Increasing the efficiency of cone-beam CT based delta-radiomics using automated contours to predict radiotherapy-related toxicities in prostate cancer.

Extracting longitudinal image quantitative data, known as delta-radiomics, has the potential to capture changes in a patient's anatomy throughout the course of radiation treatment for prostate cancer. Some of the major challenges of delta-radiomics studies are contouring the structures for individual fractions and accruing patients' data in an efficient manner. The manual contouring process is often time consuming and would limit the efficiency of accruing larger sample sizes for future studies. The problem is amplified because the contours are often made by highly trained radiation oncologists with limited time to dedicate to research studies of this nature. This work compares the use of automated prostate contours generated using a deformable image-based algorithm to make predictive models of genitourinary and changes in total international prostate symptom score in comparison to manually contours for a cohort of fifty patients. Area under the curve of manual and automated models were compared using the Delong test. This study demonstrated that the delta-radiomics models were similar for both automated and manual delta-radiomics models.

Cone beam CT-based adaptive intensity modulated proton therapy assessment using automated planning for head-and-neck cancer.

BACKGROUND: To assess the feasibility of CBCT-based adaptive intensity modulated proton therapy (IMPT) using automated planning for treatment of head and neck (HN) cancers. METHODS: Twenty HN cancer patients who received radiotherapy and had pretreatment CBCTs were included in this study. Initial IMPT plans were created using automated planning software for all patients. Synthetic CTs (sCT) were then created by deforming the planning CT (pCT) to the pretreatment CBCTs. To assess dose calculation accuracy on sCTs, repeat CTs (rCTs) were deformed to the pretreatment CBCT obtained on the same day to create deformed rCT (rCTdef), serving as gold standard. The dose recalculated on sCT and on rCTdef were compared by using Gamma analysis. The accuracy of DIR generated contours was also assessed. To explore the potential benefits of adaptive IMPT, two sets of plans were created for each patient, a non-adapted IMPT plan and an adapted IMPT plan calculated on weekly sCT images. The weekly doses for non-adaptive and adaptive IMPT plans were accumulated on the pCT, and the accumulated dosimetric parameters of two sets were compared. RESULTS: Gamma analysis of the dose recalculated on sCT and rCTdef resulted in a passing rate of 97.9% ± 1.7% using 3 mm/3% criteria. With the physician-corrected contours on the sCT, the dose deviation range of using sCT to estimate mean dose for the most organ at risk (OARs) can be reduced to (- 2.37%, 2.19%) as compared to rCTdef, while for V95 of primary or secondary CTVs, the deviation can be controlled within (- 1.09%, 0.29%). Comparison of the accumulated doses from the adaptive planning against the non-adaptive plans reduced mean dose to constrictors (- 1.42 Gy ± 2.79 Gy) and larynx (- 2.58 Gy ± 3.09 Gy). The reductions result in statistically significant reductions in the normal tissue complication probability (NTCP) of larynx edema by 7.52% ± 13.59%. 4.5% of primary CTVs, 4.1% of secondary CTVs, and 26.8% tertiary CTVs didn't meet the V95 > 95% constraint on non-adapted IMPT plans. All adaptive plans were able to meet the coverage constraint. CONCLUSION: sCTs can be a useful tool for accurate proton dose calculation. Adaptive IMPT resulted in better CTV coverage, OAR sparing and lower NTCP for some OARs as compared with non-adaptive IMPT.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Multimodal magnetic resonance imaging after experimental moderate and severe traumatic brain injury: A longitudinal correlative assessment of structural and cerebral blood flow changes.

