Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol.

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 - 53.7 Gy for case 1, 22.6 - 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9-53.6 Gy for case 1, 33.9-36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2-50.9 Gy for case 1, 33.5-36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Magnetic resonance guided adaptive post prostatectomy radiotherapy: Accumulated dose comparison of different workflows.

PURPOSE: The aim of this study was to assess the use of magnetic resonance guided adaptive radiotherapy (MRgART) in the post-prostatectomy setting; comparing dose accumulation for our initial seven patients treated with fully adaptive workflow on the Unity MR-Linac (MRL) and with non-adaptive plans generated offline. Additionally, we analyzed toxicity in patients receiving treatment. METHODS: Seven patients were treated with MRgART. The prescription was 70-72 Gy in 35-36 fractions. Patients were treated with an adapt to shape (ATS) technique. For each clinically delivered plan, a non-adaptive plan based upon the reference plan was generated and compared to the associated clinically delivered plan. A total of 468 plans were analyzed. Concordance Index of target and Organs at Risk (OARs) for each fraction with reference contours was analyzed. Acute toxicity was then assessed at six-months following completion of treatment with Common Terminology for Adverse Events (CTCAE) Toxicity Criteria. RESULTS: A total of 246 fractions were clinically delivered to seven patients; 234 fractions were delivered via MRgART and 12 fractions delivered via a traditional linear accelerator due to machine issues. Pre-treatment reference plans met CTV and OAR criteria. PTV coverage satisfaction was higher in the clinically delivered adaptive plans than non-adaptive comparison plans; 42.93% versus 7.27% respectively. Six-month CTCAE genitourinary and gastrointestinal toxicity was absent in most patients, and mild-to-moderate in a minority of patients (Grade 1 GU toxicity in one patient and Grade 2 GI toxicity in one patient). CONCLUSIONS: Daily MRgART treatment consistently met planning criteria. Target volume variability in prostate bed treatment can be mitigated by using MRgART and deliver satisfactory coverage of CTV whilst minimizing dose to adjacent OARs and reducing toxicity.

Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.

Clinical target volume delineation quality assurance for MRI-guided prostate radiotherapy using deep learning with uncertainty estimation.

BACKGROUND AND PURPOSE: Previous studies on automatic delineation quality assurance (QA) have mostly focused on CT-based planning. As MRI-guided radiotherapy is increasingly utilized in prostate cancer treatment, there is a need for more research on MRI-specific automatic QA. This work proposes a clinical target volume (CTV) delineation QA framework based on deep learning (DL) for MRI-guided prostate radiotherapy. MATERIALS AND METHODS: The proposed workflow utilized a 3D dropblock ResUnet++ (DB-ResUnet++) to generate multiple segmentation predictions via Monte Carlo dropout which were used to compute an average delineation and area of uncertainty. A logistic regression (LR) classifier was employed to classify the manual delineation as pass or discrepancy based on the spatial association between the manual delineation and the network's outputs. This approach was evaluated on a multicentre MRI-only prostate radiotherapy dataset and compared with our previously published QA framework based on AN-AG Unet. RESULTS: The proposed framework achieved an area under the receiver operating curve (AUROC) of 0.92, a true positive rate (TPR) of 0.92 and a false positive rate of 0.09 with an average processing time per delineation of 1.3 min. Compared with our previous work using AN-AG Unet, this method generated fewer false positive detections at the same TPR with a much faster processing speed. CONCLUSION: To the best of our knowledge, this is the first study to propose an automatic delineation QA tool using DL with uncertainty estimation for MRI-guided prostate radiotherapy, which can potentially be used for reviewing prostate CTV delineation in multicentre clinical trials.

Evaluating the geometric and dosimetric impact of applying anisotropic CTV to PTV margins in image-guided post-prostatectomy radiation therapy.

