Prostate Stereotactic Body Radiotherapy Research Articles

Stereotactic body radiation therapy (SBRT) for prostate cancer: Improving treatment delivery efficiency and accuracy

PurposeIn stereotactic body radiation therapy (SBRT) for prostate cancer, intrafraction motion is an important source of treatment uncertainty as it could not be completely smoothed through fractionation. Herein, we compared different arrangements and beam qualities for extreme hypofractionated treatments to minimize beam delivery time and so intrafractional errors. MethodsA retrospective dataset of 11 patients was used. Three volumetric modulated arc therapy (VMAT) beam arrangements were compared for a prescription dose of 40 Gy/5 fractions: two full arcs, 6 MV flattening filter free (FFF); one full arc, 6 MV FFF; one full arc, 10 MV FFF. A plan quality index was defined to compare achievement of the planning goals. Plan complexity was evaluated with the modulation factor. Dose delivery accuracy and efficiency were measured with patient-specific quality assurance plans. ResultsAll treatment plans fulfilled all dose objectives. No statistical differences were found both in plan quality and complexity. Very accurate dose delivery was achieved with the three arrangements, with mean γ passing rates >96.5 % (2 %/2 mm criteria). Slightly but significantly higher γ passing rates were observed with single-arc 6 MV FFF. Contrariwise, statistically significant reductions of the delivery time were obtained with single-arc geometries: the average delivery times were 1.6 min (−46.1 %) and 1.3 min (−56.2 %) for 6 and 10 MV FFF respectively. ConclusionsThe high-quality, very fast and accurate dose delivery of single-arc plans confirmed the suitability of this arrangement for prostate SBRT. In particular, the significant reduction of delivery time would improve treatment robustness against intrafraction prostate motion.

The Status and Challenges for Prostate Stereotactic Body Radiation Therapy Treatments in United States Proton Therapy Centers: An NRG Oncology Practice Survey

PurposeTo report the current practice pattern of the proton stereotactic body radiation therapy (SBRT) for prostate treatments. Materials and MethodsA survey was designed to inquire about the practice of proton SBRT treatment for prostate cancer. The survey was distributed to all 30 proton therapy centers in the United States that participate in the National Clinical Trial Network in February, 2023. The survey focused on usage, patient selection criteria, prescriptions, target contours, dose constraints, treatment plan optimization and evaluation methods, patient-specific QA, and image-guided radiation therapy (IGRT) methods. ResultsWe received responses from 25 centers (83% participation). Only 8 respondent proton centers (32%) reported performing SBRT of the prostate. The remaining 17 centers cited 3 primary reasons for not offering this treatment: no clinical need, lack of volumetric imaging, and/or lack of clinical evidence. Only 1 center cited the reduction in overall reimbursement as a concern for not offering prostate SBRT. Several common practices among the 8 centers offering SBRT for the prostate were noted, such as using Hydrogel spacers, fiducial markers, and magnetic resonance imaging (MRI) for target delineation. Most proton centers (87.5%) utilized pencil beam scanning (PBS) delivery and completed Imaging and Radiation Oncology Core (IROC) phantom credentialing. Treatment planning typically used parallel opposed lateral beams, and consistent parameters for setup and range uncertainties were used for plan optimization and robustness evaluation. Measurements-based patient-specific QA, beam delivery every other day, fiducial contours for IGRT, and total doses of 35 to 40 GyRBE were consistent across all centers. However, there was no consensus on the risk levels for patient selection. ConclusionProstate SBRT is used in about 1/3 of proton centers in the US. There was a significant consistency in practices among proton centers treating with proton SBRT. It is possible that the adoption of proton SBRT may become more common if proton SBRT is more commonly offered in clinical trials.

