Dose Accumulation Research Articles

Liver SBRT dose accumulation to assess the impact of anatomic variations on normal tissue doses and toxicity in patients treated with concurrent sorafenib

Background and PurposeUnexpected liver volume reductions occurred during trials of liver SBRT and concurrent sorafenib. The aims were to accumulate liver SBRT doses to assess the impact of these anatomic variations on normal tissue dose parameters and toxicity. Materials and MethodsThirty-two patients with hepatocellular carcinoma (HCC) or metastases treated on trials of liver SBRT (30–57 Gy, 6 fractions) and concurrent sorafenib were analyzed. SBRT doses were accumulated using biomechanical deformable registration of daily cone-beam CT. Dose deviations (accumulated-planned) for normal tissues were compared for patients with liver volume reductions > 100 cc versus stable volumes, and accumulated doses were reported for three patients with grade 3–5 luminal gastrointestinal toxicities. ResultsPatients with reduced (N = 12) liver volumes had larger mean deviations of 0.4–1.3 Gy in normal tissues, versus −0.2–0.4 Gy for stable cases (N = 20), P > 0.05. Deviations > 5% of the prescribed dose occurred in both groups. Two HCC patients with toxicities to small and large bowel had liver volume reductions and deviations to the maximum dose of 4% (accumulated 36.9 Gy) and 3% (accumulated 33.4 Gy) to these organs respectively. Another HCC patient with a toxicity of unknown location plus tumor rupture, had stable liver volumes and deviations to luminal organs of −6% to 4.5% (accumulated < 30.5 Gy). ConclusionLiver volume reductions during SBRT and concurrent sorafenib were associated with larger increases in accumulated dose to normal tissues versus stable liver volumes. These dosimetric changes may have further contributed to toxicities in HCC patients who have higher baseline risks.

A model for gastrointestinal tract motility in a 4D imaging phantom of human anatomy.

Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in radiation therapy for abdominal targets. Models for GI motility can improve the assessment of delivered dose and contribute to the development, testing, and validation of deformable image registration (DIR) and dose-accumulation algorithms. To implement GI tract motion in the 4D extended cardiac-torso (XCAT) digital phantom of human anatomy. Motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery were identified based on literature research. Search criteria included amplitude changes larger than planning risk volume expansions and durations of the order of tens of minutes. The following modes were identified: peristalsis, rhythmic segmentation, high amplitude propagating contractions (HAPCs), and tonic contractions. Peristalsis and rhythmic segmentations were modeled by traveling and standing sinusoidal waves. HAPCs and tonic contractions were modeled by traveling and stationary Gaussian waves. Wave dispersion in the temporal and spatial domain was implemented by linear, exponential, and inverse power law functions. Modeling functions were applied to the control points of the nonuniform rational B-spline surfaces defined in the reference XCAT library. GI motility was combined with the cardiac and respiratory motions available in the standard 4D-XCAT phantom. Default model parameters were estimated based on the analysis of cine MRI acquisitions in 10 patients treated in a 1.5T MR-linac. We demonstrate the ability to generate realistic 4D multimodal images that simulate GI motility combined with respiratory and cardiac motion. All modes of motility, except tonic contractions, were observed in the analysis of our cine MRI acquisitions. Peristalsis was the most common. Default parameters estimated from cine MRI were used as initial values for simulation experiments. It is shown that in patients undergoing stereotactic body radiotherapy for abdominal targets, the effects of GI motility can be comparable or larger than the effects of respiratory motion. The digital phantom provides realistic models to aid in medical imaging and radiation therapy research. The addition of GI motility will further contribute to the development, testing, and validation of DIR and dose accumulation algorithms for MR-guided radiotherapy.