INTRODUCTION: Guidelines for clinical target volume (CTV) to planning target volume (PTV) margins in post-prostatectomy radiation therapy (PPRT) are varied and often not clearly defined. Assessment of appropriateness of margins is commonly measured on prevalence of geographic miss. METHODS: Cone-beam CT (CBCT) images (n = 92) for 10 PPRT patients were incorporated to provide on-treatment information on the appropriateness of six different CTV expansion margins in terms of geographic miss and change in dose-volume statistics for CTV, rectum and bladder. Uniform margins included 10 mm, 5 mm, 10 mm + 5 mm posteriorly and 5 mm + 3 mm posteriorly. In addition, two anisotropic margins were evaluated by separating the superior and inferior portions of the CTV before expansion. Treatment plans were created for each PTV retrospectively. RESULTS: The frequency of geographic miss was the smallest for the large uniform expansions but resulted in the highest organ-at-risk (OAR) doses. Geographic miss in the smaller uniform and anisotropic PTVs was more prevalent but commonly to a small volume < 1% of CTV. When averaged over all CBCT fractions, V95% dose for all CTV margins remained > 99%. The anisotropic expansions generated smaller irradiated target volumes and consequently saw up to 7.3% reduction in bladder dose when compared with similar uniform expansion margins. CONCLUSION: Supplementing the incidence of geographic miss with dosimetric information on target coverage and OAR doses provides more informed assessment of the appropriateness of different CTV expansion margins. Our study extends the evaluation of anisotropic margins for PPRT.

Early experience with MR-guided adaptive radiotherapy using a 1.5 T MR-Linac: First 6 months of operation using adapt to shape workflow.

INTRODUCTION: The magnetic resonance linear accelerator (MRL) offers improved soft tissue visualization to guide daily adaptive radiotherapy treatment. This manuscript aims to report initial experience using a 1.5 T MRL in the first 6 months of operation, including training, workflows, timings and dosimetric accuracy. METHODS: All staff received training in MRI safety and MRL workflows. Initial sites chosen for treatment were stereotactic and hypofractionated prostate, thoraco-abdomino-pelvic metastasis, prostate bed and bladder. The Adapt To Shape (ATS) workflow was chosen to be the focus of treatment as it is the most robust solution for daily adaptive radiotherapy. A workflow was created addressing patient suitability, simulation, planning, treatment and peer review. Treatment times were recorded breaking down into the various stages of treatment. RESULTS: A total of 37 patients were treated and 317 fractions delivered (of which 313 were delivered using an ATS workflow) in our initial 6 months. Average treatment times over the entire period were 50 and 38 min for stereotactic and non-stereotactic treatments respectively. Average treatment times reduced each month. The average difference between reference planned and ionization chamber measured dose was 0.0 ± 1.4%. CONCLUSION: The MRL was successfully established in an Australian setting. A focus on training and creating a detailed workflow from patient selection, review and treatment are paramount to establishing new treatment programmes.

Analysis of data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL).

BACKGROUND: Analysis of Data to Advance Personalised Therapy with MR-Linac (ADAPT-MRL) is a multi-site, multinational, observational cohort registry designed to collect data on the use of the magnetic resonance linear accelerator (MR-Linac) for radiation therapy and patient outcomes. The registry will provide a linked repository of technical and clinical data that will form a platform for prospective studies and technology assessment. METHODS: Design: This registry aims to include an estimated 10,000 eligible participants across Australia and other countries over a 7- to 10-year period. Participants will undergo treatment and assessments in accordance with standard practice. Toxicity and survival outcomes will be assessed at baseline, during treatment, and with 3 monthly follow-up until 24 months, patient reported outcome measures will also be collected. Participants with a variety of cancers will be included. DISCUSSION: Data obtained from the ADAPT-MRL registry is expected to provide evidence on the safety and efficacy of the MR-Linac, a new technical innovation in radiation oncology. We expect this registry will generate data that will be used to optimise treatment techniques, MR-Linac software algorithms, evaluate participants' outcomes and toxicities and to create a repository of adapted plans, anatomical and functional MR sequences linked to participants' outcomes.