(016) Sexual Health Toxicity Following MRI-Guided versus CT-guided Prostate SBRT

Abstract Introduction Sexual health toxicities remain an under-reported but important health outcome for patients undergoing radiotherapy for localized prostate cancer. With the increasing adoption of higher daily doses of radiation over shorter timeframes delivered using stereotactic body radiotherapy (SBRT), the precision of radiation delivery remains an important factor that can reduce patient toxicity. MRI-guided SBRT (MRgRT) allows for improved image quality, treatment gating, and planning target volume margin reduction, offering improved radiation precision, which may translate to reduced treatment-related toxicity as compared to traditional CT-guided SBRT (CTgRT). Objective We sought to evaluate the effect of MRI-guidance on sexual health toxicity in patients following prostate SBRT for the treatment of localized prostate cancer. Methods We conducted a post-hoc analysis of patients enrolled on a phase III single-center randomized trial (MIRAGE: NCT04384770). The trial overall seeks to study the relative benefit of MRI vs CT guided SBRT (40 Gy/5 fractions) in patients with localized prostate cancer. Right and left neurovascular bundles (NVBs) and internal pudendal arteries (IPAs) were contoured on treatment planning images. Dosimetric parameters for these structures (Dmax, Dmin, Dmean, and V20Gy) were collected. Patient-reported sexual function outcomes (SHIM and EPIC-26 surveys) were also collected prior to treatment and at 1, 3, and 12 months following treatment. A clinically relevant decrement was defined as a ≥24 point decrease in the EPIC-26 sexual domain scores and a ≥9 point decrease on SHIM surveys. Unpaired t-tests and chi-square tests were used to evaluate for statistical significance. Results 152 patients received either MRgRT (n = 77) or CTgRT (n = 75). MRgRT resulted in a significant improvement in the volume receiving 20 Gy or less of radiation (V20Gy) in the left NVB (7.3cc vs 10.9cc, p = 4.4x10-8), right NVB (7.0cc vs 10.7cc, p = 2.8x10-7), and right IPA (0.42cc vs 1.35cc, p = 0.049), and trended towards significance for the left IPA (0.3cc vs 1.1cc, p = 0.066). Only 48 patients were not given hormonal therapy with radiotherapy. No statistically significant differences in clinically relevant decrements in patient-reported SHIM or EPIC scores were seen between MRgRT and CTgRT in these patients. No clear association between acute or chronic (12-months post-RT) sexual health toxicity and radiation exposure to the NVBs or IPAs was identified. Conclusions Patients treated with MRgRT had decreased radiation exposure to the bilateral NVBs and IPAs compared to patients treated with CTgRT. These data highlight the dosimetric benefits of MRgRT with regard to sexually relevant organs at risk. Power to detect associations between dosimetry and patient-reported sexual health outcomes will increase as the data matures and more patients have recovered testosterone after use of hormonal therapy. Future work will assess the impact on MRI-guided vs CT-guided radiation on sexual health outcomes at later time points. Disclosure No.

Quantifying Intrafraction Motion and the Impact of Gating for Magnetic Resonance Imaging-Guided Stereotactic Radiation therapy for Prostate Cancer: Analysis of the Magnetic Resonance Imaging Arm From the MIRAGE Phase 3 Randomized Trial

Real-time intrafraction tracking/gating is an integral component of magnetic resonance imaging-guided radiation therapy (MRgRT) and may have contributed to the acute toxicity reduction during prostate stereotactic body radiation therapy observed on the MRgRT-arm of the MIRAGE (MAGNETIC RESONANCE IMAGING-GUIDED Stereotactic Body Radiotherapy for Prostate Cancer) randomized trial (NCT04384770). Herein we characterized intrafraction prostate motion and assessed gating effectiveness. Seventy-nine patients were treated on an MR-LINAC. Real-time cine imaging was acquired at 4Hz in a sagittal plane. If >10% of the prostate area moved outside of a 3-mm gating boundary, an automatic beam hold was initiated. An in-house tool was developed to retrospectively extract gating signal for all patients and identify the tracked prostate in each cine frame for a subgroup of 40 patients. The fraction of time the prostate was within the gating window was defined as the gating duty cycle (GDC). A total of 391 treatments from 79 patients were analyzed. Median GDC was 0.974 (IQR, 0.916-0.983). Fifty (63.2%) and 24 (30.4%) patients had at least 1 fraction with GDC ≤0.9 and GDC ≤0.8, respectively. Incidence of low GDC fractions among patients appeared stochastic. Patients with minimum GDC <0.8 trended toward more frequent grade 2 genitourinary toxicity compared with those with minimum GDC >0.8 (38% vs 18%, P = .065). Prostate intrafraction motion was mostly along the bladder-rectum axis and predominantly in the superior-anterior direction. Motion in the inferior-posterior direction was associated with significantly higher rate of acute grade 2 genitourinary toxicity (66.7% vs 13.9%, P = .001). Gating limited mean prostate motion during treatment delivery in fractions with a GDC <0.9 (<0.8) to 2.9 mm (2.9 mm) versus 4.1 mm (4.7 mm) for ungated motion. Fractions with large intrafraction motion were associated with increased toxicity and their occurrence among patients appears stochastic. Real-time tracking/gating effectively mitigated this motion and is likely a major contributing factor of acute toxicity reduction associated with MRgRT.