Traumatic brain injury (TBI) is a worldwide problem that results in death or disability for millions of people every year. Progressive neurological complications and long-term impairment can significantly disrupt quality of life. We demonstrated the feasibility of multiple magnetic resonance imaging (MRI) modalities to investigate and predict aberrant changes and progressive atrophy of gray and white matter tissue at several acute and chronic time points after moderate and severe parasagittal fluid percussion TBI. T2-weighted imaging, diffusion tensor imaging (DTI), and perfusion weighted imaging (PWI) were performed. Adult Sprague-Dawley rats were imaged sequentially on days 3, 14, and 1, 4, 6, 8, and 12 months following surgery. TBI caused dynamic white and gray matter alterations with significant differences in DTI values and injury-induced alterations in cerebral blood flow (CBF) as measured by PWI. Regional abnormalities after TBI were observed in T2-weighted images that showed hyperintense cortical lesions and significant cerebral atrophy in these hyperintense areas 1 year after TBI. Temporal DTI values indicated significant injury-induced changes in anisotropy in major white matter tracts, the corpus callosum and external capsule, and in gray matter, the hippocampus and cortex, at both early and chronic time points. These alterations were primarily injury-severity dependent with severe TBI exhibiting a greater degree of change relative to uninjured controls. PWI evaluating CBF revealed sustained global reductions in the cortex and in the hippocampus at most time points in an injury-independent manner. We next sought to investigate prognostic correlations across MRI metrics, timepoints, and cerebral pathology, and found that diffusion abnormalities and reductions in CBF significantly correlated with specific vulnerable structures at multiple time points, as well as with the degree of cerebral atrophy observed 1 year after TBI. This study further supports using DTI and PWI as a means of prognostic imaging for progressive structural changes after TBI and emphasizes the progressive nature of TBI damage.

AAPM Task Group Report 307: Use of EPIDs for Patient-Specific IMRT and VMAT QA.

PURPOSE: Electronic portal imaging devices (EPIDs) have been widely utilized for patient-specific quality assurance (PSQA) and their use for transit dosimetry applications is emerging. Yet there are no specific guidelines on the potential uses, limitations, and correct utilization of EPIDs for these purposes. The American Association of Physicists in Medicine (AAPM) Task Group 307 (TG-307) provides a comprehensive review of the physics, modeling, algorithms and clinical experience with EPID-based pre-treatment and transit dosimetry techniques. This review also includes the limitations and challenges in the clinical implementation of EPIDs, including recommendations for commissioning, calibration and validation, routine QA, tolerance levels for gamma analysis and risk-based analysis. METHODS: Characteristics of the currently available EPID systems and EPID-based PSQA techniques are reviewed. The details of the physics, modeling, and algorithms for both pre-treatment and transit dosimetry methods are discussed, including clinical experience with different EPID dosimetry systems. Commissioning, calibration, and validation, tolerance levels and recommended tests, are reviewed, and analyzed. Risk-based analysis for EPID dosimetry is also addressed. RESULTS: Clinical experience, commissioning methods and tolerances for EPID-based PSQA system are described for pre-treatment and transit dosimetry applications. The sensitivity, specificity, and clinical results for EPID dosimetry techniques are presented as well as examples of patient-related and machine-related error detection by these dosimetry solutions. Limitations and challenges in clinical implementation of EPIDs for dosimetric purposes are discussed and acceptance and rejection criteria are outlined. Potential causes of and evaluations of pre-treatment and transit dosimetry failures are discussed. Guidelines and recommendations developed in this report are based on the extensive published data on EPID QA along with the clinical experience of the TG-307 members. CONCLUSION: TG-307 focused on the commercially available EPID-based dosimetric tools and provides guidance for medical physicists in the clinical implementation of EPID-based patient-specific pre-treatment and transit dosimetry QA solutions including intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) treatments.

Single Fraction and Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, and Reduced Viability of Merlin-Deficient Schwann Cells.

BACKGROUND: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). METHODS: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. RESULTS: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. CONCLUSIONS: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Cone-beam CT delta-radiomics to predict genitourinary toxicities and international prostate symptom of prostate cancer patients: a pilot study.

