Development and Internal Validation of a Novel Nomogram Predicting the Outcome of Salvage Radiation Therapy for Biochemical Recurrence after Radical Prostatectomy in Patients without Metastases on Restaging Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.

Background and objective: Owing to the greater use of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after robot-assisted radical prostatectomy (RARP), patient selection for local salvage radiation therapy (sRT) has changed. Our objective was to determine the short-term efficacy of sRT in patients with BCR after RARP, and to develop a novel nomogram predicting BCR-free survival after sRT in a nationwide contemporary cohort of patients who underwent PSMA PET/CT before sRT for BCR of PCa, without evidence of metastatic disease. Methods: All 302 eligible patients undergoing PCa sRT in four reference centers between September 2015 and August 2020 were included. We conducted multivariable logistic regression analysis using a backward elimination procedure to develop a nomogram for predicting biochemical progression of PCa, defined as prostate-specific antigen (PSA) ≥0.2 ng/ml above the post-sRT nadir within 1 yr after sRT. Key findings and limitations: Biochemical progression of disease within 1 yr after sRT was observed for 56/302 (19%) of the study patients. The final predictive model included PSA at sRT initiation, pathological grade group, surgical margin status, PSA doubling time, presence of local recurrence on PSMA PET/CT, and the presence of biochemical persistence (first PSA result ≥0.1 ng/ml) after RARP. The area under the receiver operating characteristic curve for this model was 0.72 (95% confidence interval 0.64-0.79). Using our nomogram, patients with a predicted risk of >20% had a 30.8% chance of developing biochemical progression within 1 yr after sRT. Conclusions: Our novel nomogram may facilitate better patient counseling regarding early oncological outcome after sRT. Patients with high risk of biochemical progression may be candidates for more extensive treatment. Patient summary: We developed a new tool for predicting cancer control outcomes of radiotherapy for patients with recurrence of prostate cancer after surgical removal of their prostate. This tool may help in better counseling of these patients with recurrent cancer regarding their early expected outcome after radiotherapy.

Remineralization of lytic spinal metastases after radiotherapy.

BACKGROUND CONTEXT: Palliative radiotherapy (RT) can lead to remineralization of osteolytic lesions thereby potentially restoring some of the weight-bearing capacity and preventing vertebral collapse. It is not clear, however, under which circumstances remineralization of osteolytic lesions occurs. PURPOSE: The aim of this study was to investigate the change in bone mineral density in spinal metastases after RT compared to a reference region, and find associated factors. STUDY DESIGN: Retrospective analysis within prospective observational cohort OUTCOME MEASURES: change in bone mineral density measured in Hounsfield Units (HU). PATIENT SAMPLE: patients treated with RT for (painful) bone metastases. METHODS: Patients with spinal metastases were included if computed tomography scans both pre- and post-RT were available. Bone density was measured in HU. A region of interest (ROI) was drawn manually in the metastatic lesion. As a reference, a measurement of bone density in adjacent, unaffected, and non-irradiated vertebrae was used. Factors tested for association were origin of the primary tumor, RT dose and fractionation scheme, and concomitant use of bisphosphonates. RESULTS: A total of 31 patients with 49 spinal metastases, originating from various primary tumors, were included. The median age on baseline was 58 years (IQR: 53-63) and median time between baseline and follow-up scan was 8.2 months (IQR: 3.0-18.4). Difference in HU in the lesion before and after treatment was 146.9 HU (95% CI 68.4-225.4; p<.01). Difference in HU in the reference vertebra between baseline and first follow-up was 19.1 HU (95% CI -47.9 to 86.0; p=.58). Difference between reference vertebrae and metastatic lesions on baseline was -194.1 HU (95% CI -276.2 to -112.0; p<.01). After RT, this difference was reduced to -50.3 HU (95% CI -199.6 to 99.0; p=.52). Patients using bisphosphonates showed a greater increase in HU, 194.1 HU versus 60.6 HU, p=.01. CONCLUSIONS: Palliative radiation of osteolytic lytic spinal metastases is positively associated with an increased bone mineral density at follow-up. The use of bisphosphonates was linked to an increased bone mineral density when used during or after RT.

Long-term Local Control and Overall Survival After Radiotherapy in Oligoprogressive Patients During Treatment With Checkpoint Inhibitors.