Clinical 3D/4D cumulative proton dose assessment methods for thoracic tumours with large motion

PurposeDespite the anticipated clinical benefits of intensity-modulated proton therapy (IMPT), plan robustness may be compromised due to its sensitivity to patient treatment uncertainties, especially for tumours with large motion. In this study, we investigated treatment course-wise plan robustness for intra-thoracic tumours with large motion comparing a 4D pre-clinical evaluation method (4DREM) to our clinical 3D/4D dose reconstruction and accumulation methods. Materials and methodsTwenty patients with large target motion (>10 mm) were treated with five times layered rescanned IMPT. The 3D-robust optimised plans were generated on the averaged planning 4DCT. Using multiple 4DCTs, treatment plan robustness was assessed on a weekly and treatment course-wise basis through the 3D robustness evaluation method (3DREM, based on averaged 4DCTs), the 4D robustness evaluation method (4DREM, including the time structure of treatment delivery and 4DCT phases) and 4D dose reconstruction and accumulation (4DREAL, based on fraction-wise information). ResultsBaseline target motion for all patients ranged from 11–17 mm. For the offline adapted course-wise dose assessment, adequate target dose coverage was found for all patients. The target volume receiving 95% of the prescription dose was consistent between methods with 16/20 patients showing differences < 1%. 4DREAL showed the highest target coverage (99.8 ± 0.6%, p < 0.001), while no differences were observed between 3DREM and 4DREM (99.3 ± 1.3% and 99.4 ± 1.1%, respectively). ConclusionOur results show that intra-thoracic tumours can be adequately treated with IMPT in free breathing for target motion amplitudes up to 17 mm employing any of the accumulation methods. Anatomical changes, setup and range errors demonstrated a more severe impact on target coverage than motion in these patients treated with fractionated proton radiotherapy.

Weight-Based Bisphosphonate Administration for Multiple Myeloma Patients and the Risks of Skeletal Complications

High-dose bisphosphonate for multiple myeloma patients might elevate risks of skeletal complications earlier than general expectations. This study aims to find incidences of atypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ), elucidate their risk factors, and suggest cut-off values for the safer dosing of high-dose bisphosphonate treatment. By using the clinical data warehouse of a single institute, retrospective cohort data of multiple myeloma-diagnosed patients with high-dose bisphosphonate (pamidronate or zoledronate) treatment from 2009 to 2019 was extracted. Among 644 patients, the incidence of prominent AFF requiring surgery was 0.93% (6/644) and MRONJ was diagnosed in 11.8% (76/644) of the study population. For both AFF and MRONJ, the total potency-weighted sum of total dose per body weight (OR = 1.010, p = 0.005) were significant on logistic regression. Cutoffs of the potency-weighted total dose (mg) per body weight (kg) for AFF and MRONJ were 77.00 and 57.70 mg/kg, respectively. After roughly one year of treatment with high-dose zoledronate (about four years for pamidronate), an earlier thorough re-evaluation of skeletal complications should be taken. Body weight adjustments for accumulative dose calculation in terms of permissible dosing should be taken into consideration.

Applying Multi-Metric Deformable Image Registration for Dose Accumulation in Combined Cervical Cancer Radiotherapy