Automatic radiotherapy delineation quality assurance on prostate MRI with deep learning in a multicentre clinical trial.

Volume delineation quality assurance (QA) is particularly important in clinical trial settings where consistent protocol implementation is required, as outcomes will affect future as well current patients. Currently, where feasible, this is conducted manually, which is time consuming and resource intensive. Although previous studies mostly focused on automating delineation QA on CT, magnetic resonance imaging (MRI) is being increasingly used in radiotherapy treatment. In this work, we propose to perform automatic delineation QA on prostate MRI for both the clinical target volume (CTV) and organs-at-risk (OARs) by using delineations generated by 3D Unet variants as benchmarks for QA. These networks were trained on a small gold standard atlas set and applied on a multicentre radiotherapy clinical trial dataset to generate benchmark delineations. Then, a QA stage was designed to recommend 'pass', 'minor correction' and 'major correction' for each manual delineation in the trial set by thresholding its Dice similarity coefficient to the network generated delineation. Among all 3D Unet variants explored, the Unet with anatomical gates in an AtlasNet architecture performed the best in delineation QA, achieving an area under the receiver operating characteristics curve of 0.97, 0.92, 0.89 and 0.97 for identifying unacceptable (major correction) delineations with a sensitivity of 0.93, 0.73, 0.74 and 0.90 at a specificity of 0.93, 0.86, 0.86 and 0.95 for bladder, prostate CTV, rectum and gel spacer respectively. To the best of our knowledge, this is the first study to propose automated delineation QA for a multicentre radiotherapy clinical trial with treatment planning MRI. The methods proposed in this work can potentially improve the accuracy and consistency of CTV and OAR delineation in radiotherapy treatment planning.

Comparison of peripheral blood mononuclear cell isolation techniques and the impact of cryopreservation on human lymphocytes expressing CD39 and CD73.

CD39 and CD73 are ecto-nucleotidases present on human peripheral blood mononuclear cells (PBMCs) and are emerging biomarkers on these cells in various disorders including cancer. Many factors influence PBMC quality, so it is essential to validate sample processing methods prior to incorporation in clinical studies. This study examined the impact of both PBMC cryopreservation and PBMC isolation using SepMate density gradient centrifugation on CD39 and CD73 expressing subsets. First, PBMCs were isolated from the peripheral blood of 11 healthy donors by routine Ficoll-Paque density gradient centrifugation, cryopreserved and compared with freshly isolated PBMCs by flow cytometry. The proportions of T and B cells expressing combinations of CD39 and CD73 were relatively stable over 6-month cryopreservation, although some T cell combinations revealed small but significant changes. Second, peripheral blood was collected from six healthy donors to compare PBMCs isolated by SepMate or Ficoll-Paque density gradient centrifugation. Compared with Ficoll-Paque, the more rapid SepMate method yielded 9.1% less PBMCs but did not alter cell viability or proportions of T and B cells expressing combinations of CD39 and CD73. The present study reveals that cryopreservation is suitable for studying T and B cells expressing combinations of CD39 and CD73. However, caution should be exercised when observing small differences in these cryopreserved subsets between different cohorts. Further, SepMate and Ficoll-Paque methods of PBMC isolation show similar results for T and B cell subset analysis; however, SepMate is a faster and easier approach.

Reduced motion and improved rectal dosimetry through endorectal immobilization for prostate stereotactic body radiotherapy.

