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.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases: study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design.

BACKGROUND: Standard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease. METHODS/DESIGN: This study follows the 'cohort multiple Randomized Controlled Trial' design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm. DISCUSSION: This study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability. TRIAL REGISTRATION: The Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115 . Date of trial registration February 1, 2015.

Clinical assessment of deep learning-based uncertainty maps in lung cancer segmentation.

Objective. Prior to radiation therapy planning, accurate delineation of gross tumour volume (GTVs) and organs at risk (OARs) is crucial. In the current clinical practice, tumour delineation is performed manually by radiation oncologists, which is time-consuming and prone to large inter-observer variability. With the advent of deep learning (DL) models, automated contouring has become possible, speeding up procedures and assisting clinicians. However, these tools are currently used in the clinic mostly for contouring OARs, since these systems are not reliable yet for contouring GTVs. To improve the reliability of these systems, researchers have started exploring the topic of probabilistic neural networks. However, there is still limited knowledge of the practical implementation of such networks in real clinical settings.Approach. In this work, we developed a 3D probabilistic system that generates DL-based uncertainty maps for lung cancer CT segmentations. We employed the Monte Carlo (MC) dropout technique to generate probabilistic and uncertainty maps, while the model calibration was evaluated by using reliability diagrams. A clinical validation was conducted in collaboration with a radiation oncologist to qualitatively assess the value of the uncertainty estimates. We also proposed two novel metrics, namely mean uncertainty (MU) and relative uncertainty volume (RUV), as potential indicators for clinicians to assess the need for independent visual checks of the DL-based segmentation. Main results. Our study showed that uncertainty mapping effectively identified cases of under or over-contouring. Although the overconfidence of the model, a strong correlation was observed between the clinical opinion and MU metric. Moreover, both MU and RUV revealed high AUC values in discretising between low and high uncertainty cases.Significance. Our study is one of the first attempts to clinically validate uncertainty estimates in DL-based contouring. The two proposed metrics exhibited promising potential as indicators for clinicians to independently assess the quality of tumour delineation.

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.

Recurrence characteristics after focal salvage HDR brachytherapy in prostate cancer.

BACKGROUND AND PURPOSE: Radiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: Patients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study. Imaging data were collected regarding the occurrence of local, regional and distant recurrences, including location of local recurrences (LR) in relation to the HDR radiotherapy field. RESULTS: One hundred seventy-five patients were included after focal salvage HDR brachytherapy (median follow-up 36 months (IQR 23-50)). Three-years biochemical recurrence-free survival, LR-free survival, in-field LR-free survival, out-of-field LR-free survival, any-recurrence-free survival and ADT-free survival were 43% (95%CI 34%-52%), 51% (41%-61%), 70% (61%-80%), 92% (88%-97%), 42% (32%-52%) and 86% (80%-92%), respectively. Larger GTV-size and shorter PSA doubling time were associated with in-field LR in multivariable analysis. CONCLUSION: After focal salvage HDR brachytherapy with a dose of 1x19 Gy for local prostate cancer recurrence, subsequent recurrences are mostly local and in-field.

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.

Value of Targeted Biopsies and Combined PSMA PET/CT and mp-MRI Imaging in Locally Recurrent Prostate Cancer after Primary Radiotherapy.

Radiorecurrent prostate cancer is conventionally confirmed using systematic and/or targeted biopsies. The availability of multiparametric (mp) MRI and prostate specific membrane antigen (PSMA) PET/CT has increased diagnostic accuracy. The objective was to determine the positive predictive value (PPV) of combined mp-MRI and PSMA PET/CT and whether pathology verification with MR-targeted biopsies remains necessary for patients with radiorecurrent prostate cancer. Patients with locally recurrent prostate cancer who were referred for 19 Gy single-dose MRI-guided focal salvage high dose rate (HDR) brachytherapy between 2015 and 2018 were included in the current analysis. Patients were selected if they underwent pre-biopsy mp-MRI and PSMA PET/CT. Based on these images, lesions suspect for isolated tumor recurrence were transperineally biopsied using transrectal ultrasound fused with MRI. A total of 41 patients were identified from the database who underwent cognitive targeted (n = 7) or MRI/PSMA-transrectal ultrasound (TRUS) fused targeted (n = 34) biopsies. A total of 40 (97.6%) patients had positive biopsies for recurrent cancer. Five patients initially had negative biopsies (all MRI/PSMA-TRUS fusion targeted), four of whom recurrence was confirmed after a re-biopsy. One (2.4%) patient refused re-biopsy, leading to a positive predictive value (PPV) for combined imaging of 97.6%. Biopsies can therefore safely be withheld when the results of the combined mp-MRI and PSMA PET/CT are conclusive, avoiding an unnecessary invasive and burdensome procedure.

