Improving fiducial and prostate capsule visualization for radiotherapy planning using MRI.

BACKGROUND AND PURPOSE: Intraprostatic fiducial markers (FM) improve the accuracy of radiotherapy (RT) delivery. Here we assess geometric integrity and contouring consistency using a T2*-weighted (T2*W) sequence alone, which allows visualization of the FM. MATERIAL AND METHODS: Ten patients scanned within the Prostate Advances in Comparative Evidence (PACE) trial (NCT01584258) had prostate images acquired with computed tomography (CT) and Magnetic Resonance (MR) Imaging: T2-weighted (T2W) and T2*W sequences. The prostate was contoured independently on each imaging dataset by three clinicians. Interobserver variability was assessed using comparison indices with Monaco ADMIRE (research version 2.0, Elekta AB) and examined for statistical differences between imaging sets. CT and MR images of two test objects were acquired to assess geometric distortion and accuracy of marker positioning. The first was a linear test object comprising straight tubes in three orthogonal directions, the second was a smaller test object with markers suspended in gel. RESULTS: Interobserver variability for prostate contouring was lower for both T2W and T2*W compared to CT, this was statistically significant when comparing CT and T2*W images. All markers are visible in T2*W images with 29/30 correctly identified, only 3/30 are visible in T2W images. Assessment of geometric distortion revealed in-plane displacements were under 0.375 mm in MRI, and through plane displacements could not be detected. The signal loss in the MR images is symmetric in relation to the true marker position shown in CT images. CONCLUSION: Prostate T2*W images are geometrically accurate, and yield consistent prostate contours. This single sequence can be used to identify FM and for prostate delineation in a mixed MR-CT workflow.

The delineation of intraprostatic boost regions for radiotherapy using multimodality imaging.

Dose escalation to the prostate improves tumor control but at the expense of increased rectal toxicity. Modern imaging can be used to detect the most common site of recurrence, the intraprostatic lesion (IPL), which has led to the concept of focusing dose escalation to the IPL in order to improve the therapeutic ratio. Imaging must be able to detect lesions with adequate sensitivity and specificity to accurately delineate the IPL. This information must be carefully integrated into the radiotherapy planning process to ensure the dose is targeted to the IPL. This review will consider the role and challenges of multiparametric MRI and PET computed tomography in delineating a tumor boost to be delivered by external beam radiotherapy.

Stereotactic Body Radiotherapy (SBRT) to Localised Prostate Cancer in the Era of MRI-Guided Adaptive Radiotherapy: Doses Delivered in the HERMES Trial Comparing Two- and Five-Fraction Treatments.

HERMES is a phase II trial of MRI-guided daily-adaptive radiotherapy (MRIgART) randomising men with localised prostate cancer to either 2-fractions of SBRT with a boost to the tumour or 5-fraction SBRT. In the context of this highly innovative regime the dose delivered must be carefully considered. The first ten patients recruited to HERMES were analysed in order to establish the dose received by the targets and organs at risk (OARS) in the context of intrafraction motion. A regression analysis was performed to measure how the volume of air within the rectum might further impact rectal dose secondary to the electron return effect (ERE). One hundred percent of CTV target objectives were achieved on the MRI taken prior to beam-on-time. The post-delivery MRI showed that high-dose CTV coverage was achieved in 90% of sub-fractions (each fraction is delivered in two sub-fractions) in the 2-fraction cohort and in 88% of fractions the 5-fraction cohort. Rectal D1 cm3 was the most exceeded constraint; three patients exceeded the D1 cm3 < 20.8 Gy in the 2-fraction cohort and one patient exceeded the D1 cm3 < 36 Gy in the 5-fraction cohort. The volume of rectal gas within 1 cm of the prostate was directly proportional to the increase in rectal D1 cm3, with a strong (R = 0.69) and very strong (R = 0.90) correlation in the 2-fraction and 5-fraction cohort respectively. Dose delivery specified in HERMES is feasible, although for some patients delivered doses to both target and OARs may vary from those planned.