Urethra-Sparing Prostate Cancer Stereotactic Body Radiation Therapy: Sexual Function and Radiation Dose to the Penile Bulb, the Crura, and the Internal Pudendal Arteries From a Randomized Phase 2 Trial

PurposeErectile dysfunction (ED) is a common side effect after prostate cancer stereotactic body radiotherapy (SBRT). We aimed to assess the correlation between the dose to the penile bulb (PB), internal pudendal arteries (IPA), and crura with the development of ED after ultra-hypofractionation as part of a phase II clinical trial of urethra-sparing prostate SBRT. Material and methodsAmong the 170 patients with localized prostate cancer from 9 centers included in the trial, 90 men with CTCAE v4.03 grade 0-1 ED (ED-) at baseline treated with 36.25Gy in 5 fractions were selected for the present analysis. Doses delivered to the PB, crura, and IPA were analyzed and correlated with grade 2-3 ED (ED+) development. The impact on QoL assessed by the EORTC PR-25 questionnaire was reported. ResultsAfter a median follow-up of 6.5 years, 43% (n=39) of the patients developed ED+, while 57% (n=51) remained ED-. The dose delivered to the crura was significantly higher in ED+ patients than in ED- patients (7.7 Gy vs 3.6 Gy (p=0.014) for the Dmean and 18.5 Gy vs 7.2 Gy (p=0.015) for the D2%, respectively). No statistically significant difference between ED+ and ED- patients was observed for the dose delivered to the PB and the IPA. The median ED+ free-survival was worse in patients receiving a crura Dmean ≥ 4.7 Gy vs < 4.7 Gy (51.5% vs 71.7%, p=0.005), and a crura D2% >12 Gy vs ≤ 12 Gy (54.9% vs 68.9%, p =0.015). No ED+ free-survival differences were observed for doses delivered to PB and IPA. Decline in EORTC PR-25 sexual functioning was significantly more pronounced in patients with higher doses to the crura. ConclusionsBy keeping a Dmean and D2% to crura below 4.7 Gy and 12 Gy respectively, the risk to develop ED+ following prostate SBRT may be significantly reduced.

Performance characterization of a novel hybrid dosimetry insert for simultaneous spatial, temporal, and motion-included dosimetry for MR-linac.

Several (online) adaptive radiotherapy procedures are available to maximize healthy tissue sparing in the presence of inter/intrafractional motion during stereotactic body radiotherapy (SBRT) on an MR-linac. The increased treatment complexity and the motion-delivery interplay during these treatments require MR-compatible motion phantoms with time-resolved dosimeters to validate end-to-end workflows. This is not possible with currently available phantoms. Here, we demonstrate a new commercial hybrid film-scintillator cassette, combining high spatial resolution radiochromic film with four time-resolved plastic scintillator dosimeters (PSDs) in an MRI-compatible motion phantom. First, the PSD's performance for consistency, dose linearity, and pulse repetition frequency (PRF) dependence was evaluated using an RW3 solid water slab phantom. We then demonstrated the MRI4D scintillator cassette's suitability for time-resolved and motion-included quality assurance for adapt-to-shape (ATS), trailing, gating, and multileaf collimator (MLC) tracking adaptations on a 1.5 T MR-linac. To do this, the cassette was inserted into the Quasar MRI4D phantom, which we used statically or programmed with artificial and patient-derived motion. Simultaneously with dose measurements, the beam-gating latency was estimated from the time difference between the target entering/leaving the gating window and the beam-on/off times derived from the time-resolved dose measurements. Experiments revealed excellent detector consistency (standard deviation 0.6%), dose linearity (R2 = 1), and only very low PRF dependence ( 0.4%). The dosimetry cassette demonstrated a near-perfect agreement during an ATS workflow between the time-resolved PSD and treatment planning system (TPS) dose (0%-2%). The high spatial resolution film measurements confirmed this with a 1%/1-mm local gamma pass-rate of 90%. When trailing patient-derived prostate motion for a prostate SBRT delivery, the time-resolved cassette measurements demonstrated how trailing mitigated the motion-induced dose reductions from 1%-17% to 1%-2% compared to TPS dose. The cassette's simultaneously measured spatial dose distribution highlighted the dosimetric gain of trailing by improving the 3%/3-mm local gamma pass-rates from 80% to 97% compared to the static dose. Similarly, the cassette demonstrated the benefit of real-time adaptations when compensating patient-derived respiratory motion by showing how the TPS dose was restored from 2%-56% to 0%-12% (gating) and 1%-26% to 1%-7% (MLC tracking) differences. Larger differences are explainable by TPS-PSD coregistration uncertainty combined with a steep dose gradient outside the PTV. The cassette also demonstrated how the spatial dose distributions were drastically improved by the real-time adaptations with 1%/1-mm local gamma pass-rates that were increased from 8 to 79% (gating) and from 35 to 89% (MLC tracking). The cassette-determined beam-gating latency agreed within 12 ms with the ground truth latency measurement. Film and PSD dose agreed well for most cases (differences relative to TPS dose 4%), while film-PSD coregistration uncertainty caused relative differences of 5%-8%. This study demonstrates the excellent suitability of a new commercial hybrid film-scintillator cassette for simultaneous spatial, temporal, and motion-includeddosimetry.