OBJECTIVE: PROMETHEUS (ACTRN12615000223538) is a multicentre clinical trial investigating the feasibility of 19 Gy in 2 fractions of stereotactic body radiotherapy (SBRT) as a boost technique for prostate cancer. The objective of this substudy was to evaluate intrafraction motion using cine MRI and assess the dosimetric impact of using a rectal displacement device (RDD). METHODS: The initial 10 patients recruited underwent planning CT and MRI, with and without a RDD. Cine MRI images were captured using an interleaved T2 HASTE sequence in sagittal and axial planes with a temporal resolution of 5.2 s acquired over 4.3 min. Points of interest (POIs) were defined and a validated tracking algorithm measured displacement of these points over the 4.3 min in the anteroposterior, superior-inferior and left-right directions. Plans were generated with and without a RDD to examine the impact on dosimetry. RESULTS: There was an overall trend for increasing displacement in all directions as time progressed when no RDD was in situ . points of interest remained comparatively stable with the RDD. In the sagittal plane, the RDD resulted in statistically significant improvement in the range of anteroposterior displacement for the rectal wall, anterior prostate, prostate apex and base. Dosimetrically, the use of a RDD significantly reduced rectal V16, V14 and Dmax, as well as the percentage of posterior rectal wall receiving 8.5 Gy. CONCLUSION: The RDD used in stereotactic prostate radiotherapy leads to reduced intrafraction motion of the prostate and rectum, with increasing improvement with time. It also results in significant improvement in rectal wall dosimetry. ADVANCES IN KNOWLEDGE: It was found that the rectal displacement device improved prostate stabilization significantly, improved rectum stabilization and dosimetry significantly. The rectal displacement device did not improve target volume dosimetry.

Multi-observer contouring of male pelvic anatomy: Highly variable agreement across conventional and emerging structures of interest.

INTRODUCTION: This study quantified inter-observer contouring variations for multiple male pelvic structures, many of which are of emerging relevance for prostate cancer radiotherapy progression and toxicity response studies. METHODS: Five prostate cancer patient datasets (CT and T2-weighted MR) were distributed to 13 observers for contouring. CT structures contoured included the clinical target volume (CTV), seminal vesicles, rectum, colon, bowel bag, bladder and peri-rectal space (PRS). MR contours included CTV, trigone, membranous urethra, penile bulb, neurovascular bundle and multiple pelvic floor muscles. Contouring variations were assessed using the intraclass correlation coefficient (ICC), Dice similarity coefficient (DSC), and multiple additional metrics. RESULTS: Clinical target volume (CT and MR), bladder, rectum and PRS contours showed excellent inter-observer agreement (median ICC = 0.97; 0.99; 1.00; 0.95; 0.90, DSC = 0.83 ± 0.05; 0.88 ± 0.05; 0.93 ± 0.03; 0.81 ± 0.07; 0.80 ± 0.06, respectively). Seminal vesicle contours were more variable (ICC = 0.75, DSC = 0.73 ± 0.14), while colon and bowel bag contoured volumes were consistent (ICC = 0.97; 0.97), but displayed poor overlap (DSC = 0.58 ± 0.22; 0.67 ± 0.21). Smaller MR structures showed significant inter-observer variations, with poor overlap for trigone, membranous urethra, penile bulb, and left and right neurovascular bundles (DSC = 0.44 ± 0.22; 0.41 ± 0.21; 0.66 ± 0.21; 0.16 ± 0.17; 0.15 ± 0.15). Pelvic floor muscles recorded moderate to strong inter-observer agreement (ICC = 0.50-0.97), although large outlier variations were observed. CONCLUSIONS: Inter-observer contouring variation was significant for multiple pelvic structures contoured on MR.

Long-term outcomes in 1121 Australian prostate cancer patients treated with definitive radiotherapy.

INTRODUCTION: Optimal definitive treatment of prostate cancer is controversial, especially in high-risk patients. We report the largest prospective cohort of Australian patients treated with radiotherapy for localised prostate cancer. METHODS: One thousand, one hundred and twenty-one patients with prostate cancer were prospectively registered and treated to a dose of 70-74 Gy. Patients were classified as low, intermediate or high risk based on PSA, clinical staging and Gleason score. Intermediate-risk patients were treated with 0-6 months of hormonal therapy (ADT) and high-risk patients were offered neoadjuvant and adjuvant ADT. Overall survival (OS) and biochemical relapse-free survival (bNED) were calculated using the Kaplan-Meier method. RESULTS: Median follow-up was 92 months. Eight-year OS and bNED were 78.4% and 68.1% respectively in the entire cohort. OS for the low, intermediate and high-risk groups was 84.5%, 78.4% and 68% respectively. For these risk groups, bNED was 80.3%, 65.7% and 53.7% respectively. In the intermediate and high-risk group, OS and bNED decreased with increasing number of risk factors. CONCLUSION: Definitive radiotherapy is an effective treatment for prostate cancer, including in high-risk cases.