Interim Toxicity Analysis From the Randomized HERMES Trial of 2- and 5-Fraction Magnetic Resonance Imaging-Guided Adaptive Prostate Radiation Therapy.

PURPOSE: Ultrahypofractionated radiation therapy (UHRT) is an effective treatment for localized prostate cancer with an acceptable toxicity profile; boosting the visible intraprostatic tumor has been shown to improve biochemical disease-free survival with no significant effect on genitourinary (GU) and gastrointestinal (GI) toxicity. METHODS AND MATERIALS: HERMES is a single-center noncomparative randomized phase 2 trial in men with intermediate or lower high risk prostate cancer. Patients were allocated (1:1) to 36.25 Gy in 5 fractions over 2 weeks or 24 Gy in 2 fractions over 8 days with an integrated boost to the magnetic resonance imaging (MRI) visible tumor of 27 Gy in 2 fractions. A minimization algorithm with a random element with risk group as a balancing factor was used for participant randomization. Treatment was delivered on the Unity MR-Linac (Elekta AB) with daily online adaption. The primary endpoint was acute GU Common Terminology Criteria for Adverse Events version 5.0 toxicity with the aim of excluding a doubling of the rate of acute grade 2+ GU toxicity seen in PACE. Analysis was by treatment received and included all participants who received at least 1 fraction of study treatment. This interim analysis was prespecified (stage 1 of a 2-stage Simon design) for when 10 participants in each treatment group had completed the acute toxicity monitoring period (12 weeks after radiation therapy). RESULTS: Acute grade 2 GU toxicity was reported in 1 (10%) patient in the 5-fraction group and 2 (20%) patients in the 2-fraction group. No grade 3+ GU toxicities were reported. CONCLUSIONS: At this interim analysis, the rate of GU toxicity in the 2-fraction and 5-fraction treatment groups was found to be below the prespecified threshold (5/10 grade 2+) and continuation of the study to complete recruitment of 23 participants per group was recommended.

Weekly ultra-hypofractionated radiotherapy in localised prostate cancer.

Background: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily. Methods: The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015. Results: A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively. Conclusion: Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option.

MRI-guided radiotherapy in twenty fractions for localised prostate cancer; results from the MOMENTUM study.

Background and purpose: MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac. Materials and methods: Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Results: Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months. Conclusion: This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.

Evaluation of therapeutic radiographer contouring for magnetic resonance image guided online adaptive prostate radiotherapy.

BACKGROUND AND PURPOSE: The implementation of MRI-guided online adaptive radiotherapy has facilitated the extension of therapeutic radiographers' roles to include contouring, thus releasing the clinician from attending daily treatment. Following undergoing a specifically designed training programme, an online interobserver variability study was performed. MATERIALS AND METHODS: 117 images from six patients treated on a MR Linac were contoured online by either radiographer or clinician and the same images contoured offline by the alternate profession. Dice similarity coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD) and volume metrics were used to analyse contours. Additionally, the online radiographer contours and optimised plans (n = 59) were analysed using the offline clinician defined contours. After clinical implementation of radiographer contouring, target volume comparison and dose analysis was performed on 20 contours from five patients. RESULTS: Comparison of the radiographers' and clinicians' contours resulted in a median (range) DSC of 0.92 (0.86 - 0.99), median (range) MDA of 0.98 mm (0.2-1.7) and median (range) HD of 6.3 mm (2.5-11.5) for all 117 fractions. There was no significant difference in volume size between the two groups. Of the 59 plans created with radiographer online contours and overlaid with clinicians' offline contours, 39 met mandatory dose constraints and 12 were acceptable because 95 % of the high dose PTV was covered by 95 % dose, or the high dose PTV was within 3 % of online plan. A clinician blindly reviewed the eight remaining fractions and, using trial quality assurance metrics, deemed all to be acceptable. Following clinical implementation of radiographer contouring, the median (range) DSC of CTV was 0.93 (0.88-1.0), median (range) MDA was 0.8 mm (0.04-1.18) and HD was 5.15 mm (2.09-8.54) respectively. Of the 20 plans created using radiographer online contours overlaid with clinicians' offline contours, 18 met the dosimetric success criteria, the remaining 2 were deemed acceptable by a clinician. CONCLUSION: Radiographer and clinician prostate and seminal vesicle contours on MRI for an online adaptive workflow are comparable and produce clinically acceptable plans. Radiographer contouring for prostate treatment on a MR-linac can be effectively introduced with appropriate training and evaluation. A DSC threshold for target structures could be implemented to streamline future training.