BACKGROUND/AIM: Recent studies described the safety and clinical utility of combined anti-programmed cell death protein-1 (anti-PD1) checkpoint inhibition with radiotherapy. However, long-term follow-up data are lacking. Abscopal effects have been hypothesized, though clinical proof is still scarce. PATIENTS AND METHODS: We analyzed the efficacy and toxicity of combined (stereotactic) radiotherapy and anti-PD1 in consecutive oligoprogressive melanoma and non-small cell lung cancer (NSCLC) patients who were irradiated for 1 to 3 progressive metastases during anti-PD-1 in our institute between January 2017 and January 2019 and verified one-dimensional RECIST measurements by volumetric assessments. RESULTS: Out of 361 patients, 11 melanoma and 5 NSCLC patients were included in this series. Radiotherapy was applied after a median of 11 months (range=1-30 months) from the start of anti-PD1 treatment. No increased risk of adverse events for the combined treatments was observed. With a median follow-up of 4.9 years since the start of anti-PD1, 69% of patients were alive. Six of 16 patients had stable disease after a median follow-up of 4.1 years after radiotherapy. Abscopal effects were suspected in three out of 16 patients. However, if volumetric assessment was used, two of these patients already had tumor shrinkage prior to radiotherapy, not detected by one-dimensional measurements. CONCLUSION: Stereotactic radiotherapy for oligoprogressive disease during PD1-inhibition can induce long-term disease control. Although abscopal effects were suspected in three patients, they were not confirmed with volumetric assessment in two patients. The discrepancy found between one-dimensional and volumetric response assessment argues for including volumetric assessment in further studies.

Online adaptive MR-guided radiotherapy: Conformity of contour adaptation for prostate cancer, rectal cancer and lymph node oligometastases among radiation therapists and radiation oncologists.

Background and purpose: Online adaptive MR-guided treatment planning workflows facilitate daily contour adaptation to the actual anatomy. Allocating contour adaptation to radiation therapists (RTTs) instead of radiation oncologists (ROs) might allow for increasing workflow efficiency. This study investigates conformity of adapted target contours provided by dedicated RTTs and ROs. Materials and methods: In a simulated online procedure, 6 RTTs and 6 ROs recontoured targets and organs at risk (OAR) in prostate cancer (n = 2), rectal cancer (n = 2) and lymph node-oligometastases (n = 2) cases. RTTs gained contouring competence beforehand by following a specific in-house training program. For all target contours and the reference delineations volumetric differences were determined and Dice similarity coefficient (DSC), conformity index (CI) and generalized CI were calculated. Delineation time and -confidence were registered for targets and OAR. Impact of contour adaptation on treatment plan quality was investigated. Results: Delineation conformity was generally high with DSC, CI and generalized CI values in the range of 0.81-0.94, 0.87-0.95 and 0.63-0.85 for prostate cancer, rectal cancer and LN-oligometastasis, respectively. Target volumes were comparable for both, RTTs and ROs. Time needed and confidence in contour adaptation was comparable as well. Treatment plans derived with adapted contours did not violate dose volume constrains as used in clinical routine. Conclusion: After tumor site specific training, daily contour adaptations as needed in adaptive online radiotherapy workflows can be accurately performed by RTTs. Conformity of the derived contours is high and comparable to contours as provided by ROs.

Impact of magnetic resonance-guided versus conventional radiotherapy workflows on organ at risk doses in stereotactic body radiotherapy for lymph node oligometastases.

Background and purpose: Magnetic resonance (MR)-linac delivery is expected to improve organ at risk (OAR) sparing. In this study, OAR doses were compared for online adaptive MR-linac treatments and conventional cone beam computed tomography (CBCT)-linac radiotherapy, taking into account differences in clinical workflows, especially longer session times for MR-linac delivery. Materials and methods: For 25 patients with pelvic/abdominal lymph node oligometastases, OAR doses were calculated for clinical pre-treatment and daily optimized 1.5 T MR-linac treatment plans (5 × 7 Gy) and compared with simulated CBCT-linac plans for the pre-treatment and online anatomical situation. Bowelbag and duodenum were re-contoured on MR-imaging acquired before, during and after each treatment session. OAR hard constraint violations, D0.5cc and D10cc values were evaluated, focusing on bowelbag and duodenum. Results: Overall, hard constraints for all OAR were violated less often in daily online MR-linac treatment plans compared with CBCT-linac: in 5% versus 22% of fractions, respectively. D0.5cc and D10cc values did not differ significantly. When taking treatment duration and intrafraction motion into account, estimated delivered doses to bowelbag and duodenum were lower with CBCT-linac if identical planning target volume (PTV) margins were used for both modalities. When reduced PTV margins were achievable with MR-linac treatment, bowelbag doses were lower compared with CBCT-linac. Conclusions: Compared with CBCT-linac treatments, the online adaptive MR-linac approach resulted in fewer hard planning constraint violations compared with single-plan CBCT-linac delivery. With respect to other bowelbag/duodenum dose-volume parameters, the longer duration of MR-linac treatment sessions negatively impacts the potential dosimetric benefit of daily adaptive treatment planning.