(1) Purpose: Challenges remain in dose accumulation for cervical cancer radiotherapy combined with external beam radiotherapy (EBRT) and brachytherapy (BT) as there are many large and complex organ deformations between different treatments. This study aims to improve deformable image registration (DIR) accuracy with the introduction of multi-metric objectives for dose accumulation of EBRT and BT. (2) Materials and methods: Twenty cervical cancer patients treated with EBRT (45-50 Gy/25 fractions) and high-dose-rate BT (≥20 Gy in 4 fractions) were included for DIR. The multi-metric DIR algorithm included an intensity-based metric, three contour-based metrics, and a penalty term. Nonrigid B-spine transformation was used to transform the planning CT images from EBRT to the first BT, with a six-level resolution registration strategy. To evaluate its performance, the multi-metric DIR was compared with a hybrid DIR provided by commercial software. The DIR accuracy was measured by the Dice similarity coefficient (DSC) and Hausdorff distance (HD) between deformed and reference organ contours. The accumulated maximum dose of 2 cc (D2cc) of the bladder and rectum was calculated and compared to simply addition of D2cc from EBRT and BT (ΔD2cc). (3) Results: The mean DSC of all organ contours for the multi-metric DIR were significantly higher than those for the hybrid DIR (p ≤ 0.011). In total, 70% of patients had DSC > 0.8 using the multi-metric DIR, while 15% of patients had DSC > 0.8 using the commercial hybrid DIR. The mean ΔD2cc of the bladder and rectum for the multi-metric DIR were 3.25 ± 2.29 and 3.54 ± 2.02 GyEQD2, respectively, whereas those for the hybrid DIR were 2.68 ± 2.56 and 2.32 ± 3.25 GyEQD2, respectively. The multi-metric DIR resulted in a much lower proportion of unrealistic D2cc than the hybrid DIR (2.5% vs. 17.5%). (4) Conclusions: Compared with the commercial hybrid DIR, the introduced multi-metric DIR significantly improved the registration accuracy and resulted in a more reasonable accumulated dose distribution.

Enzalutamide induced non-ischemic cardiomyopathy. A case report and review of literature on anti-androgen therapy-related cardiovascular events

Prostate cancer has a very high prevalence among elder men, and this could potentially increase as longevity in many parts of the world is increasing. Early stages of prostate cancer can have surgical options, but the more advanced stages require some form of anti-androgen therapy. There are novel anti-androgen agents that were recently approved. Cardiovascular toxicity has been reported with some of these drugs. This is a novel report of likely cardiovascular toxicity due to Enzalutamide, which typically has a safer cardiovascular profile than Abiraterone.We describe a 72-year-old male with repeated recurrence of prostate cancer with metastasis. The second time it recurred was within 2 years of the 1st recurrence and was treated with Enzalutamide.However, within 2 weeks he developed systolic congestive heart failure that improved with stopping the drug and medical optimization.Literature review shows that Abiraterone has more cardiovascular side effects than Enzalutamide which more commonly causes hypertension. The timeline in our case suggests Enzalutamide causing congestive heart failure which is a novel finding. This finding warrants further research regarding the safety profile of novel anti-androgen therapy. This includes risk stratification for potential cardiovascular adverse events and risk/benefit analysis prior to initiating therapy. Data on cumulative dose accumulation and risks can also be an area of future research.

Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination—the SPIRAL study

BackgroundOpioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain.MethodsTrial design: a single-center, randomized, three-arm, open-label, exploratory trial.Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists.Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol®, containing 6.3% Δ9-tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period.Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia.Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations.DiscussionThe trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia.Trial registration {2a and 2b}EU trial register 2019–001861-33, URL https://www.clinicaltrialsregister.eu, on July 17, 2019; World Health Organization International Clinical Trials Research Platform NL7902, URL https://trialsearch.who.int, on July 26, 2019.

Dose accumulation for MR-guided adaptive radiotherapy: From practical considerations to state-of-the-art clinical implementation.

MRI-linear accelerator (MR-linac) devices have been introduced into clinical practice in recent years and have enabled MR-guided adaptive radiation therapy (MRgART). However, by accounting for anatomical changes throughout radiation therapy (RT) and delivering different treatment plans at each fraction, adaptive radiation therapy (ART) highlights several challenges in terms of calculating the total delivered dose. Dose accumulation strategies-which typically involve deformable image registration between planning images, deformable dose mapping, and voxel-wise dose summation-can be employed for ART to estimate the delivered dose. In MRgART, plan adaptation on MRI instead of CT necessitates additional considerations in the dose accumulation process because MRI pixel values do not contain the quantitative information used for dose calculation. In this review, we discuss considerations for dose accumulation specific to MRgART and in relation to current MR-linac clinical workflows. We present a general dose accumulation framework for MRgART and discuss relevant quality assurance criteria. Finally, we highlight the clinical importance of dose accumulation in the ART era as well as the possible ways in which dose accumulation can transform clinical practice and improve our ability to deliver personalized RT.