Superior target volume and organ stability with the use of endorectal balloons in post-prostatectomy radiotherapy.

INTRODUCTION: We investigated the endorectal balloon (ERB) as a method to improve post-prostatectomy clinical target volume (CTV) stability. METHODS: Seventy cone-beam CT (CBCT) obtained during radiotherapy treatment from seven patients treated with an ERB and 68 CBCT from seven patients treated without an ERB were contoured according to published guidelines. CTV was subdivided into superior and inferior CTV; whole rectal volume was subdivided into superior and inferior rectum and anal volume. Concordance index (CI) of CBCT treatment volumes compared with planning volumes was calculated and displacements were measured. RESULTS: Whole rectal, superior and inferior rectum and anal CI were significantly improved with the ERB by 21%, 17%, 26% and 17% respectively (P < 0.0001). Overall CTV and inferior CTV CI was improved by 4% with the ERB (overall CTV P = 0.021; Inferior CTV P < 0.0001). In the ERB cohort, average displacement for superior CTV was 0.37 cm anterior-posterior (AP) and 0.10 cm left-right (LR). Average standard deviation was 0.27 cm AP and 0.11 cm LR. Inferior CTV average displacement was 0.11 cm AP and 0.02 cm LR. Average standard deviation was 0.11 cm AP and 0.02 cm LR. In the non-ERB cohort, average displacement for superior CTV was 0.43 cm AP and 0.10 mm left-right (LR). Average standard deviation was 0.45 cm AP and 0.13 cm LR. Inferior CTV average displacement was 0.16 cm AP and 0.01 cm LR. Average standard deviation was 0.17 cm AP and 0.03 cm LR. There was no statistically significant impact of bladder filling on CTV CI in ERB patients (P = 0.551) as opposed to non-ERB patients (P = 0.0421). CONCLUSION: ERBs in the post-prostatectomy setting resulted in increased rectal and CTV stability while negating the effects of bladder filling on CTV stability.

Endorectal balloons in the post prostatectomy setting: do gains in stability lead to more predictable dosimetry?

PURPOSE: To perform a comparative study assessing potential benefits of endorectal-balloons (ERB) in post-prostatectomy patients. METHOD AND MATERIALS: Ten retrospective post-prostatectomy patients treated without ERB and ten prospective patients treated with the ERB in situ were recruited. All patients received IMRT and IGRT using kilovoltage cone-beam computed tomography (kVCBCT). kVCBCT datasets were registered to the planning dataset, recontoured and the original plan recalculated on the kVCBCTs to recreate anatomical conditions during treatment. The imaging, structure and dose data were imported into in-house software for the assessment of geometric variation and cumulative equivalent uniform dose (EUD) in the two groups. RESULTS: The difference in location (ΔCOV) for the bladder between planning and each CBCT was similar for each group. The range of mean ΔCOV for the rectum was 0.15-0.58 cm and 0.15-0.59 cm for the non-ERB and ERB groups. For superior-CTV and inferior-CTV the difference between planned and delivered D95% (mean ± SD) for the non-ERB group was 2.1 ± 6.0 Gy and -0.04 ± 0.20 Gy. While for the ERB group the difference in D95% was 8.7 ± 12.6 Gy and 0.003 ± 0.104 Gy. CONCLUSIONS: The use of ERBs in the post-prostatectomy setting did improve geometric reproducibility of the target and surrounding normal tissues, however no improvement in dosimetric stability was observed for the margins employed.