Interobserver variation of clinical oncologists compared to therapeutic radiographers (RTT) prostate contours on T2 weighted MRI.

The implementation of MRI-guided online adaptive radiotherapy has enabled extension of therapeutic radiographers' roles to include contouring. An offline interobserver variability study compared five radiographers' and five clinicians' contours on 10 MRIs acquired on a MR-Linac from 10 patients. All contours were compared to a "gold standard" created from an average of clinicians' contours. The median (range) DSC of radiographers' and clinicians' contours compared to the "gold standard" was 0.91 (0.86-0.96), and 0.93 (0.88-0.97) respectively illustrating non-inferiority of the radiographers' contours to the clinicians. There was no significant difference in HD, MDA or volume size between the groups.

Oligoprogression in Metastatic, Castrate-Resistant Prostate Cancer-Prevalence and Current Clinical Practice.

Aims: Oligoprogression is poorly defined in current literature. Little is known about the natural history and significance of oligoprogression in patients with hormone-resistant prostate cancer on abiraterone or enzalutamide treatment [termed androgen receptor-targeted therapy (ARTT)]. The aim of this study was to determine the prevalence of oligoprogression, describe the characteristics of oligoprogression in a cohort of patients from a single center, and identify the number of patients potentially treatable with stereotactic body radiotherapy (SBRT). Methods: Castration-resistant prostate cancer (CRPC) patients who radiologically progressed while on ARTT were included. Patients with oligoprogressive disease (OPD) (≤3 lesions) on any imaging were identified in a retrospective analysis of electronic patient records. Kaplan-Meier method and log-rank test were used to calculate progression-free and overall survival. Results: A total of 102 patients with metastatic CRPC on ARTT were included. Thirty (29%) patients presented with oligoprogression (46 lesions in total); 21 (21% of total) patients had lesions suitable for SBRT. The majority of lesions were in the bone (21, 46%) or lymph nodes (15, 33%). Patients with oligoprogression while on ARTT had a significantly better prostate-specific antigen (PSA) response on commencing ARTT as compared to patients who later developed polyprogression. However, PSA doubling time immediately prior to progression did not predict OPD. Median progression-free survival to oligoprogression versus polyprogression was 16.8 vs. 11.7 months. Time to further progression after oligoprogression was 13.6 months in those treated with radiotherapy (RT) for oligoprogression vs. 5.7 months in those treated with the continuation of ARTT alone. Conclusions: In this study, nearly a third of patients on ARTT for CRPC were found to have OPD. OPD patients had a better PSA response on ART and a longer duration on ARTT before developing OPD as compared to those developing polyprogressive disease (Poly-PD). The majority of patients (70%) with OPD had lesions suitable for SBRT treatment. Prospective randomized control trials are needed to establish if there is a survival benefit of SBRT in oligoprogressive prostate cancer and to determine predictive indicators.

Dosimetric comparison of automatically propagated prostate contours with manually drawn contours in MRI-guided radiotherapy: A step towards a contouring free workflow?

