto-segmentation method was tested against the manually segmented air-regions. The dosimetry impacts of the air-segmentation methods were studied. Air-regions in the abdomen can be segmented on MRI within 1 mm accuracy using a multi-step auto-segmentation method as compared to manually delineated contours. The air delineation based on the MR threshold formula was improved using the MRI texture differences between air and tissues, as judged by the area under the receiver operating characteristic curve of 81% when two texture features (autocorrelation and contrast) were used. The performance increased to 82% with using three features (autocorrelation, sum-variance, and contrast). Dosimetric analysis showed no significant difference between the auto-segmentation and manual MR air delineation on commonly used dose volume parameters. The proposed techniques consisting of intensity-based auto-thresholding and image texture-based voxel classification can automatically and accurately segment air-regions on MRI, allowing synthetic CT to be generated quickly and precisely for MR-guided adaptive radiation therapy.

Automatic Seizure Detection using Fully Convolutional Nested LSTM.

The automatic seizure detection system can effectively help doctors to monitor and diagnose epilepsy thus reducing their workload. Many outstanding studies have given good results in the two-class seizure detection problems, but most of them are based on hand-wrought feature extraction. This study proposes an end-to-end automatic seizure detection system based on deep learning, which does not require heavy preprocessing on the EEG data or feature engineering. The fully convolutional network with three convolution blocks is first used to learn the expressive seizure characteristics from EEG data. Then these robust EEG features pertinent to seizures are presented as an input to the Nested Long Short-Term Memory (NLSTM) model to explore the inherent temporal dependencies in EEG signals. Lastly, the high-level features obtained from the NLSTM model are fed into the softmax layer to output predicted labels. The proposed method yields an accuracy range of 98.44-100% in 10 different experiments based on the Bonn University database. A larger EEG database is then used to evaluate the performance of the proposed method in real-life situations. The average sensitivity of 97.47%, specificity of 96.17%, and false detection rate of 0.487 per hour are yielded. For CHB-MIT Scalp EEG database, the proposed model also achieves a segment-level sensitivity of 94.07% with a false detection rate of 0.66 per hour. The excellent results obtained on three different EEG databases demonstrate that the proposed method has good robustness and generalization power under ideal and real-life conditions.

High dose radiation therapy based on normal tissue constraints with concurrent chemotherapy achieves promising survival of patients with unresectable stage III non-small cell lung cancer.

BACKGROUND AND PURPOSE: We aimed to investigate the potential of individual isotoxic dose escalation based on normal tissue constraints (NTC), hypothesizing that high dose radiation therapy would be superior to standard-dose in concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Individually prescribed radiation doses were calculated based on NTC. Patients with total tumour radiation doses ≥66 Gy were assigned to the high dose (HD, ≥66 Gy) group, and all other patients were assigned to the standard-dose (SD, <66 Gy) group. Each patient was retrospectively assigned an Eighth edition of American Joint Committee on Cancer disease stage based on the imaging data of initial diagnosis to avoid over- and under-staging. Intensity modulated radiation therapy plans were optimized to minimize the volumes of organs at risk exposed to radiation. The primary endpoint was overall survival. RESULTS: From March 2006 to September 2012, 140 patients were enrolled and assigned to two groups: 71 patients into the HD group and 69 patients into the SD group. The median survival time (MST) was significantly higher in the HD group (33.5 months) than in the SD group (21 months), (p < 0.0001). Overall 5-year survival rates were significantly higher in the HD group than in the SD group (37.8% vs 16.7%). Median progression-free survival was 19 months in the HD group and 11 months in the SD group (p < 0.0001). No difference in severe (grade 3-5) toxic effects was noted between the two groups. CONCLUSIONS: The significant positive association observed between prescribed dose and survival suggests that individualized isotoxic dose-escalated radiation based on NTC might improve survival in this cohort of stage III NSCLC Chinese patients.

A machine learning based delta-radiomics process for early prediction of treatment response of pancreatic cancer.