Clinical utility of convolutional neural networks for treatment planning in radiotherapy for spinal metastases.

BACKGROUND AND PURPOSE: Spine delineation is essential for high quality radiotherapy treatment planning of spinal metastases. However, manual delineation is time-consuming and prone to interobserver variability. Automatic spine delineation, especially using deep learning, has shown promising results in healthy subjects. We aimed to evaluate the clinical utility of deep learning-based vertebral body delineations for radiotherapy planning purposes. MATERIALS AND METHODS: A multi-scale convolutional neural network (CNN) was used for automatic segmentation and labeling. Two approaches were tested: the combined approach using one CNN for both segmentation and labeling, and the sequential approach using separate CNN's for these tasks. Training and internal validation data included 580 vertebrae, external validation data included 202 vertebrae. For quantitative assessment, Dice similarity coefficient (DSC) and Hausdorff distance (HD) were used. Axial slices from external images were presented to radiation oncologists for subjective evaluation. RESULTS: Both approaches performed comparably during the internal validation (DSC: 96.7%, HD: 3.6 mm), but the sequential approach proved more robust during the external validation (DSC: 94.5% vs 94.4%, p < 0.001, HD: 4.5 vs 7.1 mm, p < 0.001). Subsequently, subjective evaluation of this sequential approach showed that experienced radiation oncologists could distinguish automatic from human-made contours in 63% of cases. They rated automatic contours clinically acceptable in 77% of cases, compared to 88% of human-made contours. CONCLUSION: We present a feasible approach for automatic vertebral body delineation using two variants of a multi-scale CNN. This approach generates high quality automatic delineations, which can save time in a clinical radiotherapy workflow.

Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Is Associated with Improved Oncological Outcome in Men Treated with Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer.

BACKGROUND: Radiolabeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has shown superior diagnostic accuracy to conventional imaging for the detection of prostate cancer deposits . Consequently, clinical management changes have been reported in patients with biochemical recurrence (BCR) of disease after robot-assisted radical prostatectomy (RARP). We hypothesized that, due to the exclusion of patients with metastatic disease on PSMA-PET/CT, those who underwent local salvage radiation therapy (SRT) after restaging PSMA-PET/CT for BCR may have better oncological outcomes than patients who underwent "blind" SRT. OBJECTIVE: To compare the oncological outcome of a patient cohort that underwent PSMA-PET imaging prior to SRT with that of a patient cohort that did not have PSMA-PET imaging before SRT. DESIGN, SETTING, AND PARTICIPANTS: We included 610 patients who underwent SRT, of whom 298 underwent PSMA-PET/CT prior to SRT and 312 did not. No additional hormonal therapy was prescribed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To compare both cohorts, case-control matching was performed, using the prostate-specific antigen (PSA) value at the initiation of SRT, pathological grade group, pathological T stage, surgical margin status, and biochemical persistence after RARP as matching variables. The outcome variable was biochemical progression at 1 yr after SRT, defined as either a rise of PSA ≥0.2 ng/ml above the nadir after SRT or the start of additional treatment. RESULTS AND LIMITATIONS: After case-control matching, 216 patients were matched in both cohorts (108 patients per cohort). In the patient cohort without PSMA-PET/CT prior to SRT, of 108 patients, 23 (21%) had biochemical progression of disease at 1 yr after SRT, compared with nine (8%) who underwent restaging PSMA-PET/CT prior to SRT (p = 0.007). CONCLUSIONS: PSMA-PET/CT is found to be associated with an improved oncological outcome in patients who undergo SRT for BCR after RARP. PATIENT SUMMARY: Performing prostate-specific membrane antigen positron emission tomography/computed tomography imaging in patients with biochemical recurrence of disease after robot-assisted radical prostatectomy, before initiating salvage radiation therapy, resulted in improved short-term oncological outcomes.

Development and internal validation of multivariable prediction models for biochemical failure after MRI-guided focal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer.