Prostate volume variation during 1.5T MR-guided adaptive stereotactic body radiotherapy (SBRT) and correlation with treatment toxicity

IntroductionTo evaluate prostate volume change during daily-adaptive prostate SBRT on 1.5 T MR-linac and to correlate it with treatment toxicity. Methodsa series of patients affected by low-to-intermediate risk prostate cancer was treated by 5-fraction SBRT within a prospective study (Prot. n° 23748). Total dose was 35 Gy and 36.25 Gy delivered every day or on alternate days. Treatment toxicity was recorded with the following patient reported outcomes (PROMs): IPSS, ICIQ-SF, and EPIC-26. Results254 patients were included in the analysis. Baseline median CTV volume was 55 cc (range 15.3–163.3). Mean prostate volume were 58.9 cc, and 62.7 cc at first and last fraction respectively (mean volume increase 6.4 %; p = <0.0001). We observed prostate swelling (mean 15.4 % increase) in 50 % of cases, stable volume (≤5% volume change) in 39 % of patients, and prostate shrinkage in 11 % of cases (mean 12.2 % reduction). Baseline CTV > 55 cc showed a trend towards higher CTV shrinkage (-10.5 % versus −14.5 %; p = 0.052). We found no correlation between CTV change and PROMs. Prostate swelling was generally compensated by the planned PTV expansion, even though the mean setup volume dropped from 47.4 cc to 38.9 cc at last fraction, with few cases not covered by initial setup margins. ConclusionThe present study reported a significant prostate volume change during prostate SBRT on 1.5T MR-linac. We observed both prostate swelling in half of cases and few cases of prostate shrinkage. No correlations were found with PROMs in this population treatment with daily-adaptive strategy.

Patient adherence and early biochemical outcomes following relugolix with stereotactic body radiation therapy (SBRT) for unfavorable prostate cancer.

526 Background: Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventional radiotherapy. Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following Relugolix and SBRT for unfavorable prostate cancer. Methods: This prospective study sought to evaluate early testosterone suppression and PSA response following Relugolix and SBRT for unfavorable prostate cancer. Relugolix was initiated at least 2 months prior to SBRT. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone &lt; 20 ng/dL. Poor drug adherence was delineated as failure to reach profound castration. PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and &lt; 0.2 ng/mL during the first 4 months post SBRT. Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with Relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were black and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were &gt; Grade Group 3. 44 patients were intermediate- and 8 were high-risk. The disease volume was high (mean 43.6% of total cores involved). Patients initiated Relugolix at a median of 3.6 months prior to SBRT with a median of 6.2 total months. 92.3%of patients achieved profound castration during Relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue Relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively. Conclusions: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. Given the potential benefits of Relugolix over injectable GnRH receptor agonists, its usage may be preferred, especially in specific patient populations (fear of needles, prior cardiovascular events). We observed a 96% compliance rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients can consistently and successfully follow an oral ADT protocol in a real-world setting. Future studies should focus on barriers to medication access.