Inter- and intrafractional 4D dose accumulation for evaluating ΔNTCP robustness in lung cancer

Background and purposeModel-based selection of proton therapy patients relies on a predefined reduction in normal tissue complication probability (NTCP) with respect to photon therapy. The decision is necessarily made based on the treatment plan, but NTCP can be affected when the delivered treatment deviates from the plan due to delivery inaccuracies. Especially for proton therapy of lung cancer, this can be important because of tissue density changes and, with pencil beam scanning, the interplay effect between the proton beam and breathing motion. Materials and methodsIn this work, we verified whether the expected benefit of proton therapy is retained despite delivery inaccuracies by reconstructing the delivered treatment using log-file based dose reconstruction and inter- and intrafractional accumulation. Additionally, the importance of two uncertain parameters for treatment reconstruction, namely deformable image registration (DIR) algorithm and α/β ratio, was assessed. ResultsThe expected benefit or proton therapy was confirmed in 97% of all studied cases, despite regular differences up to 2 percent point (p.p.) NTCP between the delivered and planned treatments. The choice of DIR algorithm affected NTCP up to 1.6 p.p., an order of magnitude higher than the effect of α/β ratio. ConclusionFor the patient population and treatment technique employed, the predicted clinical benefit for patients selected for proton therapy was confirmed for 97.0% percent of all cases, although the NTCP based proton selection was subject to 2 p.p. variations due to delivery inaccuracies.

Machine-learning-based prediction of the effectiveness of the delivered dose by exhale-gated radiotherapy for locally advanced lung cancer: The additional value of geometric over dosimetric parameters alone.

This study aimed to assess interfraction stability of the delivered dose distribution by exhale-gated volumetric modulated arc therapy (VMAT) or intensity-modulated arc therapy (IMAT) for lung cancer and to determine dominant prognostic dosimetric and geometric factors. Clinical target volume (CTVPlan) from the planning CT was deformed to the exhale-gated daily CBCT scans to determine CTVi, treated by the respective dose fraction. The equivalent uniform dose of the CTVi was determined by the power law (gEUDi) and cell survival model (EUDiSF) as effectiveness measure for the delivered dose distribution. The following prognostic factors were analyzed: (I) minimum dose within the CTVi (Dmin_i), (II) Hausdorff distance (HDDi) between CTVi and CTVPlan, (III) doses and deformations at the point in CTVPlan at which the global minimum dose over all fractions per patient occurs (PDmin_global_i), and (IV) deformations at the point over all CTVi margins per patient with the largest Hausdorff distance (HDPworst). Prognostic value and generalizability of the prognostic factors were examined using cross-validated random forest or multilayer perceptron neural network (MLP) classifiers. Dose accumulation was performed using back deformation of the dose distribution from CTVi to CTVPlan. Altogether, 218 dose fractions (10 patients) were evaluated. There was a significant interpatient heterogeneity between the distributions of the normalized gEUDi values (p<0.0001, Kruskal-Wallis tests). Accumulated gEUD over all fractions per patient was 1.004-1.023 times of the prescribed dose. Accumulation led to tolerance of ~20% of fractions with gEUDi <93% of the prescribed dose. Normalized Dmin >60% was associated with predicted gEUD values above 95%. Dmin had the highest importance for predicting the gEUD over all analyzed prognostic parameters by out-of-bag loss reduction using the random forest procedure. Cross-validated random forest classifier based on Dmin as the sole input had the largest Pearson correlation coefficient (R=0.897) in comparison to classifiers using additional input variables. The neural network performed better than the random forest classifier, and the gEUD values predicted by the MLP classifier with Dmin as the sole input were correlated with the gEUD values characterized by R=0.933 (95% CI, 0.913-0.948). The performance of the full MLP model with all geometric input parameters was slightly better (R=0.952) than that based on Dmin (p=0.0034, Z-test). Accumulated dose distributions over the treatment series were robust against interfraction CTV deformations using exhale gating and online image guidance. Dmin was the most important parameter for gEUD prediction for a single fraction. All other parameters did not lead to a markedly improved generalizable prediction. Dosimetric information, especially location and value of Dmin within the CTV i , are vital information for image-guided radiation treatment.