BACKGROUND AND PURPOSE: Magnetic resonance-guided focal salvage high-dose-rate brachytherapy (FS-HDR-BT) for radiorecurrent prostate cancer (PCa) shows low toxicity rates. However, biochemical failure (BF) after treatment occurs frequently. We developed two prediction models for BF (Phoenix definition) with the aim of enhancing patient counselling before FS-HDR-BT and during follow-up. MATERIALS AND METHODS: A prospective cohort of 150 radiorecurrent PCa patients treated with FS-HDR-BT between 2013 and 2020 was used for model development and internal validation. Multivariable Cox Proportional Hazards regression was applied. For model 1, only pre-salvage variables were included as candidate predictors. For model 2, additional (post-)salvage characteristics were tested. After calibration, nomograms and webtools were constructed. Finally, three risk groups were identified. RESULTS: Sixty-one patients (41%) experienced BF. At baseline (model 1), age, gross tumour volume, pre-salvage PSA, and pre-salvage PSA doubling time (PSADT) were predictive of BF. During follow-up (model 2), age, pre-salvage PSA and PSADT, seminal vesicle involvement, post-salvage time to PSA nadir, and percentage PSA reduction were predictive of BF. The adjusted C-statistics were 0.73 (95% CI: 0.66-0.81) and 0.84 (95% CI: 0.78-0.90), respectively, with acceptable calibration. Estimated 2-year biochemical disease-free survival for the low-, intermediate-, and high-risk groups were 84%, 70%, and 31% (model 1), and 100%, 71%, and 5% (model 2). CONCLUSION: Two models are provided for prediction of BF in patients with radiorecurrent PCa treated with FS-HDR-BT. Based on pre- and post-salvage characteristics, we are able to identify patients with a high risk of BF. These findings can aid patient counselling for FS-HDR-BT.

Progression-free survival in patients with 68Ga-PSMA-PET-directed SBRT for lymph node oligometastases.

BACKGROUND: Prostate cancer oligometastatic disease can be treated using stereotactic body radiotherapy (SBRT) in order to postpone start of systemic treatments such as androgen deprivation therapy (ADT). 68Ga-PSMA-PET/CT imaging allows for diagnosis of oligometastases at lower PSA values. We analysed a cohort of patients with prostate cancer lymph node oligometastases detected on PSMA-PET/CT. MATERIALS AND METHODS: Ninety patients with metachronous oligometastatic prostate cancer received SBRT for 1-3 lymph node metastases diagnosed on 68Ga-PSMA-PET/CT. The primary end point was progression free survival (PFS), with disease progression defined as occurrence of either target lesion progression, new metastatic lesion or biochemical progression. Secondary outcomes were biochemical PFS (BPFS), ADT-free survival (ADT-FS), toxicity and quality of life (QoL). Baseline patient characteristics were tested for association with PFS and a preliminary risk score was created. RESULTS: Median follow-up was 21 months (interquartile range 10-31 months). Median PFS and BPFS were 16 and 21 months, respectively. Median ADT-FS was not reached (73% (95%-CI 62-86%) at 24 months). In multivariable analysis, younger age, higher PSA prior to SBRT and extrapelvic location were associated with shorter PFS. Grade 1 fatigue was the most predominant acute toxicity (34%). Highest grade toxicity was grade 2 for acute and late events. QoL analysis showed mild, transient increase in fatigue at 1-4 weeks after SBRT. CONCLUSION: A median PFS of 16 months was attained after SBRT for patients with PSMA-PET positive oligometastatic lymph nodes from prostate cancer. Higher pre-SBRT PSA, younger age and extrapelvic location were found to be predictors of shorter PFS.

Combining radiotherapy and focused ultrasound for pain palliation of cancer induced bone pain; a stage I/IIa study according to the IDEAL framework.

BACKGROUND: Cancer induced bone pain (CIBP) strongly interferes with patient's quality of life. Currently, the standard of care includes external beam radiotherapy (EBRT), resulting in pain relief in approximately 60% of patients. Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) is a promising treatment modality for CIBP. METHODS: A single arm, R-IDEAL stage I/IIa study was conducted. Patients presenting at the department of radiation oncology with symptomatic bone metastases in the appendicular skeleton, as well as in the sacrum and sternum were eligible for inclusion. All participants underwent EBRT, followed by MR-HIFU within 4 days. Safety and feasibility were assessed, and pain scores were monitored for 4 weeks after completing the combined treatment. RESULTS: Six patients were enrolled. Median age was 67 years, median lesion diameter was 56,5 mm. In all patients it was logistically possible to plan and perform the MR-HIFU treatment within 4 days after EBRT. All patients tolerated the combined procedure well. Pain response was reported by 5 out of 6 patients at 7 days after completion of the combined treatment, and stabilized on 60% at 4 weeks follow up. No treatment related serious adverse events occurred. CONCLUSION: This is the first study to combine EBRT with MR-HIFU. Our results show that combined EBRT and MR-HIFU in first-line treatment of CIBP is safe and feasible, and is well tolerated by patients. Superiority over standard EBRT, in terms of (time to) pain relief and quality of life need to be evaluated in comparative (randomized) study.

Dosimetric feasibility of hypofractionation for SBRT treatment of lymph node oligometastases on the 1.5T MR-linac.