CT-based online adaptive radiotherapy improves target coverage and organ at risk (OAR) avoidance in stereotactic body radiation therapy (SBRT) for prostate cancer

IntroductionStereotactic body radiation therapy (SBRT) is an emerging treatment modality for clinically localized prostate cancer (PCa). Online daily adaptive radiotherapy (ART) could potentially improve the therapeutic ratio of prostate SBRT by accounting for inter-fraction variation in target and OAR volumes. To our knowledge, no group has evaluated the clinical utility of a novel AI-augmented CT-based ART system for prostate SBRT. In this study we hypothesized that adaptive prostate SBRT plans would result in improved target coverage and lower dose to OARs in comparison to unadapted treatment plans. MethodsSeven patients with favorable intermediate to oligometastatic PCa treated with 5-fx prostate adaptive SBRT were retrospectively reviewed. Patients were treated with 3625 cGy to the prostate and seminal vesicles. 6 patients additionally received 2500 cGy to the pelvic nodes, 5 patients underwent a boost to 4000 cGy to the prostate. For each fraction, a CBCT was acquired and OARs (rectum, bladder, bowel, sigmoid, femurs) were segmented/deformed using AI. CTVs were rigidly registered. Volumes were adjusted manually and PTV expansions added. Adaptive treatment plans were developed based on the contoured targets and OARs and dose to these volumes for the adapted vs. initial plans were compared for each fraction. V100 and the D0.03 cc between scheduled and adapted treatment plans were compared using a Student’s t-test, with significance threshold of P < 0.05. ResultsSeven patients completed 35 Fx’s of adaptive RT. Daily adaptation resulted in a statistically significant mean improvement in PTV V100 for all targets: [21.4 % ± 4.3 % for PTV 4000 (p < 0.0001); 8.7 % ± 1.1 % for PTV 3625 (p < 0.0001); and 11.5 % ± 3.1 % for PTV 2500 (p = 0.0013)]. Mean rectal D0.03 was significantly reduced by 38.8 cGy ± 5.95 cGy (p < 0.0001) per fraction (194 cGy/5 fractions) compared to the initial plans. There was a modest increase in bladder dose of 10.9 cGy ± 4.93 cGy per fraction (p = 0.0424) for the adaptive plans. The adaptive plans met bladder constraints for every fraction. There were no statistically significant differences between sigmoid or bowel dose for adapted vs. initial plans. No patients experienced acute CTCAE grade ≥ 3 GI/GU adverse events (median F/U 9.5 months). All statistically significant differences were maintained in the presence and absence of rectal hydrogel spacer (p < 0.05). ConclusionsCT-based online adaptive SBRT resulted in statistically significant and clinically meaningful improvements in PTV coverage and D0.03 cc dose to the rectum. A trial evaluating CT adaptive whole-pelvis prostate SBRT is underway.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging–Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial

PurposeEmerging data suggest that trigone dosimetry may be more associated with post-stereotactic body radiotherapy (SBRT) urinary toxicity than whole bladder dosimetry. Herein, we quantify the dosimetric impact of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pre-treatment 0.35T MRI images. MethodsSeventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase III single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and five on-board pre-treatment MRIs. Dice Similarity Coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03cc, Dmean, V40Gy, V39Gy, V38Gy, and V20Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (CTCAE v4.03 scale) as well as patient-reported (IPSS and EPIC-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. ResultsThe average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for less than 2% of the bladder volume. Median DSC for the bladder was 0.79 while the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade 2 or greater GU toxicity were identified, though numerically, patients with GU toxicity (grade ≥ 2) had higher intermediate doses to the bladder (V20Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40Gy, V39Gy, and V38Gy). ConclusionsThe trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Evaluation of kV Triggered Fiducial Tracking for Prostate SBRT Intrafraction Motion Management.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for localized prostate cancer. Given the high dose per fraction, a high degree of precision is needed during SBRT treatment delivery. Fiducial marker tracking is a means of monitoring intrafraction motion, ensuring precise treatment delivery and potentially allowing for decreased planning target volume (PTV) margins. We present a 5-year single institution experience to characterize the performance of fiducial tracking. We analyzed 132 consecutive patients treated at our institution with prostate SBRT between July 2017 and November 2022 using fiducial tracking with the TrueBeam Auto Beam Hold feature. Patients were treated using a 5-fraction dose escalation protocol, with many receiving a simultaneous integrated boost to the GTV up to 45 Gy. All patients underwent pre-treatment cone-beam CT and planar kV imaging with rigid registration to the fiducial markers. Cine kV images were acquired every 3-5 seconds during treatment delivery and the beam was paused when a fiducial deviated from a given 4 mm diameter tolerance region. Additional intrafraction 2D or 3D imaging techniques were then used to realign the fiducials. Data was retrieved from the record and verify system including: number and type of intrafraction images, number of treatment interruptions, number of and magnitude of shifts, and total treatment time. The average number of cine kV images acquired per fraction and for the total 5 fraction SBRT course were 86.6 ± 26.8 and 425.6 ± 136.8 respectively. Assuming 1.3 mGy/kV image, the fiducial tracking process delivered an average additional 55.3 cGy over the full treatment course. On average, the beam was paused 5.0 ± 2.5 times per fraction (range 1-21 interruptions) and shifts were applied 4.1 ± 2.1 times (range 0-10.2 times) per fraction. Over the 2560 total shifts applied for all the patients, the average(max) translations were 0.6 (12) mm vrt, 0.7 (22) mm lng, and 0.9 (5) mm lat and the average(max) rotations were 0.19 (5.9)° pitch, 0.01 (2.4)° roll, and 0.16 (6.4)° rtn. Overall, 2.4% of shifts were greater than the 4 mm PTV margin and 4.2% of vertical shifts were greater than the 2.5 mm posterior margin. Average fraction treatment time was 27 ± 9.7 minutes. Fiducial tracking affords the potential to increase daily treatment precision when delivering prostate SBRT. Our data indicate that the beam is typically paused several times during a prostate SBRT fraction, with occasional large shifts required, suggesting the importance of intrafraction motion management. Downsides of kV triggered fiducial tracking include extension of treatment times and delivery of additional radiation dose to the patient. We are investigating if this method of motion management might allow for a reduction in PTV margins to reduce normal tissue dosing.