Dosimetric impact of deformable image registration using radiophotoluminescent glass dosimeters with a physical geometric phantom.

To study the dosimetry impact of deformable image registration (DIR) using radiophotoluminescent glass dosimeter (RPLD) and custom developed phantom with various inserts. The phantom was developed to facilitate simultaneous evaluation of geometric and dosimetric accuracy of DIR. Four computed tomography (CT) images of the phantom were acquired with four different configurations. Four volumetric modulated arc therapy (VMAT) plans were computed for different phantom. Two different patterns were applied to combination of four phantom configurations. RPLD dose measurement was combined between corresponding two phantom configurations. DIR-based dose accumulation was calculated between corresponding two CT images with two commercial DIR software and various DIR parameter settings, and an open source software. Accumulated dose calculated using DIR was then compared with measured dose using RPLD. The mean±standard deviation (SD) of dose difference was 2.71±0.23% (range, 2.22%-3.01%) for tumor-proxy and 3.74±0.79% (range, 1.56%-4.83%) for rectum-proxy. The mean±SD of target registration error (TRE) was 1.66±1.36mm (range, 0.03-4.43mm) for tumor-proxy and 6.87±5.49mm (range, 0.54-17.47mm) for rectum-proxy. These results suggested that DIR accuracy had wide range among DIR parameter setting. The dose difference observed in our study was 3% for tumor-proxy and within 5% for rectum-proxy. The custom developed physical phantom with inserts showed potential for accurate evaluation of DIR-based dose accumulation. The prospect of simultaneous evaluation of geometric and dosimetric DIR accuracy in a single phantom may be useful for validation of DIR for clinical use.

Real-time, volumetric imaging of radiation dose delivery deep into the liver during cancer treatment.

Ionizing radiation acoustic imaging (iRAI) allows online monitoring of radiation's interactions with tissues during radiation therapy, providing real-time, adaptive feedback for cancer treatments. We describe an iRAI volumetric imaging system that enables mapping of the three-dimensional (3D) radiation dose distribution in a complex clinical radiotherapy treatment. The method relies on a two-dimensional matrix array transducer and a matching multi-channel preamplifier board. The feasibility of imaging temporal 3D dose accumulation was first validated in a tissue-mimicking phantom. Next, semiquantitative iRAI relative dose measurements were verified in vivo in a rabbit model. Finally, real-time visualization of the 3D radiation dose delivered to a patient with liver metastases was accomplished with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the 3D radiation dose deposition during treatment, potentially improving radiotherapy treatment efficacy using real-time adaptive treatment.

Analysis of the effect of cytomegalovirus infection in clinical outcomes and prolonged duration of SARS-CoV-2 shedding in intensive care unit patients with COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) is a global outbreak disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cytomegalovirus (CMV) infection can occur in critical COVID-19 patients and is associated with adverse clinical outcomes. The aim of this study was to explore the clinical characteristics and outcome of CMV infection in critical COVID-19 patients. This was a retrospective cohort study. From May to September 2021, SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients with intensive care unit (ICU) admission were enrolled. CMV infection was confirmed by PCR. Baseline characteristics, critical illness data and clinical outcomes were recorded and analyzed. Seventy-two RT-PCR-confirmed COVID-19 patients with ICU admission were included during the study period and 48 (66.7%) patients required mechanical ventilation (MV). Overall, in-hospital mortality was 19.4%. Twenty-one (29.2%) patients developed CMV infection. Patients with CMV infection had a higher likelihood of diabetes, higher lactate dehydrogenase and lactate levels, and higher proportions of MV, anticoagulant, and steroid use. Patients with CMV infection were associated with longer duration of SARS-CoV-2 shedding, longer ICU and hospital stay, and fewer ventilator-free days. The independent risk factor for development of CMV infection was a higher accumulative steroid dose. CMV infection adversely impacted the outcomes of critical COVID-19 patients, resulting in longer ICU stays, longer mechanical ventilation uses and prolonged shedding of SARS-CoV-2.