PURPOSE: At our department, MR-guided stereotactic body radiation therapy (SBRT) using the 1.5T MR-linac system (Unity, Elekta AB, Stockholm, Sweden) has been initiated for patients with lymph node oligometastases. Superior soft tissue contrast and the possibility for online plan adaptation on the Unity may allow for hypofractionated treatment. The purpose of this study was to investigate the dosimetric feasibility and compare the plan quality of different hypofractionated schemes. METHODS AND MATERIALS: Data was used from 12 patients with single lymph node oligometastases (10 pelvic, 2 para-aortic), which were all treated on the Unity with a prescribed dose of 5x7 Gy to 95% of the PTV. Hypofractionation was investigated for 3x10 Gy and 1x20 Gy schemes (all 60 Gy BED α/ß = 10). The pre-treatment plans were evaluated based on dose criteria and plan quality. If all criteria were met, the number of online adapted plans which also met all dose criteria was investigated. For pre-treatment plans meeting the criteria for all three fractionation schemes, the plan quality after online adaptation was compared using the four parameters described in the NRG-BR001 phase 1 trial. RESULTS: Pre-treatment plans met all clinical criteria for the three different fractionation schemes in 10, 9 and 6 cases. 50/50, 45/45 17/30 of the corresponding online adapted plans met all criteria, respectively. Violations were primarily caused by surrounding organs at risk overlapping or adjacent to the PTV. The 1x20 Gy treatment plans were, in general, of lesser quality than the 5x7 Gy and 3x10 Gy plans. CONCLUSION: Hypofractionated radiotherapy for lymph node oligometastases on the 1.5T MR-linac is feasible based on dose criteria and plan quality metrics. The location of the target relative to critical structures should be considered in choosing the most suitable fractionation scheme. Especially for single fraction treatment, meeting all dose criteria in the pre-treatment situation does not guarantee that this also applies during online treatment.

Impact of a vacuum cushion on intrafraction motion during online adaptive MR-guided SBRT for pelvic and para-aortic lymph node oligometastases.

BACKGROUND AND PURPOSE: Vacuum cushion immobilization is commonly used during stereotactic body radiotherapy (SBRT) to reduce intrafraction motion. We investigated target and bony anatomy intrafraction motion (translations and rotations) during online adaptive SBRT on an MR-linac for pelvic/para-aortic lymph node metastases with and without vacuum cushion. MATERIALS AND METHODS: Thirty-nine patients underwent 5x7 Gy SBRT on a 1.5T MR-linac, 19 patients were treated with vacuum cushion, 19 without and 1 patient sequentially with and without. Intrafraction motion was calculated for target lymph nodes (GTVs) and nearby bony anatomy, for three time intervals (pre-position verification (PV), pre-post, PV-post, relating to the online MRI scans) per treatment fraction. RESULTS: Vacuum cushion immobilization significantly reduced anterior-posterior translations for the pre-PV and pre-post intervals, for bony anatomy and pre-post interval for GTV (p < 0.05). Mean GTV intrafraction motion reduction in posterior direction was 0.7 mm (95% confidence interval 0.3-1.1 mm) for pre-post interval (mean time = 32 min). Shifts in other directions were not significantly reduced. More motion occurred in pre-PV interval than in PV-post interval (mean time = 16 min for both); vacuum cushion immobilization did not reduce intrafraction motion during the beam-on period. CONCLUSION: A vacuum cushion reduces GTV and bony anatomy intrafraction motion in posterior direction during pelvic/para-aortic lymph node SBRT. This motion reduction was found for the first 16 min per session. For single targets this motion can be corrected for directly with an MR-linac. Intrafraction motion was not reduced during the second half of the session, the period of radiotherapy delivery on an MR-linac. Vacuum cushion immobilization may not be necessary for patients with single lymph node oligometastases undergoing SBRT on an MR-linac.

Pain Response After Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy in Patients With Bone Metastases-A Phase 2 Randomized Controlled Trial Within a Prospective Cohort.