For prostate cancer (PCa) patients treated with definitive radiotherapy (RT), acute and late RT-related genitourinary (GU) toxicities adversely impact disease-specific quality of life. Early warning of potential RT toxicities can prompt interventions that may prevent or mitigate future adverse events. During intensity modulated RT (IMRT) of PCa, daily cone-beam computed tomography (CBCT) images are used to improve treatment accuracy through image guidance. This work investigated the performance of CBCT-based delta-radiomic features (DRF) models to predict acute and sub-acute International Prostate Symptom Scores (IPSS) and Common Terminology Criteria for Adverse Events (CTCAE) version 5 GU toxicity grades for 50 PCa patients treated with definitive RT. Delta-radiomics models were built using logistic regression, random forest for feature selection, and a 1000 iteration bootstrapping leave one analysis for cross validation. To our knowledge, no prior studies of PCa have used DRF models based on daily CBCT images. AUC of 0.83 for IPSS and greater than 0.7 for CTCAE grades were achieved as early as week 1 of treatment. DRF extracted from CBCT images showed promise for the development of models predictive of RT outcomes. Future studies will include using artificial intelligence and machine learning to expand CBCT sample sizes available for radiomics analysis.

Multi-parametric MRI (mpMRI) for treatment response assessment of radiation therapy.

Magnetic resonance imaging (MRI) plays an important role in the modern radiation therapy (RT) workflow. In comparison with computed tomography (CT) imaging, which is the dominant imaging modality in RT, MRI possesses excellent soft-tissue contrast for radiographic evaluation. Based on quantitative models, MRI can be used to assess tissue functional and physiological information. With the developments of scanner design, acquisition strategy, advanced data analysis, and modeling, multiparametric MRI (mpMRI), a combination of morphologic and functional imaging modalities, has been increasingly adopted for disease detection, localization, and characterization. Integration of mpMRI techniques into RT enriches the opportunities to individualize RT. In particular, RT response assessment using mpMRI allows for accurate characterization of both tissue anatomical and biochemical changes to support decision-making in monotherapy of radiation treatment and/or systematic cancer management. In recent years, accumulating evidence have, indeed, demonstrated the potentials of mpMRI in RT response assessment regarding patient stratification, trial benchmarking, early treatment intervention, and outcome modeling. Clinical application of mpMRI for treatment response assessment in routine radiation oncology workflow, however, is more complex than implementing an additional imaging protocol; mpMRI requires additional focus on optimal study design, practice standardization, and unified statistical reporting strategy to realize its full potential in the context of RT. In this article, the mpMRI theories, including image mechanism, protocol design, and data analysis, will be reviewed with a focus on the radiation oncology field. Representative works will be discussed to demonstrate how mpMRI can be used for RT response assessment. Additionally, issues and limits of current works, as well as challenges and potential future research directions, will also be discussed.

Knowledge-Based Planning for Robustly Optimized Intensity-Modulated Proton Therapy of Head and Neck Cancer Patients.

PURPOSE: To assess the performance of a proton-specific knowledge-based planning (KBP) model in the creation of robustly optimized intensity-modulated proton therapy (IMPT) plans for treatment of advanced head and neck (HN) cancer patients. METHODS: Seventy-three patients diagnosed with advanced HN cancer previously treated with volumetric modulated arc therapy (VMAT) were selected and replanned with robustly optimized IMPT. A proton-specific KBP model, RapidPlanPT (RPP), was generated using 53 patients (20 unilateral cases and 33 bilateral cases). The remaining 20 patients (10 unilateral and 10 bilateral cases) were used for model validation. The model was validated by comparing the target coverage and organ at risk (OAR) sparing in the RPP-generated IMPT plans with those in the expert plans. To account for the robustness of the plan, all uncertainty scenarios were included in the analysis. RESULTS: All the RPP plans generated were clinically acceptable. For unilateral cases, RPP plans had higher CTV_primary V100 (1.59% ± 1.24%) but higher homogeneity index (HI) (0.7 ± 0.73) than had the expert plans. In addition, the RPP plans had better ipsilateral cochlea Dmean (-5.76 ± 6.11 Gy), with marginal to no significant difference between RPP plans and expert plans for all other OAR dosimetric indices. For the bilateral cases, the V100 for all clinical target volumes (CTVs) was higher for the RPP plans than for the expert plans, especially the CTV_primary V100 (5.08% ± 3.02%), with no significant difference in the HI. With respect to OAR sparing, RPP plans had a lower spinal cord Dmax (-5.74 ± 5.72 Gy), lower cochlea Dmean (left, -6.05 ± 4.33 Gy; right, -4.84 ± 4.66 Gy), lower left and right parotid V20Gy (left, -6.45% ± 5.32%; right, -6.92% ± 3.45%), and a lower integral dose (-0.19 ± 0.19 Gy). However, RPP plans increased the Dmax in the body outside of CTV (body-CTV) (1.2 ± 1.43 Gy), indicating a slightly higher hotspot produced by the RPP plans. CONCLUSION: IMPT plans generated by a broad-scope RPP model have a quality that is, at minimum, comparable with, and at times superior to, that of the expert plans. The RPP plans demonstrated a greater robustness for CTV coverage and better sparing for several OARs.