Background: The prostate demonstrates inter- and intra- fractional changes and thus adaptive radiotherapy would be required to ensure optimal coverage. Daily adaptive radiotherapy for MRI-guided radiotherapy can be both time and resource intensive when structure delineation is completed manually. Contours can be auto-generated on the MR-Linac via a deformable image registration (DIR) based mapping process from the reference image. This study evaluates the performance of automatically generated target structure contours against manually delineated contours by radiation oncologists for prostate radiotherapy on the Elekta Unity MR-Linac. Methods: Plans were generated from prostate contours propagated by DIR and rigid image registration (RIR) for forty fractions from ten patients. A two-dose level SIB (simultaneous integrated boost) IMRT plan is used to treat localised prostate cancer; 6000 cGy to the prostate and 4860 cGy to the seminal vesicles. The dose coverage of the PTV 6000 and PTV 4860 created from the manually drawn target structures was evaluated with each plan. If the dose objectives were met, the plan was considered successful in covering the gold standard (clinician-delineated) volume. Results: The mandatory PTV 6000 dose objective (D98% > 5580 cGy) was met in 81 % of DIR plans and 45 % of RIR plans. The SV were mapped by DIR only and for all the plans, the PTV 4860 dose objective met the optimal target (D98% > 4617 cGy). The plans created by RIR led to under-coverage of the clinician-delineated prostate, predominantly at the apex or the bladder-prostate interface. Conclusion: Plans created from DIR propagation of prostate contours outperform those created from RIR propagation. In approximately 1 in 5 DIR plans, dosimetric coverage of the gold standard PTV was not clinically acceptable. Thus, at our institution, we use a combination of DIR propagation of contours alongside manual editing of contours where deemed necessary for online treatments.

Automatic reconstruction of the delivered dose of the day using MR-linac treatment log files and online MR imaging.

BACKGROUND AND PURPOSE: Anatomical changes during external beam radiotherapy prevent the accurate delivery of the intended dose distribution. Resolving the delivered dose, which is currently unknown, is crucial to link radiotherapy doses to clinical outcomes and ultimately improve the standard of care. MATERIAL AND METHODS: In this study, we present a dose reconstruction workflow based on data routinely acquired during MR-guided radiotherapy. It employs 3D MR images, 2D cine MR images and treatment machine log files to calculate the delivered dose taking intrafractional motion into account. The developed pipeline was used to measure anatomical changes and assess their dosimetric impact in 89 prostate radiotherapy fractions delivered with a 1.5 T MR-linac at our institute. RESULTS: Over the course of radiation delivery, the CTV shifted 0.6 mm ± 2.1 mm posteriorly and 1.3 mm ± 1.5 mm inferiorly. When extrapolating the dose changes in each case to 20 fractions, the mean clinical target volume D98% and clinical target volume D50% dose-volume metrics decreased by 1.1 Gy ± 1.6 Gy and 0.1 Gy ± 0.2 Gy, respectively. Bladder D3% did not change (0.0 Gy ± 1.2 Gy), while rectum D3% decreased by 1.0 Gy ± 2.0 Gy. Although anatomical changes and their dosimetric impact were small in the majority of cases, large intrafractional motion caused the delivered dose to substantially deviate from the intended plan in some fractions. CONCLUSIONS: The presented end-to-end workflow is able to reliably, non-invasively and automatically reconstruct the delivered prostate radiotherapy dose by processing MR-linac treatment log files and online MR images. In the future, we envision this workflow to be adapted to other cancer sites and ultimately to enter widespread clinical use.

Daily adaptive radiotherapy for patients with prostate cancer using a high field MR-linac: Initial clinical experiences and assessment of delivered doses compared to a C-arm linac.

INTRODUCTION: MR-guided adapted radiotherapy (MRgART) using a high field MR-linac has recently become available. We report the estimated delivered fractional dose of the first five prostate cancer patients treated at our centre using MRgART and compare this to C-Arm linac daily Image Guided Radiotherapy (IGRT). METHODS: Patients were treated using adapted treatment plans shaped to their daily anatomy. The treatments were recalculated on an MR image acquired immediately prior to treatment delivery in order to estimate the delivered fractional dose. C-arm linac non-adapted VMAT treatment plans were recalculated on the same MR images to estimate the fractional dose that would have been delivered using conventional radiotherapy techniques using a daily IGRT protocol. RESULTS: 95% and 93% of mandatory target coverage objectives and organ at risk dose constraints were achieved by MRgART and C-arm linac delivered dose estimates, respectively. Both delivery techniques were estimated to have achieved 98% of mandatory Organ At Risk (OAR) dose constraints whereas for the target clinical goals, 86% and 80% were achieved by MRgART and C-arm linac delivered dose estimates. CONCLUSIONS: Prostate MRgART can be delivered using the a high field MR-linac. Radiotherapy performed on a C-arm linac offers a good solution for prostate cancer patients who present with favourable anatomy at the time of reference imaging and demonstrate stable anatomy throughout the course of their treatment. For patients with critical OARs abutting target volumes on their reference image we have demonstrated the potential for a target dose coverage improvement for MRgART compared to C-arm linac treatment.