PURPOSE: Pain response after conventional external beam radiation therapy (cRT) in patients with painful bone metastases is observed in 60% to 70% of patients. The aim of the VERTICAL trial was to investigate whether stereotactic body radiation therapy (SBRT) improves pain response. METHODS AND MATERIALS: This single-center, phase 2, randomized controlled trial was conducted within the PRESENT cohort, which consists of patients referred for radiation therapy of bone metastases to our tertiary center. Cohort participants with painful bone metastases who gave broad informed consent for randomization were randomly assigned to cRT or SBRT. Only patients in the intervention arm received information about the trial and were offered SBRT (1 × 18 Gy, 3 × 10 Gy, or 5 × 7 Gy), which they could accept or refuse. Patients who refused SBRT underwent standard cRT (1 × 8 Gy, 5 × 4 Gy, or 10 × 3 Gy). Patients in the control arm were not informed. Primary endpoint was pain response at 3 months after radiation therapy. Secondary outcomes were pain response at any point within 3 months, mean pain scores, and toxicity. Data were analyzed intention to treat (ITT) and per protocol (PP). This trial was registered with Clinicaltrials.gov, NCT02364115. RESULTS: Between January 29, 2015, and March 20, 2019, 110 patients were randomized. ITT analysis included 44 patients in the cRT arm and 45 patients in the SBRT arm. In the intervention arm, 12 patients (27%) declined SBRT, and 7 patients (16%) were unable to complete the SBRT treatment. In ITT, 14 of 44 patients (32%; 95% confidence interval [CI], 18%-45%) in the control arm and 18 of 45 patients (40%; 95% CI, 26%-54%) in the SBRT arm reported a pain response at 3 months (P = .42). In PP, these proportions were 14 of 44 (32%; 95% CI, 18%-45%) and 12 of 23 patients (46%; 95% CI, 27%-66%), respectively (P = .55). In ITT, a pain response within 3 months was reported by 30 of 44 control patients (82%; 95% CI, 68%-90%) and 38 of 45 patients (84%; 95% CI, 71%-92%) in the SBRT arm (P = .12). In PP, these proportions were 36 of 44 (82%; 95% CI, 68%-90%) and 26 of 27 patients (96%; 95% CI; 81%-100%), respectively (P = .12). No grade 3 or 4 toxicity was observed in either arm. CONCLUSIONS: SBRT did not significantly improve pain response in patients with painful bone metastases. One in 4 patients preferred to undergo cRT over SBRT, and 1 in 5 patients starting SBRT was unable to complete this treatment. Because of this selective dropout, which can be attributed to the character of the intervention, the trial was underpowered to detect the prespecified difference in pain response.

Target coverage and dose criteria based evaluation of the first clinical 1.5T MR-linac SBRT treatments of lymph node oligometastases compared with conventional CBCT-linac treatment.

BACKGROUND AND PURPOSE: Patients were treated at our institute for single and multiple lymph node oligometastases on the 1.5T MR-linac since August 2018. The superior soft-tissue contrast and additional software features of the MR-linac compared to CBCT-linacs allow for online adaptive treatment planning. The purpose of this study was to perform a target coverage and dose criteria based evaluation of the clinically delivered online adaptive radiotherapy treatment compared with conventional CBCT-linac treatment. MATERIALS AND METHODS: Patient data was used from 14 patients with single lymph node oligometastases and 6 patients with multiple (2-3) metastases. All patients were treated on the 1.5T MR-linac with a prescribed dose of 5 × 7 Gy to 95% of the PTV and a CBCT-linac plan was created for each patient. The difference in target coverage between these plans was compared and plans were evaluated based on dose criteria for each fraction after calculating the CBCT-plan on the daily anatomy. The GTV coverage was evaluated based on the online planning and the post-delivery MRI. RESULTS: For both single and multiple lymph node oligometastases the GTV V35Gy had a median value of 100% for both the MR-linac plans and CBCT-plans pre- and post-delivery and did not significantly differ. The percentage of plans that met all dose constraints was improved from 19% to 84% and 20% to 67% for single and multiple lymph node cases, respectively. CONCLUSION: Target coverage and dose criteria based evaluation of the first clinical 1.5T MR-linac SBRT treatments of lymph node oligometastases compared with conventional CBCT-linac treatment shows a smaller amount of unplanned violations of high dose criteria. The GTV coverage was comparable. Benefit is primarily gained in patients treated for multiple lymph node oligometastases: geometrical deformations are accounted for, dose can be delivered in one plan and margins can be reduced.

MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients.