Changes of radiomic features over time in longitudinal images, delta radiomics, can potentially be used as a biomarker to predict treatment response. This study aims to develop a delta-radiomic process based on machine learning by (1) acquiring and registering longitudinal images, (2) segmenting and populating regions of interest (ROIs), (3) extracting radiomic features and calculating their changes (delta-radiomic features, DRFs), (4) reducing feature space and determining candidate DRFs showing treatment-induced changes, and (5) creating outcome prediction models using machine learning. This process was demonstrated by retrospectively analyzing daily non-contrast CTs acquired during routine CT-guided-chemoradiation therapy for 90 pancreatic cancer patients. A total of 2520 CT sets (28-daily-fractions-per-patient) along with their pathological response were analyzed. Over 1300 radiomic features were extracted from the segmented ROIs. Highly correlated DRFs were ruled out using Spearman correlations. Correlation between the selected DRFs and pathological response was established using linear-regression-models. T test and linear-mixed-effects-models were used to determine which DRFs changed significantly compared with first fraction. A Bayesian-regularization-neural-network was used to build a response prediction model. The model was trained using 50 patients and leave-one-out-cross-validation. Performance was judged using the area-under-ROC-curve. External independent validation was done using data from the remaining 40 patients. The results show that 13 DRFs passed the tests and demonstrated significant changes following 2-4 weeks of treatment. The best performing combination differentiating good versus bad responders (CV-AUC = 0.94) was obtained using normalized-entropy-to-standard-deviation-difference-(NESTD), kurtosis, and coarseness. With further studies using larger data sets, delta radiomics may develop into a biomarker for early prediction of treatment response.

In vitro determination of radiation sensitivity parameters for DU-145 prostate cancer cells.

PURPOSE: The prolonged delivery times associated with intensity modulated radiation therapy (IMRT) may reduce treatment effectiveness of radiation therapy for cancers with short repair half-times. In this study, in vitro radiation experiments with DU-145 prostate cancer cells were designed to quantify the half-time of sublethal damage repair. METHOD AND MATERIALS: A series of single-fraction and split-dose clonogenic survival experiments were performed and analyzed using the linear-quadratic (LQ) survival model with mono-/two-component exponential and reciprocal-time repair kinetic models. RESULTS: Our data indicate that DU-145 cells are very radiosensitive (alpha = 0.44 Gy(-1), standard CI: 0.41-0.49 Gy(-1)) and are relatively insensitive to dose fractionation (alpha/beta = 16 Gy, standard CI: 12-34 Gy). The estimated repair half-time is 23 min (standard CI: 10-97 min) with some evidence that a small portion of the sublethal damage is repaired more slowly. CONCLUSION: The reported radiosensitivity parameters (alpha and alpha/beta) are larger than those derived from other in vitro experiments and clinical data. In contrast, the half-time for sublethal damage repair ( approximately 23 min) is close to the one derived from clinical data ( approximately 16 min). For such short repair half-times, the effectiveness of IMRT treatments may be substantially improved by decreasing the fraction delivery time.

A graphical approach to optimizing variable-kernel smoothing parameters for improved deformable registration of CT and cone beam CT images.

A systematic method is presented for determining optimal parameters in variable-kernel deformable image registration of cone beam CT and CT images, in order to improve accuracy and convergence for potential use in online adaptive radiotherapy. Assessed conditions included the noise constant (symmetric force demons), the kernel reduction rate, the kernel reduction percentage, and the kernel adjustment criteria. Four such parameters were tested in conjunction with reductions of 5, 10, 15, 20, 30, and 40%. Noise constants ranged from 1.0 to 1.9 for pelvic images in ten prostate cancer patients. A total of 516 tests were performed and assessed using the structural similarity index. Registration accuracy was plotted as a function of iteration number and a least-squares regression line was calculated, which implied an average improvement of 0.0236% per iteration. This baseline was used to determine if a given set of parameters under- or over-performed. The most accurate parameters within this range were applied to contoured images. The mean Dice similarity coefficient was calculated for bladder, prostate, and rectum with mean values of 98.26%, 97.58%, and 96.73%, respectively; corresponding to improvements of 2.3%, 9.8%, and 1.2% over previously reported values for the same organ contours. This graphical approach to registration analysis could aid in determining optimal parameters for Demons-based algorithms. It also establishes expectation values for convergence rates and could serve as an indicator of non-physical warping, which often occurred in cases >0.6% from the regression line.