Comparison of prostate delineation on multimodality imaging for MR-guided radiotherapy.

OBJECTIVE:: With increasing incorporation of MRI in radiotherapy, we investigate two MRI sequences for prostate delineation in radiographer-led image guidance. METHODS:: Five therapeutic radiographers contoured the prostate individually on CT, T2 weighted (T2W) and T2* weighted (T2*W) imaging for 10 patients. Contours were analysed with Monaco ADMIRE (research v. 2.0) to assess interobserver variability and accuracy by comparison with a gold standard clinician contour. Observers recorded time taken for contouring and scored image quality and confidence in contouring. RESULTS:: There is good agreement when comparing radiographer contours to the gold-standard for all three imaging types with Dice similarity co-efficient 0.91-0.94, Cohen's κ 0.85-0.91, Hausdorff distance 4.6-7.6 mm and mean distance between contours 0.9-1.2 mm. In addition, there is good concordance between radiographers across all imaging modalities. Both T2W and T2*W MRI show reduced interobserver variability and improved accuracy compared to CT, this was statistically significant for T2*W imaging compared to CT across all four comparison metrics. Comparing MRI sequences reveals significantly reduced interobserver variability and significantly improved accuracy on T2*W compared to T2W MRI for DSC and Cohen's κ. Both MRI sequences scored significantly higher compared to CT for image quality and confidence in contouring, particularly T2*W. This was also reflected in the shorter time for contouring, measuring 15.4, 9.6 and 9.8 min for CT, T2W and T2*W MRI respectively. Conclusion: Therapeutic radiographer prostate contours are more accurate, show less interobserver variability and are more confidently and quickly outlined on MRI compared to CT, particularly using T2*W MRI. Advances in knowledge: Our work is relevant for MRI sequence choice and development of the roles of the interprofessional team in the advancement of MRI-guided radiotherapy.

Magnetic Resonance Imaging-Guided Adaptive Radiation Therapy: A "Game Changer" for Prostate Treatment?

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/ß ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.

Analysis of loco-regional failures in head and neck cancer after radical radiation therapy.

OBJECTIVES: To investigate the anatomical distribution of loco-regional treatment failures (LRF) in patients with head and neck squamous cell carcinoma (HNSCC) in relation to clinical target volume (CTV) delineation. MATERIALS AND METHODS: 56 patients with LRF were retrospectively identified. Patients were previously treated with radical intensity modulated radiotherapy (IMRT) +/- chemotherapy. Target volumes include gross tumour volume (GTV), its volumetric expansion of 10mm (GTV-HD), CTV high dose (CTV-HD) delineated by anatomic expansion from GTV and CTV low dose (CTV-LD) defined to receive a prophylactic dose. LRF were evaluated by PET-CT or CT scan. We analysed the association between sites of LRF and target volumes and dosimetry, using image co-registration. Based on percentage of volume that received 95% of prescribed dose, LRF were classified as in-field, marginal or out-field. RESULTS: Median interval time from end of treatment to LRF was 186days. 65 (95.6%) LRF were classified as in-field. Considering primary target volumes, 40 (58.8%) LRF occurred inside GTV, 13 (19.1%) in GTV-HD and 7 (10.3%) in CTV-HD. The overall 1-year and 2-year post-failure survival (PFS) was 45.8% and 24.2%, respectively. Post radiation LRF managed with salvage surgery had a significantly higher median PFS when compared with palliative treatments (p=0.003). CONCLUSIONS: The majority of LRF occurred within GTV/GTV-HD, suggesting it is safe to reduce the CTV to a volumetric expansion. Given the low incidence of geographical misses, future studies should be directed towards dose escalation of high-risk volumes. Potential reduction of RT-related toxicity with volumetric expansion could facilitate salvage surgery.