Evaluation of RayStation's delivered dose and accumulated dose features for spine stereotactic radiotherapy

<h2>Abstract</h2> We investigated delivered dose and dose accumulation features in the dose tracking module of RayStation version 11B before potential integration into the spine stereotactic radiosurgery (SSRS) program at our institution. End-to-end testing with a rigid Rando phantom was performed, and 10 retrospective clinical cases were selected for evaluation. Pre-treatment cone beam CTs (pCBCT) were corrected for Hounsfield unit (HU) integrity and contours were rigidly copied from the reference plan. We then calculated the delivered dose to the corrected cone beam CT (cCBCT). A deformable image registration (DIR) was generated between cCBCT and reference planning CT (rCT) using controlling region of interests. Deformed delivered dose to the rCT was summed to generate the accumulated dose for multiple fractions. The end-to-end tests of the phantom study revealed an improvement of cCBCT HU information by > 100 HU compared to the pCBCT. When compared to the reference plan, the delivered dose and deformed delivered dose were within 1.0% for the GTV and CTV and 3.0% for the spinal cord, respectively. Nearly all 10 clinical cases demonstrated delivered dose and accumulated dose deviations < 3.0% from the reference plan. However, 2 patients rendered delivered dose deviations between 3.0% and 4.0%, showing the effectiveness of the module. The dose tracking module in RayStation version 11B could potentially be utilized to aid clinical decision-making for external body shape change or positional deviation in SSRS for rigid target and critical structures. Evaluation before clinical application under one's specific practice is required, and results must be carefully analyzed specially near the high dose gradient area.

Growing Season, Cultivar, and Nitrogen Supply Affect Leaf and Fruit Micronutrient Status of Field-Grown Kiwiberry Vines

The N uptake can affect kiwiberry yield and quality; however, the relationship between an increasing N dose and micronutrient accumulation in leaves and fruit is still to be elucidated. Interrelationships between essential nutrients are one of the most important issues in terms of effectiveness in plant mineral nutrition. A pattern in leaf nutrient accumulation throughout the growing period is required to indicate a suitable sampling time for the purpose of nutrient diagnostics and controlled plant feeding. The experiment was conducted on two commercially available cultivars of kiwiberry, 'Weiki' and 'Geneva', during the 2015-2016 growing seasons with an increasing soil N fertility (30-50-80 mg N kg-1 soil DW) to test the relationship between soil N level and leaf/fruit micronutrient concentration. The leaf Zn, Cu, Fe, and Mn concentrations significantly increased with a higher N supply in 'Geneva', while in 'Weiki' only Mn increased. Leaf B, Fe, and Mn gradually increased throughout the growing season, while Cu decreased. Between mid-July and the beginning of August, the lowest fluctuations in the micronutrient contents were recorded. The effect of the growing season on leaf micronutrient accumulation was highly significant; except for Fe, significantly higher micronutrient levels were revealed in 2016. Compared to the leaves, the growing season effect was smaller in the case of fruit micronutrient concentrations. Irrespective of cultivar, the increase in N fertilization resulted in a higher fruit Mn concentration and was insignificant in the case of other micronutrients. The results indicate that the N dose may affect the accumulation of micronutrients within a certain range depending on the tissue type and the genotype.

