Progression-free survival in patients with Ga-68-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

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, 2para-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/ β=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

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, D 0.5cc and D 10cc 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. D 0.5cc and D 10cc 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

MR-guided radiotherapy for patients with lymph node oligometastases

Magnetic resonance imaging (MRI) provides superior soft tissue contrast compared with computed tomography (CT) imaging. Image guidance during radiotherapy treatments is of pivotal importance to ensure accurate deposition of the radiation dose at the clinical target. Therefore, most radiotherapy treatment facilities offer fast imaging before each treatment session, but often this relies on cone beam CT (CBCT) imaging. The MR-linac is a treatment facility that combines an MRI scanner and a linear accelerator (linac), and it allows diagnostic-quality soft tissue contrast to guide each radiotherapy delivery. In this thesis, the application of stereotactic body radiotherapy (SBRT) for patients with very limited metastatic disease (oligometastases) in lymph nodes is investigated, with a focus on delivery using the 1.5 T MR-linac. Feasibility of multi-fraction SBRT delivery using the 1.5 T MR-linac has been shown for five patients with lymph node oligometastases. This was the first clinical application of 1.5 T MR-linac after acquisition of the Conformité Européenne (CE)-certification. In this feasibility study new treatment plans were generated for each treatment session based on the daily anatomy, all treatment sessions were completed within 60 minutes and all quality assurance tests were passed, including independent 3D dose calculations and film measurements. Dosimetric evaluations of the MR-linac treatments compose a large part of this thesis. Different methods for daily online plan optimization were compared, treatment margins were evaluated, the need for patient immobilization using a vacuum cushion was investigated and the online adaptive MR-guided treatments were benchmarked against conventional treatments on CBCT-linac. From these dosimetric evaluations, it was concluded that extensive daily re-planning with manual contour adaptation is needed to gain profit from treatment on an MR-linac compared with a CBCT-linac, such as for patients with multiple target volumes or for patients with a critical healthy organ nearby for which adherence to a dose limit was challenging. However, the longer duration of treatment sessions on an MR-linac seems to impact the dosimetric benefit of daily MR-guided plan adaptation. Repeated plan adaptation during the treatment sessions and faster workflows including (improved) automatic segmentation and faster plan optimization are expected to increase the benefit from MR-linac treatments in the future. The second part of this thesis has been focused on the clinical outcomes after SBRT for lymph node oligometastases. Most patients were treated for prostate cancer lymph node oligometastases, which had been diagnosed using prostate-specific membrane antigen (PSMA)-PET scans. For these patients, the median progression-free survival (PFS), defined as time to occurrence of a new metastatic lesion or biochemical progression, was found to be 16 months at a median follow-up of 21 months. Baseline patient characteristics were investigated as potential predictors of shorter PFS and a preliminary risk score for PFS was created. Because of the relatively short PFS, most patients might benefit from combined treatments consisting of SBRT and some form of systemic therapy. Finally, SBRT was confirmed to be a safe treatment for lymph node oligometastases, with limited toxicity and a mild and transient impact on quality of life, mainly fatigue

Outcomes & predictors of progression: SBRT for lymph node oligorecurrent prostate cancer on PSMA-PET

Purpose or Objective To describe outcomes and identify predictors of progression for patients with lymph node oligorecurrent prostate cancer diagnosed on PSMA-PET and treated with stereotactic body radiotherapy (SBRT). Materials and Methods Patients from a prospective cohort study were included if they had 1-3 lymph node metastases diagnosed with PSMA-PET after initial treatment for primary prostate cancer and had not received hormonal therapy in the preceding 24 months. Patients were treated with 5 x 7 Gy or 3 x 10 Gy using MRI- or CBCT-guided SBRT. Acute toxicity was assessed until 3 months post-SBRT. PSA was measured pre-SBRT, after 3 months and then at the discretion of the referring physician. QoL questionnaires were sent pre-SBRT and at 1 and 4 weeks, 3 and 6 months after SBRT and then every 6 months. Clinical and treatment-related variables were assessed for their influence on progression free survival (PFS) using Kaplan-Meier analyses and Cox-regression. Multiple imputation was used for missing data. Progression was defined as a local recurrence (>20% increase in short axis diameter of a target lesion), a newly diagnosed metastatic site, biochemical progression (PSA nadir + 2 ng/mL and >25% increase) or start of ADT. Secondary outcomes were ADT-free survival, biochemical PFS (BPFS), toxicity and QoL. A preliminary risk score was created based on quantiles of the linear predictor from multivariable analysis for PFS. Results 92 patients were included, median follow-up was 26 months. 54 (59%) patients developed at least one progression: diagnosis of a new metastasis in 48 (52%) patients, biochemical progression in 40 (43%) patients and start of ADT in 17 (18%) patients. No local recurrences were observed. Median PFS and BPFS were 15.5 and 20.9 months, respectively. Median ADT-FS was not reached, ADT-FS at 24 months was 73% (95%-CI 62-86%). After correcting for age in multivariable analysis, higher PSA prior to SBRT was significantly associated with worse PFS (Table 1). The risk score, based on multivariable analysis, is depicted in Figure 1. It subdivides patients in low, intermediate and high risk groups, for which significant differences in PFS were observed. Two (1.7%) and five (5.4%) patients experienced acute and late grade 2 genitourinary toxicity, respectively. Grade 1 fatigue was the most predominant acute toxicity (n=40, 34%). No ≥ grade 3 toxicities were observed. QoL analysis only showed a mild increase in fatigue at 1 and 4 weeks after SBRT (median EORTC-C30 fatigue increased from 11 to 22 at 4 weeks compared with baseline, on a 100-point scale). This was normalised again at 6 months and other QoL aspects were unaffected. Conclusion Median PFS of >12 months was attained in patients with lymph node oligometastatic prostate cancer who have been diagnosed on PSMA-PET and treated with image-guided SBRT. Higher pre-SBRT PSA and younger age were found to be predictors of shorter PFS. Toxicity was minor and only transient mild fatigue was observed in quality of life analysis

Simulated dosimetric impact of online replanning for stereotactic body radiation therapy of lymph node oligometastases on the 1.5T MR-linac

PURPOSE: Online 1.5T MR imaging on the MR-linac gives better target visualization compared to CBCT and facilitates online adaptive treatment strategies including daily replanning. In this simulation study, the dosimetric impact of online replanning was investigated for SBRT of lymph node oligometastases as a method for correcting for inter-fraction anatomical changes. METHODS: Pre-treatment plans were created for 17 pelvic and para-aortic lymph nodes, with 3 and 8 mm PTV margins reflecting our clinical practice for lymph nodes with good and poor visibility on CBCT. The dose-volume parameters of the pre-treatment plans were evaluated on daily anatomy as visible on the repeated MRIs and compared to online replanning. RESULTS: With online MRI-based replanning significant dosimetric improvements are obtained for the rectum, bladder, bowel and sigmoid without compromising the target dose. The amount of unintended violations of the dose constraints for target and surrounding organs could be reduced by 75% for 8 mm and 66% for 3 mm PTV margins. CONCLUSION: The use of online replanning based on the actual anatomy as seen on repeated MRI compared to online position correction for lymph node oligometastases SBRT gives beneficial dosimetric outcomes and reduces the amount of unplanned violations of dose constraints