Assessment of CT to CBCT contour mapping for radiomic feature analysis in prostate cancer.

This study provides a quantitative assessment of the accuracy of a commercially available deformable image registration (DIR) algorithm to automatically generate prostate contours and additionally investigates the robustness of radiomic features to differing contours. Twenty-eight prostate cancer patients enrolled on an institutional review board (IRB) approved protocol were selected. Planning CTs (pCTs) were deformably registered to daily cone-beam CTs (CBCTs) to generate prostate contours (auto contours). The prostate contours were also manually drawn by a physician. Quantitative assessment of deformed versus manually drawn prostate contours on daily CBCT images was performed using Dice similarity coefficient (DSC), mean distance-to-agreement (MDA), difference in center-of-mass position (ΔCM) and difference in volume (ΔVol). Radiomic features from 6 classes were extracted from each contour. Lin's concordance correlation coefficient (CCC) and mean absolute percent difference in radiomic feature-derived data (mean |%Δ|RF) between auto and manual contours were calculated. The mean (± SD) DSC, MDA, ΔCM and ΔVol between the auto and manual prostate contours were 0.90 ± 0.04, 1.81 ± 0.47 mm, 2.17 ± 1.26 mm and 5.1 ± 4.1% respectively. Of the 1,010 fractions under consideration, 94.8% of DIRs were within TG-132 recommended tolerance. 30 radiomic features had a CCC > 0.90 and 21 had a mean |%∆|RF < 5%. Auto-propagation of prostate contours resulted in nearly 95% of DIRs within tolerance recommendations of TG-132, leading to the majority of features being regarded as acceptably robust. The use of auto contours for radiomic feature analysis is promising but must be done with caution.

Assessment of Knowledge-Based Planning for Prostate Intensity Modulated Proton Therapy.

PURPOSE: To assess the performance of a proton-specific knowledge based planning (KBPP) model in creation of robustly optimized intensity-modulated proton therapy (IMPT) plans for treatment of patients with prostate cancer. MATERIALS AND METHODS: Forty-five patients with localized prostate cancer, who had previously been treated with volumetric modulated arc therapy, were selected and replanned with robustly optimized IMPT. A KBPP model was generated from the results of 30 of the patients, and the remaining 15 patient results were used for validation. The KBPP model quality and accuracy were evaluated with the model-provided organ-at-risk regression plots and metrics. The KBPP quality was also assessed through comparison of expert and KBPP-generated IMPT plans for target coverage and organ-at-risk sparing. RESULTS: The resulting R 2 (mean ± SD, 0.87 ± 0.07) between dosimetric and geometric features, as well as the χ2 test (1.17 ± 0.07) between the original and estimated data, showed the model had good quality. All the KBPP plans were clinically acceptable. Compared with the expert plans, the KBPP plans had marginally higher dose-volume indices for the rectum V65Gy (0.8% ± 2.94%), but delivered a lower dose to the bladder (-1.06% ± 2.9% for bladder V65Gy). In addition, KBPP plans achieved lower hotspot (-0.67Gy ± 2.17Gy) and lower integral dose (-0.09Gy ± 0.3Gy) than the expert plans did. Moreover, the KBPP generated better plans that demonstrated slightly greater clinical target volume V95 (0.1% ± 0.68%) and lower homogeneity index (-1.13 ± 2.34). CONCLUSIONS: The results demonstrated that robustly optimized IMPT plans created by the KBPP model are of high quality and are comparable to expert plans. Furthermore, the KBPP model can generate more-robust and more-homogenous plans compared with those of expert plans. More studies need to be done for the validation of the proton KBPP model at more-complicated treatment sites.