Comprehensive MRI simulation methodology using a dedicated MRI scanner in radiation oncology for external beam radiation treatment planning.

PURPOSE: The use of magnetic resonance imaging (MRI) in radiation oncology is expanding rapidly, and more clinics are integrating MRI into their radiation therapy workflows. However, radiation therapy presents a new set of challenges and places additional constraints on MRI compared to diagnostic radiology that, if not properly addressed, can undermine the advantages MRI offers for radiation treatment planning (RTP). The authors introduce here strategies to manage several challenges of using MRI for virtual simulation in external beam RTP. METHODS: A total of 810 clinical MRI simulation exams were performed using a dedicated MRI scanner for external beam RTP of brain, breast, cervix, head and neck, liver, pancreas, prostate, and sarcoma cancers. Patients were imaged in treatment position using MRI-optimal immobilization devices. Radiofrequency (RF) coil configurations and scan protocols were optimized based on RTP constraints. Off-resonance and gradient nonlinearity-induced geometric distortions were minimized or corrected prior to using images for RTP. A multidisciplinary MRI simulation guide, along with window width and level presets, was created to standardize use of MR images during RTP. A quality assurance program was implemented to maintain accuracy and repeatability of MRI simulation exams. RESULTS: The combination of a large bore scanner, high field strength, and circumferentially wrapped, flexible phased array RF receive coils permitted acquisition of thin slice images with high contrast-to-noise ratio (CNR) and image intensity uniformity, while simultaneously accommodating patient setup and immobilization devices. Postprocessing corrections and alternative acquisition methods were required to reduce or correct off-resonance and gradient nonlinearity induced geometric distortions. CONCLUSIONS: The methodology described herein contains practical strategies the authors have implemented through lessons learned performing clinical MRI simulation exams. In their experience, these strategies provide robust, high fidelity, high contrast MR images suitable for external beam RTP.

Consolidating duodenal and small bowel toxicity data via isoeffective dose calculations based on compiled clinical data.

PURPOSE: To consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose-volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented. METHODS AND MATERIALS: A set of NTCP model parameters for duodenum toxicity were estimated by the χ(2) fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D(MLQED2),v) and convert these parameters to an isoeffective dose at another NTCP (D(MLQED2'),v). RESULTS: The literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD50(1)(model) = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy(-1). Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D(MLQED2'),v) between different NTCP levels remain consistent over a range of 5%-20%. CONCLUSIONS: MLQ-based isoeffective calculations of dose-response data corresponding to grade ≥2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D(MLQED2),v) data could be used to determine duodenum and small bowel dose-volume constraints for new dose escalation strategies.

Accelerated fractionation with a concurrent boost for early stage breast cancer.

Hypofractionated radiation refers to treatment with greater than 2 Gy per fraction, usually in fewer number and an overall shorter treatment period, compared to conventional radiation fractionation. Randomized prospective trials of hypofractionated whole breast irradiation (WBI) have demonstrated comparable outcomes as conventional fractionation in early stage postlumpectomy radiation in selected groups of patients. These data have changed the traditional radiobiology estimation of the alpha/beta ratio that predicted fractionation sensitivity for breast cancer, suggesting that further increase in dose per fraction is possible for early stage breast cancer without significantly increasing late effects. Many questions remain regarding hypofractionated WBI and span from optimal patient selection to radiation technique including dose planning optimization and the incorporation of a tumor bed boost. A concurrent radiation boost has been studied in a number of single institution studies and has shown to be feasible with acceptable acute and short-term late toxicity. A phase III trial by the Radiation Therapy Oncology Group (RTOG 1005) in North America and other trials in Europe are currently studying in-breast cancer control from hypofractionated WBI with a concurrent tumor bed boost. Results from these current trials could improve the acceptance and broaden the applicability of hypofractionation treatment courses for the treatment of patients with early stage breast cancer.

A phase I/II study piloting accelerated partial breast irradiation using CT-guided intensity modulated radiation therapy in the prone position.