Interfractional dose accumulation for MR-guided liver SBRT: Variation among algorithms is highly patient- and fraction-dependent

Background and purposeDaily plan adaptations could take the dose delivered in previous fractions into account. Due to high dose delivered per fraction, low number of fractions, steep dose gradients, and large interfractional organ deformations, this might be particularly important for liver SBRT. This study investigates inter-algorithm variation of interfractional dose accumulation for MR-guided liver SBRT. Materials and methodsWe assessed 27 consecutive MR-guided liver SBRT treatments of 67.5 Gy in three (n = 15) or 50 Gy in five fractions (n = 12), both prescribed to the GTV. We calculated fraction doses on daily patient anatomy, warped these doses to the simulation MRI using seven different algorithms, and accumulated the warped doses. Thus, we obtained differences in planned doses and warped or accumulated doses for each algorithm. This enabled us to calculate the inter-algorithm variations in warped doses per fraction and in accumulated doses per treatment course. ResultsThe four intensity-based algorithms were more consistent with planned PTV dose than affine or contour-based algorithms. The mean (range) variation of the dose difference for PTV D95% due to dose warping by these intensity-based algorithms was 10.4 percentage points (0.3 to 43.7) between fractions and 8.6 (0.3 to 24.9) between accumulated treatment doses. As seen by these ranges, the variation was very dependent on the patient and the fraction being analyzed. Nevertheless, no correlations between patient or plan characteristics on the one hand and inter-algorithm dose warping variation on the other hand was found. ConclusionInter-algorithm dose accumulation variation is highly patient- and fraction-dependent for MR-guided liver SBRT. We advise against trusting a single algorithm for dose accumulation in liver SBRT.

Detailed dosimetric evaluation of inter-fraction and respiratory motion in lung stereotactic body radiation therapy based on daily 4D cone beam CT images

Objective. Periodic respiratory motion and inter-fraction variations are sources of geometric uncertainty in stereotactic body radiation therapy (SBRT) of pulmonary lesions. This study extensively evaluates and validates the separate and combined dosimetric effect of both factors using 4D-CT and daily 4D-cone beam CT (CBCT) dose accumulation scenarios. Approach. A first cohort of twenty early stage or metastatic disease lung cancer patients were retrospectively selected to evaluate each scenario. The planned-dose (3DRef) was optimized on a 3D mid-position CT. To estimate the dosimetric impact of respiratory motion (4DRef), inter-fractional variations (3DAcc) and the combined effect of both factors (4DAcc), three dose accumulation scenarios based on 4D-CT, daily mid-cone beam CT (CBCT) position and 4D-CBCT were implemented via CT-CT/CT-CBCT deformable image registration (DIR) techniques. Each scenario was compared to 3DRef. A separate cohort of ten lung SBRT patients was selected to validate DIR techniques. The distance discordance metric (DDM) was implemented per voxel and per patient for tumor and organs at risk (OARs), and the dosimetric impact for CT-CBCT DIR geometric errors was calculated. Main results. Median and interquartile range (IQR) of the dose difference per voxel were 0.05/2.69 Gy and −0.12/2.68 Gy for and For the IQR was considerably smaller −0.15/0.78 Gy. These findings were confirmed by dose volume histogram parameters calculated in tumor and OARs. For CT-CT/CT-CBCT DIR validation, DDM (95th percentile) was highest for heart (6.26 mm)/spinal cord (8.00 mm), and below 3 mm for tumor and the rest of OARs. The dosimetric impact of CT-CBCT DIR errors was below 2 Gy for tumor and OARs. Significance. The dosimetric impact of inter-fraction variations were shown to dominate those of periodic respiration in SBRT for pulmonary lesions. Therefore, treatment evaluation and dose-effect studies would benefit more from dose accumulation focusing on day-to-day changes then those that focus on respiratory motion.