International Multi-institutional Patterns of Contouring Practice and Clinical Target Volume Recommendations for Stereotactic Body Radiation Therapy for Non-Spine Bone Metastases.

PURPOSE: Despite the increasing use of stereotactic body radiation therapy for non-spine bone metastases (NSBM), there is no established standard for target delineation. The objective of this study was to provide consensus recommendations on clinical target volume (CTV) delineation based on international expert contours. METHODS AND MATERIALS: Eleven cases of NSBM were contoured by 9 international radiation oncologists. For each case, the gross tumor volume was provided on the simulation computed tomography scans with accompanying magnetic resonance imaging. Participants contoured the CTV and completed a clinical survey. Agreement between CTV contours were analyzed with simultaneous truth and performance level estimation using the kappa coefficient and the Dice similarity coefficient (DSC) and summarized to establish contouring recommendations. A direction-dependent analysis was applied to the consensus contours to quantify margins. RESULTS: All CTV contours were completed. Six participants used a single-dose level, whereas 3 used a 2-dose level simultaneous integrated boost (SIB) technique. For the SIB cases, the largest volume receiving a stereotactic body radiation therapy (SBRT) dose was used for contour analysis. There was substantial agreement between contours across cases with a mean kappa of 0.72 (mean sensitivity 0.85, mean specificity 0.97). The mean DSC value was 0.77 (range, 0.67-0.87). Consensus CTV contouring recommendations were (1) an intraosseous CTV margin of 5 to 10 mm should be strongly considered within contiguous bone; (2) an extraosseous margin of 5 to 10 mm should be strongly considered where there is soft tissue disease or cortical bone disruption; (3) CTVs should be manually cropped to respect anatomic barriers to spread (eg, peritoneal cavity, pleura, uninvolved joint space and cortical bone). CONCLUSIONS: CTV contouring recommendations for NSBM-SBRT were established based on analysis of international expert consensus contours with a high level of agreement. These principles may provide guidance to treating physicians and inform future study until prospective clinical data can provide further refinement.

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.

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.

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.

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.

Determining the safety of ultrafocal salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer: A toxicity assessment of 150 patients.

BACKGROUND AND PURPOSE: Local re-treatment of radiorecurrent prostate cancer is potentially curative. However, the increased risk of severe toxicity may outweigh the opportunity of cancer control. This study aims to evaluate treatment-related toxicity from ultrafocal salvage high-dose-rate brachytherapy (HDR-BT) and to investigate potential risk factors. MATERIALS AND METHODS: Toxicity data from 150 treated patients (July 2013-November 2019) was collected from a prospective registry. The treatment aim was to deliver a single dose of 19 Gy to the recurrent lesion as identified on multiparametric MRI and PET-CT. Treating physicians graded genitourinary (GU) and gastro-intestinal (GI) toxicity and erectile dysfunction (ED) using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0, at baseline and during follow-up. Domains with substantial (≥10%) new-onset grade ≥ 2 toxicity were further evaluated using mixed effects logistic regression to find potential risk factors. RESULTS: Median follow-up time was 20 months (IQR 12-31). Over time, new-onset grade 2 and 3 toxicity was recorded in 41% and 3% (GU), 5% and 0% (GI) and 22% and 15% (ED). While GI toxicity remained stably low, grade ≥ 2 GU toxicity and ED were seen twice as frequent in the late phase (>3 months after treatment). Significant risk factors for grade ≥ 2 toxicity were baseline GU toxicity (grade ≥ 2), baseline ED (grade ≥ 2), IPSS (cut-off ≥ 14) and urethral dose (D10%, cut-off ≥ 17 Gy). CONCLUSION: Ultrafocal salvage HDR-BT is a safe re-treatment option, especially in patients with a favorable symptom profile at baseline. Adherence to urethral dose constraints is important to avoid GU toxicity.

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.

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.

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.

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.