PURPOSE: Most patients with local prostate cancer recurrence after radiation therapy undergo palliative androgen deprivation therapy because whole-gland salvage treatments have a high risk of severe toxicity. Focal treatment reduces this risk while offering a second opportunity for cure. We report updated outcomes of ultrafocal salvage high-dose-rate brachytherapy (HDR-BT). METHODS AND MATERIALS: Prospectively collected data from the first 50 treated patients were analyzed. Disease status was assessed by 3T multiparametric magnetic resonance imaging (MRI), 18F-Choline or 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography, and systematic or tumor-targeted biopsies. Ultrafocal salvage HDR-BT (1 × 19 Gy) was performed by implanting the clinical target volume (CTV: gross tumor volume + 5 mm margin) under fused transrectal ultrasound/MRI guidance. Follow-up included toxicity grading (using Common Terminology Criteria for Adverse Events 4.0), quality of life assessment, and prostate-specific antigen (PSA) testing. RESULTS: Median follow-up was 31 months. Median CTV D95% was 18.8 Gy. We observed 2% grade 3 genitourinary toxicity, no grade 3 gastrointestinal toxicity, and 22% newly developed grade 3 erectile dysfunction. Five of 13 patients (38%) with self-reported pretreatment potency (International Index of Erectile Function >17) remained potent. Clinically relevant quality of life deterioration was reported for only 6 of 31 items and was not statistically significant. Biochemical failure (nadir + 2) occurred in 26 patients. Among intraprostatic recurrences, 73% were in field. After 2.5 years, biochemical disease-free survival was 51% (95% confidence interval, 37%-69%), metastases-free survival was 75% (64%-89%), androgen deprivation therapy-free survival was 90% (82%-99%), and overall survival was 98% (94%-100%). Presalvage PSA, CTV size, and stage ≥T3 were significantly associated with biochemical failure. Higher-risk patients (stage ≥T3, PSA ≥10, or PSA double time ≤9 months) had 25% biochemical disease-free survival at 2.5 years versus 71% for lower-risk patients. CONCLUSIONS: At this early stage, MRI-guided ultrafocal HDR-BT seems to be a safe salvage treatment option, with acceptable biochemical control in a well-selected group of patients and potential for effectively postponing androgen deprivation therapy.

Does an immobilization mask have added value during planning magnetic resonance imaging for stereotactic radiotherapy of brain tumours?

BACKGROUND AND PURPOSE: When using an immobilization mask, a magnetic resonance imaging (MRI) head receive coil cannot be used and patients may experience discomfort during the examination. We therefore wish to assess the added value of an immobilization mask during all MRI scans intended for cranial stereotactic radiotherapy (SRT) planning. MATERIALS AND METHODS: An MRI was acquired with and without a thermoplastic immobilization mask in ten patients eligible for SRT. A planning computed tomography (CT) scan was also made, to which the two MRIs were independently registered. Additionally, the MRI without immobilization was registered to the MRI in mask. On each sequence, gross tumour volume (GTV), the right eye, brain stem and chiasm were delineated. The absolute differences in centre-of-gravity coordinates and Dice coefficients of the volumes of the delineated structures between the two MRIs were compared. RESULTS: Differences in GTV volume between the two MRIs were low, with median Dice coefficients between 0.88 and 0.91. Similarly, the median absolute differences in centre-of-gravity coordinates between the GTVs, organs at risk and landmarks delineated on the two MRIs were within 0.5 mm. The 95% confidence intervals of the median absolute differences in the three GTV coordinates was within 1 mm, which corresponds to the target volume safety margin used to account for possible errors during the SRT treatment chain. CONCLUSIONS: The effect of scanning a patient without the immobilization mask falls within acceptable bounds of error for the geometrical accuracy of the SRT treatment chain. Consequently, placing the head in treatment position during all MRI scans for patients undergoing radiotherapy of brain metastasis is deemed unnecessary.

Individual lymph nodes: "See it and Zap it".

BACKGROUND AND PURPOSE: With magnetic resonance imaging (MRI)-guided radiotherapy systems such as the 1.5T MR-linac the daily anatomy can be visualized before, during and after radiation delivery. With these treatment systems, seeing metastatic nodes with MRI and zapping them with stereotactic body radiotherapy (SBRT) comes into reach. The purpose of this study is to investigate different online treatment planning strategies and to determine the planning target volume (PTV) margin needed for adequate target coverage when treating lymph node oligometastases with SBRT on the 1.5T MR-linac. MATERIALS AND METHODS: Ten patients were treated for single pelvic or para-aortic lymph node metastases on the 1.5T MR-linac with a prescribed dose of 5x7Gy with a 3 mm isotropic GTV- PTV margin. Based on the daily MRI and actual contours, a completely new treatment plan was generated for each session (adapt to shape, ATS). These were compared with plans optimized on pre-treatment CT contours after correcting for the online target position (adapt to position, ATP). At the end of each treatment session, a post-radiation delivery MRI was acquired on which the GTV was delineated to evaluate the GTV coverage and PTV margins. RESULTS: The median PTV V35Gy was 99.9% [90.7-100%] for the clinically delivered ATS plans compared to 93.6% [76.3-99.7%] when using ATP. The median GTV V35Gy during radiotherapy delivery was 100% [98-100%] on the online planning and post-delivery MRIs for ATS and 100% [93.9-100%] for ATP, respectively. The applied 3 mm isotropic PTV margin is considered adequate. CONCLUSION: For pelvic and para-aortic metastatic lymph nodes, online MRI-guided adaptive treatment planning results in adequate PTV and GTV coverage when taking the actual patient anatomy into account (ATS). Generally, GTV coverage remained adequate throughout the treatment session for both adaptive planning strategies. "Seeing and zapping" metastatic lymph nodes comes within reach for MRI-guided SBRT.