A temporo-spatial description of moving tumor and organs by the probability of presence time proportion: concept and implementation for 4D dose calculation and optimization

Objective. The binary definition of the internal target volume (ITV) artificially separates tumor from healthy organs at motion overlapping area for dose evaluation and optimization, bringing confusion about taking partial organs as tumor or adversely. In this work, the probability of presence time (PPT) proportion of a moving anatomic voxel at a geometric voxel is defined to construct a temporo-spatial description of moving objects. The geometric overlapping of tumor and organs in 3D space is distinguished by individual residence time proportion. The dose deposition at a geometric voxel is decomposed into individual dose delivered to tumor and organs for accumulative dose calculation and optimization. Approach. A novel PPT-based plan optimization strategy is proposed to generate an optimized non-uniform dose distribution based on the temporo-spatial relationship between tumor and organs. Main results. Results from a simulation study on phantoms show that the proposed method provides promising performance for surrounding organs at risk (OAR) avoidance with a reduction of mean and maximum dose at a range of 22.6%–23.1% and 23.6%–28.3% compared with ITV-based plans under different geometric conditions, while keeping the clinical target volume dose as prescription. Significance. The PPT definition constructs a unified framework to deal with the 4D temporo-spatial distribution, accumulative dose calculation and optimization of moving tumor and organs. The advantages of the PPT-based dose calculation and optimization approach are demonstrated by simulation study with significant reduction of OARs dose level compared with conventional ITV-based plan.

Paper based radiochromic film for the detection and measurement of therapeutic radiation doses in radiotherapy: A preliminary study

Radiotherapy is an effective and complex treatment modality for the ablation of malignant tumors. Despite several technological advances, precise determination of the radiation dose delivered to the tumor and its neighbouring healthy tissues remains a challenge. This work focuses on the synthesis and characterisation of a symmetrically substituted diacetylene which is coated on a paper to function as a radiochromic film. The paper-based film exhibits distinct color change from white to varying shades of blue from the 0.5–20 Gy dose range administered in radiotherapy. The difference in the color intensity of the radiochromic film is used as a quantitative indicator of the radiation dose delivered. A comprehensive evaluation of general optical characteristics, dosimetric properties and stability of the dose response is performed. The prepared film is tissue-equivalent with weak dependence on dosimetric parameters like energy, dose rate and dose accumulation. It can be stored under normal room conditions as the influence of variation in temperature, light intensity and post irradiation time was found to be <2%. The uncertainty in the dose response based on the calibration curve was found to be 2.74%. The therapeutic range of radiation dose detection, facile fabrication and implementation of this radiochromic film can be potentially translated into different radiotherapy clinical applications.

Development of a multi-layer quality assurance program to evaluate the uncertainty of deformable dose accumulation in adaptive radiotherapy.

Deformable dose accumulation (DDA) has uncertainties which impede the implementation of DDA-based adaptive radiotherapy (ART) in clinic. The purpose of this study is to develop a multi-layer quality assurance (MLQA) program to evaluate uncertainties in DDA. A computer program is developed to generate a pseudo-inverse displacement vector field (DVF) for each deformable image registration (DIR) performed in Accuray's PreciseART. The pseudo-inverse DVF is first used to calculate a pseudo-inverse consistency error (PICE) and then implemented in an energy and mass congruent mapping (EMCM) method to reconstruct a deformed dose. The PICE is taken as a metric to estimate DIR uncertainties. A pseudo-inverse dose agreement rate (PIDAR) is used to evaluate the consequence of the DIR uncertainties in DDA and the principle of energy conservation is used to validate the integrity of dose mappings. The developed MLQA program was tested using the data collected from five representative cancer patients treated with tomotherapy. DIRs were performed in PreciseART to generate primary DVFs for the five patients. The fidelity index and PICE of these DVFs on average are equal to 0.028mm and 0.169mm, respectively. With the criteria of 3mm/3% and 5mm/5%, the PIDARs of the PreciseART-reconstructed doses are 73.9±4.4% and 87.2±3.3%, respectively. The PreciseART and EMCM-based dose reconstructions have their deposited energy changed by 5.6±3.9% and 2.6±1.5% in five GTVs, and by 9.2±7.8% and 4.7±3.6% in 30 OARs, respectively. A pseudo-inverse map-based EMCM program has been developed to evaluate DIR and dose mapping uncertainties. This program could also be used as a sanity check tool for DDA-based ART.