Online Magnetic Resonance-Guided Radiotherapy (oMRgRT) for Gynecological Cancers.

Radiation therapy (RT) is increasingly being used in gynecological cancer management. RT delivered with curative or palliative intent can be administered alone or combined with chemotherapy or surgery. Advanced treatment planning and delivery techniques such as intensity-modulated radiation therapy, including volumetric modulated arc therapy, and image-guided adaptive brachytherapy allow for highly conformal radiation dose delivery leading to improved tumor control rates and less treatment toxicity. Quality on-board imaging that provides accurate visualization of target and surrounding organs at risk is a critical feature of these advanced techniques. As soft tissue contrast resolution is superior with magnetic resonance imaging (MRI) compared to other imaging modalities, MRI has been used increasingly to delineate tumor from adjacent soft tissues and organs at risk from initial diagnosis to tumor response evaluation. Gynecological cancers often have poor contrast resolution compared to the surrounding tissues on computed tomography scan, and consequently the benefit of MRI is high. One example is in management of locally advanced cervix cancer where adaptive MRI guidance has been broadly implemented for adaptive brachytherapy. The role of MRI for external beam RT is also steadily increasing. MRI information is being used for treatment planning, predicting, and monitoring position shifts and accounting for tissue deformation and target regression during treatment. The recent clinical introduction of online MRI-guided radiation therapy (oMRgRT) could be the next step in high-precision RT. This technology provides a tool to take full advantage of MRI not only at the time of initial treatment planning but as well as for daily position verification and online plan adaptation. Cervical, endometrial, vaginal, and oligometastatic ovarian cancers are being treated on MRI linear accelerator systems throughout the world. This review summarizes the current state, early experience, ongoing trials, and future directions of oMRgRT in the management of gynecological cancers.

CBCT-Based Adaptive Assessment Workflow for Intensity Modulated Proton Therapy for Head and Neck Cancer.

PURPOSE: Anatomical changes and patient setup uncertainties during intensity modulated proton therapy (IMPT) of head and neck (HN) cancers demand frequent evaluation of delivered dose. This work investigated a cone-beam computed tomography (CBCT) and deformable image registration based therapy workflow to demonstrate the feasibility of proton dose calculation on synthetic computed tomography (sCT) for adaptive IMPT treatment of HN cancer. MATERIALS AND METHODS: Twenty-one patients with HN cancer were enrolled in this study, a retrospective institutional review board protocol. They had previously been treated with volumetric modulated arc therapy and had daily iterative CBCT. For each patient, robust optimization (RO) IMPT plans were generated using ±3 mm patient setup and ±3% proton range uncertainties. The sCTs were created and the weekly delivered dose was recalculated using an adaptive dose accumulation workflow in which the planning computed tomography (CT) was deformably registered to CBCTs and Hounsfield units transferred from the planning CT. Accumulated doses from ±3 mm/±3% RO-IMPT plans were evaluated using clinical dose-volume constraints for targets (clinical target volume, or CTV) and organs at risk. RESULTS: Evaluation of weekly recalculated dose on sCTs showed that most of the patient plans maintained target dose coverage. The primary CTV remained covered by the V95 > 95% (95% of the volume receiving more than 95% of the prescription dose) worst-case scenario for 84.5% of the weekly fractions. The oral cavity accumulated mean dose remained lower than the worst-case scenario for all patients. Parotid accumulated mean dose remained within the uncertainty bands for 18 of the 21 patients, and all were kept lower than RO-IMPT worst-case scenario for 88.7% and 84.5% for left and right parotids, respectively. CONCLUSION: This study demonstrated that RO-IMPT plans account for most setup and anatomical uncertainties, except for large weight-loss changes that need to be tracked throughout the treatment course. We showed that sCTs could be a powerful decision tool for adaptation of these cases in order to reduce workload when using repeat CTs.