Adaptive radiotherapy: The Elekta Unity MR-linac concept.

BACKGROUND AND PURPOSE: The promise of the MR-linac is that one can visualize all anatomical changes during the course of radiotherapy and hence adapt the treatment plan in order to always have the optimal treatment. Yet, there is a trade-off to be made between the time spent for adapting the treatment plan against the dosimetric gain. In this work, the various daily plan adaptation methods will be presented and applied on a variety of tumour sites. The aim is to provide an insight in the behavior of the state-of-the-art 1.5 T MRI guided on-line adaptive radiotherapy methods. MATERIALS AND METHODS: To explore the different available plan adaptation workflows and methods, we have simulated online plan adaptation for five cases with varying levels of inter-fraction motion, regions of interest and target sizes: prostate, rectum, esophagus and lymph node oligometastases (single and multiple target). The plans were evaluated based on the clinical dose constraints and the optimization time was measured. RESULTS: The time needed for plan adaptation ranged between 17 and 485 s. More advanced plan adaptation methods generally resulted in more plans that met the clinical dose criteria. Violations were often caused by insufficient PTV coverage or, for the multiple lymph node case, a too high dose to OAR in the vicinity of the PTV. With full online replanning it was possible to create plans that met all clinical dose constraints for all cases. CONCLUSION: Daily full online replanning is the most robust adaptive planning method for Unity. It is feasible for specific sites in clinically acceptable times. Faster methods are available, but before applying these, the specific use cases should be explored dosimetrically.

Feasibility of stereotactic radiotherapy using a 1.5 T MR-linac: Multi-fraction treatment of pelvic lymph node oligometastases.

Online adaptive radiotherapy using the 1.5 Tesla MR-linac is feasible for SBRT (5 × 7 Gy) of pelvic lymph node oligometastases. The workflow allows full online planning based on daily anatomy. Session duration is less than 60 min. Quality assurance tests, including independent 3D dose calculations and film measurements were passed.

MRI-Guided Ultrafocal HDR Brachytherapy for Localized Prostate Cancer: Median 4-Year Results of a feasibility study.

PURPOSE: For the treatment of localized prostate cancer, focal therapy has the potential to cure with fewer side effects than traditional whole-gland treatments. We report an update on toxicity, quality of life (QoL), and tumor control in our magnetic resonance imaging (MRI)-guided ultrafocal high-dose-rate brachytherapy cohort. METHODS AND MATERIALS: Disease status was evaluated by systematic biopsies and 3T multiparametric MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by a 1.5 T MRI for contour adjustments and catheter position verification. A single dose of 19 Gy was delivered to the tumor with a margin of 5 mm. Genitourinary (GU) toxicity, gastrointestinal (GI) toxicity, and erectile dysfunction (ED) were graded with the Common Terminology Criteria for Adverse Events version 4.0. QoL was measured with RAND-36, European Organisation for Research and Treatment of Cancer QLQ-C30 and PR25. International Prostate Symptom Scores and International Index of Erectile Function scores were obtained. Prostate-specific antigen level was monitored, with biochemical recurrence defined as nadir + 2 ng/mL (Phoenix). RESULTS: Thirty patients with National Comprehensive Cancer Network low- (13%) to intermediate-risk (87%) prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4 years. Median age was 71 years (interquartile range, 68-73) and median initial prostate-specific antigen level was 7.3 ng/mL (5.2-8.1). Maximum Gleason score was 4 + 3 = 7 (in 2 patients). All tumors were radiologic (MRI) stage T2. No grade >2 GU or >1 GI toxicity occurred. International Prostate Symptom Scores only deteriorated temporarily. Mild pretreatment ED deteriorated to moderate/severe ED in 50% of patients. Long-term clinically relevant QoL deterioration was seen in sexual activity and tiredness, whereas emotional and cognitive functioning improved. At 4 years, biochemical disease-free survival was 70% (95% confidence interval, 52%-93%), metastases-free survival was 93% (85%-100%), and overall survival was 100%. Of intraprostatic recurrences, 7 of 9 were out of field. CONCLUSIONS: Ultrafocal high-dose-rate brachytherapy conveys minimal GU or GI toxicity and has a marginal effect on QoL. An early decline in erectile function was seen. Tumor control outcomes are poor (biochemical disease-free survival of 70% [52%-93%] at 4 years), most likely as a result of poor patient selection.