BACKGROUND AND PURPOSE: External beam accelerated partial breast irradiation (EB-aPBI) is noninvasive with broader potential applicability than aPBI using brachytherapy. However, it has inherent challenges in daily reproducibility. Image-guide radiotherapy (IGRT) can improve daily reproducibility, allowing smaller treatment margins. Our institution proposed IG-IMRT in the prone position to evaluate dose homogeneity, conformality, normal tissue avoidance, and reliable targeting for EB-aPBI. We report preliminary results and toxicity from a phase I/II study evaluating the feasibility of EB-aPBI in the prone position using IG-IMRT. MATERIALS AND METHODS: Twenty post-menopausal women with node-negative breast cancer, excised tumors <3.0 cm, negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG-IMRT on an IRB-approved phase I/II study. All patients underwent CT planning in the prone position. The lumpectomy cavity PTV represented a 2.0 cm expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered >99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. RESULTS: The median patient age was 61.5. Mean tumor size was 1.0 cm. 35% of patients had DCIS. Median PTV was 243 cc (108-530) and median breast reference volume was 1698 cc (647-3627). Average daily shifts for IGRT were (0.6, -4.6, 1.7 mm) with standard deviations of (6.3, 6.5, 6.4mm). Acute toxicity was G1 erythema in 80%, and G2 erythema, G2 fatigue, and G2 breast pain each occurred in 1 patient. With a median follow-up of 18.9 months (12-35), 40% of patients have G1 fibrosis and 30% have G1 hyperpigmentation. 95% of patients have good to excellent cosmesis. There have been no recurrences. CONCLUSIONS: These data demonstrate that EB-aPBI in the prone position using IG-IMRT is well tolerated, yields good dosimetric conformality, and results in promising early toxicity profiles.

10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model.

PURPOSE: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. MATERIALS AND METHODS: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. RESULTS: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 +/- 8 vs. 58 +/- 6; 82 +/- 8 vs. 13 +/- 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 +/- 4% and 28 +/- 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 +/- 4% and 35 +/- 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 +/- 8 vs. 46 +/- 7%) and circumferential strain (-8 +/- 3 vs. -15 +/- 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. CONCLUSIONS: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.

Dose perturbations due to contrast medium and air in MammoSite® treatment: An experimental and Monte Carlo study.

In the management of early breast cancer, a partial breast irradiation technique called MammoSite® (Proxima Therapeutic Inc., Alpharetta, GA) has been advocated in recent years. In MammoSite, a balloon implanted at the surgical cavity during tumor excision is filled with a radio-opaque solution, and radiation is delivered via a high dose rate brachytherapy source situated at the center of the balloon. Frequently air may be introduced during placement of the balloon and/or injection of the contrast solution into the balloon. The purpose of this work is to quantify as well as to understand dose perturbations due to the presence of a high-Z contrast medium and/or an air bubble with measurements and Monte Carlo calculations. In addition, the measured dose distribution is compared with that obtained from a commercial treatment planning system (Nucletron PLATO system). For a balloon diameter of 42 mm, the dose variation as a function of distance from the balloon surface is measured for various concentrations of a radio-opaque solution (in the range 5%-25% by volume) with a small volume parallel plate ion chamber and a micro-diode detector placed perpendicular to the balloon axis. Monte Carlo simulations are performed to provide a basic understanding of the interaction mechanism and the magnitude of dose perturbation at the interface near balloon surface. Our results show that the radio-opaque concentration produces dose perturbation up to 6%. The dose perturbation occurs mostly within the distances <1mm from the balloon surface. The Plato system that does not include heterogeneity correction may be sufficient for dose planning at distances ⩾10mm from the balloon surface for the iodine concentrations used in the MammoSite procedures. The dose enhancement effect near the balloon surface (<1mm) due to the higher iodine concentration is not correctly predicted by the Plato system. The dose near the balloon surface may be increased by 0.5%percm3 of air. Monte Carlo simulation suggests that the interface effect (enhanced dose near surface) is primarily due to Compton electrons of short range (<0.5mm). For more accurate dosimetry in MammoSite delivery, the dose perturbation due to the presence of a radio-opaque contrast medium and air bubbles should be considered in a brachytherapy planning system.