Repeatability of CBCT radiomic features and their correlation with CT radiomic features for prostate cancer.

PURPOSE: Radiomic features of cone-beam CT (CBCT) images have potential as biomarkers to predict treatment response and prognosis for patients of prostate cancer. Previous studies of radiomic feature analysis for prostate cancer were assessed in a variety of imaging modalities, including MRI, PET, and CT, but usually limited to a pretreatment setting. However, CBCT images may provide an opportunity to capture early morphological changes to the tumor during treatment that could lead to timely treatment adaptation. This work investigated the quality of CBCT-based radiomic features and their relationship with reconstruction methods applied to the CBCT projections and the preprocessing methods used in feature extraction. Moreover, CBCT features were correlated with planning CT (pCT) features to further assess the viability of CBCT radiomic features. METHODS: The quality of 42 CBCT-based radiomic features was assessed according to their repeatability and reproducibility. Repeatability was quantified by correlating radiomic features between 20 CBCT scans that also had repeated scans within 15 minutes. Reproducibility was quantified by correlating radiomic features between the planning CT (pCT) and the first fraction CBCT for 20 patients. Concordance correlation coefficients (CCC) of radiomic features were used to estimate the repeatability and reproducibility of radiomic features. The same patient dataset was assessed using different reconstruction methods applied to the CBCT projections. CBCT images were generated using 18 reconstruction methods using iterative (iCBCT) and standard (sCBCT) reconstructions, three convolution filters, and five noise suppression filters. Eighteen preprocessing settings were also considered. RESULTS: Overall, CBCT radiomic features were more repeatable than reproducible. Five radiomic features are repeatable in > 97% of the reconstruction and preprocessing methods, and come from the gray-level size zone matrix (GLSZM), neighborhood gray-tone difference matrix (NGTDM), and gray-level-run length matrix (GLRLM) radiomic feature classes. These radiomic features were reproducible in > 9.8% of the reconstruction and preprocessing methods. Noise suppression and convolution filter smoothing increased radiomic features repeatability, but decreased reproducibility. The top-repeatable iCBCT method (iCBCT-Sharp-VeryHigh) is more repeatable than the top-repeatable sCBCT method (sCBCT-Smooth) in 64% of the radiomic features. CONCLUSION: Methods for reconstruction and preprocessing that improve CBCT radiomic feature repeatability often decrease reproducibility. The best approach may be to use methods that strike a balance repeatability and reproducibility such as iCBCT-Sharp-VeryLow-1-Lloyd-256 that has 17 repeatable and eight reproducible radiomic features. Previous radiomic studies that only used pCT radiomic features have generated prognostic models of prostate cancer outcome. Since our study indicates that CBCT radiomic features correlated well with a subset of pCT radiomic features, one may expect CBCT radiomics to also generate prognostic models for prostate cancer.

Assessment of daily dose accumulation for robustly optimized intensity modulated proton therapy treatment of prostate cancer.

PURPOSE: To implement a daily CBCT based dose accumulation technique in order to assess ideal robust optimization (RO) parameters for IMPT treatment of prostate cancer. METHODS: Ten prostate cancer patients previously treated with VMAT and having daily CBCT were included. First, RO-IMPT plans were created with ± 3 mm and ± 5 mm patient setup and ± 3% proton range uncertainties, respectively. Second, the planning CT (pCT) was deformably registered to the CBCT to create a synthetic CT (sCT). Both daily and weekly sampling strategies were employed to determine optimal dose accumulation frequency. Doses were recalculated on sCTs for both ± 3 mm/±3% and ± 5 mm/±3% uncertainties and were accumulated back to the pCT. Accumulated doses generated from ± 3 mm/±3% and ± 5 mm/±3% RO-IMPT plans were evaluated using the clinical dose volume constraints for CTV, bladder, and rectum. RESULTS: Daily accumulated dose based on both ± 3mm/±3% and ±5 mm/±3% uncertainties for RO-IMPT plans resulted in satisfactory CTV coverage (RO-IMPT3mm/3% CTVV95 = 99.01 ± 0.87% vs. RO-IMPT5mm/3% CTVV95 = 99.81 ± 0.2%, P = 0.002). However, the accumulated dose based on ± 3 mm/3% RO-IMPT plans consistently provided greater OAR sparing than ±5 mm/±3% RO-IMPT plans (RO-IMPT3mm/3% rectumV65Gy = 2.93 ± 2.39% vs. RO-IMPT5mm/3% rectumV65Gy = 4.38 ± 3%, P < 0.01; RO-IMPT3mm/3% bladderV65Gy = 5.2 ± 7.12% vs. RO-IMPT5mm/3% bladderV65Gy = 7.12 ± 9.59%, P < 0.01). The gamma analysis showed high dosimetric agreement between weekly and daily accumulated dose distributions. CONCLUSIONS: This study demonstrated that for RO-IMPT optimization, ±3mm/±3% uncertainty is sufficient to create plans that meet desired CTV coverage while achieving superior sparing to OARs when compared with ± 5 mm/±3% uncertainty. Furthermore, weekly dose accumulation can accurately estimate the overall dose delivered to prostate cancer patients.

Assessment of online adaptive MR-guided stereotactic body radiotherapy of liver cancers.

PURPOSE/OBJECTIVE: Online Adaptive Radiotherapy (ART) with daily MR-imaging has the potential to improve dosimetric accuracy by accounting for inter-fractional anatomical changes. This study provides an assessment for the feasibility and potential benefits of online adaptive MRI-Guided Stereotactic Body Radiotherapy (SBRT) for treatment of liver cancer. MATERIALS/METHODS: Ten patients with liver cancer treated with MR-Guided SBRT were included. Prescription doses ranged between 27 and 50 Gy in 3-5 fx. All SBRT fractions employed daily MR-guided setup while utilizing cine-MR gating. Organs-at-risk (OARs) included duodenum, bowel, stomach, kidneys and spinal cord. Daily MRIs and contours were utilized to create each adapted plan. Adapted plans used the beam-parameters and optimization-objectives from the initial plan. Planning target volume (PTV) coverage and OAR constraints were used to compare non-adaptive and adaptive plans. RESULTS: PTV coverage for non-adapted treatment plans was below the prescribed coverage for 32/47 fractions (68%), with 11 fractions failing by more than 10%. All 47 adapted fractions met prescribed coverage. OAR constraint violations were also compared for several organs. The duodenum exceeded tolerance for 5/23 non-adapted and 0/23 for adapted fractions. The bowel exceeded tolerance for 5/34 non-adaptive and 1/34 adaptive fractions. The stomach exceeded tolerance for 4/19 non-adapted and 1/19 for adaptive fractions. Accumulated dose volume histograms were also generated for each patient. CONCLUSION: Online adaptive MR-Guided SBRT of liver cancer using daily re-optimization resulted in better target conformality, coverage and OAR sparing compared with non-adaptive SBRT. Daily adaptive planning may allow for PTV dose escalation without compromising OAR sparing.

Margin verification for hypofractionated prostate radiotherapy using a novel dose accumulation workflow and iterative CBCT.

PURPOSE: Hypofractionated radiotherapy for prostate cancer reduces the inconvenience of an extended treatment course but the appropriate treatment margin to ensure tumor control while minimizing toxicity is not standardized. Using a novel dose accumulation workflow with iterative CBCT (iCBCT) images, we were able to validate treatment margins. METHODS: Sixteen patients treated to the prostate on a hypofractionated clinical trial were selected. Prescription dose was 3625 cGy to > 95% of the PTV in 5 fractions with a boost to 4000 cGy to the high risk GTV (if applicable). PTV margin expansion was 5 mm isotropic except 3 mm posterior, no margin for the GTV. Daily iCBCT images were obtained while practicing strict bladder and rectal filling protocols. Using a novel adaptive dose accumulation workflow, synthetic CTs were created and the daily delivered dose was recalculated. The daily dose distributions were accumulated and target coverage and organ dose were assessed. RESULTS: Although the PTV coverage dropped for the accumulated dose, the prostate coverage was not compromised. The differences in bladder and anorectum dose were not significantly different. Four patients received a boost to the GTV and a significant decrease in coverage was noted in the accumulated dose. CONCLUSIONS: The novel dose accumulation workflow demonstrated that daily iCBCT images can be used for dose accumulation. We found that our clinical treatment margins resulted in adequate dose to the prostate while sparing OARs. If the goal is to deliver the full dose to an intra-prostatic GTV, a margin may be appropriate.

Dosimetric Benefits and Practical Pitfalls of Daily Online Adaptive MRI-Guided Stereotactic Radiation Therapy for Pancreatic Cancer.

PURPOSE: Magnetic resonance imaging guided (MRI-g) radiation therapy provides visualization of the target and organs at risk (OARs), allowing for daily online adaptive radiation therapy (OART). We hypothesized that MRI-g OART would improve OAR sparing and target coverage in patients with pancreatic cancer treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Ten patients received pancreas SBRT to a dose of 33 to 40 Gy in 5 fractions. The dose was prescribed to 90% coverage of the planning target volume at 100% isodose (PTV100). After each fraction's setup magnetic resonance imaging scan, the target position was aligned by 3-dimensional shifts, the normal anatomy was recontoured, and the original radiation therapy plan was recalculated to create a nonadaptive plan. A reoptimized (adaptive) plan was then generated for each fraction and renormalized to 90% coverage of PTV100. Target and OAR doses between nonadaptive and adaptive plans were compared to assess the dosimetric impact of daily adaptation. RESULTS: The PTV100 mean for adaptive and nonadaptive techniques was 90% and 80.4% (range, 46%-97%), respectively (P = .0008). Point maximum (Dmax) 38 Gy duodenum objectives were met in 43 adaptive fractions compared with 32 nonadaptive fractions (P = .022). Both PTV100 ≥90% and all OAR objectives were achieved in 28 adaptive fractions compared with only 3 nonadaptive fractions. For nonadaptive plans, interfraction increases in stomach volume correlated with higher stomach V33 (P = .004), stomach Dmax (P = .009), duodenum V33 (P = .021), and duodenum Dmax (P = .105). No correlation was observed between stomach volume and OAR doses for adaptive plans. OART plans with Dmax violations of the spinal cord (20 Gy) in 4 fractions and large bowel (38 Gy) in 5 fractions were identified (although not delivered). CONCLUSIONS: MRI-g OART improves target coverage and OAR sparing for pancreas SBRT. This benefit partially results from mitigation of interfraction variability in stomach volume. Caution must be exercised to evaluate all OARs near the treatment area.

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs.

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected. We set out to create moderate severity T9 injuries in Yucatan minipigs by conducting a bridging study adapting methods previously developed in infant piglets. The injury severity was varied according to two pneumatic impactor parameters: the piston compression depth into tissue or the velocity. To stratify locomotor recovery, a 10-point scale used in prior piglet studies was redefined through longitudinal observations of spontaneous recovery. Using hindlimb body weight support to discriminate injury severity, we found that end-point recovery was strongly bimodal to either non-weight-bearing plegia with reciprocating leg movements (<5/10) or recovery of weight bearing that improved toward a ceiling effect (≥ 8/10). No intermediate recovery animals were observed at 2 months post-injury. The ability of intra-operative ultrasound and acute magnetic resonance imaging (MRI) to provide immediate predictive feedback regarding tissue and vascular changes following SCI was assessed. There was an inverse association between locomotor outcome and early gray matter hemorrhage on MRI and ultrasound. Epicenter blood flow following contusion predicted recovery or non-recovery of weight-bearing. The depth of the dorsal cerebrospinal fluid space, which varied between animals, influenced injury severity and confounded the results in this fixed-stroke paradigm.