Low Incidence of Late Lymphopenia Following Stereotactic Body Radiotherapy for Localized Prostate Cancer.

Stereotactic body radiotherapy (SBRT) is increasing in use for the treatment of localized prostate cancer. The utilization of highly conformal photon therapy such as SBRT may increase the whole-body integral dose. Lymphocytes are very radiation sensitive. This dose increase could lead to unintended consequences such as lymphopenia. Prior studies have shown that lymphopenia following radiation therapy may negatively impact long-term outcomes. This study sought to evaluate the incidence and timeline of chronic lymphopenia following prostate SBRT. Institutional IRB (IRB#: 2012-1175) approval was obtained. The absolute lymphocyte count was measured 1-2 hours prior to robotic SBRT (35-36.25 Gy in 5 fractions) and at each follow-up (3, 6, 12, 18 and 24 months). Lymphopenia was graded using the CTCAEv.4: Grade 1 (1.0-0.8 k/μl), Grade 2 (0.8-0.5 k/μl), Grade 3 (0.5-0.2 k/μl) and Grade 4 (<0.2 k/μl). Late lymphopenia was defined as lymphopenia occurring 3 or more months post-SBRT. From 2019 to 2022, 198 localized prostate cancer patients (23 low-, 148 intermediate-, and 27 high-risk according to the D'Amico classification) at a median age of 73.5 years were treated with SBRT (35-36.25 Gy) at Georgetown University Hospital on a prospective clinical trial. Baseline lymphopenia was uncommon: Grade 1 (3.5%), Grade 2 (1.5%) and Grade 3 (0%). The baseline ALC of 1.9 k/μl decreased to 1.5 k/μl at 3 months post-SBRT and then remained stable for the remainder of the two-year follow-up. Overall, 14.6% of men experienced lymphopenia in the two years following SBRT: Grade 1 (7.6%), Grade 2 (6.6%) and Grade 3 (0.5%). No patient experienced Grade 4 lymphopenia. Prostate SBRT leads to a low rate of late lymphopenia with the vast majority of toxicities being low grade. The peak incidence occurred at 3 months post-SBRT. Resolution of lymphopenia occurs in most patients within two years after SBRT. Future studies should explore the possible impact on quality of life and cancer control outcomes.

Is the Motion Causing a Commotion? Two-Fraction Prostate SBRT on the MR-Linac.

In HERMES (NCT04595019) men with localized prostate cancer are treated on the Unity MR-Linac platform (MRL, Elekta AB, Stockholm) and randomized between stereotactic body radiotherapy (SBRT) with 36.25 Gy in 5 fractions and 24 Gy in 2 fractions. Patients randomized to two fractions receive 24 Gy to the high risk PTV, 20 Gy to the low risk PTV and a boost of 27 Gy to the dominant intraprostatic lesion. This study explores dose received by the target and organs at risk (OARs) when considering intrafraction motion in two fraction SBRT. Targets and OARs were delineated and a reference plan generated on Monaco v5.40.01 (Elekta). An Adapt-to-Shape (ATS) workflow was used. Contours were propagated to the session MRI (MRIsession) and edited accordingly. Prior to delivery, a verification MRI (MRIverif) was acquired with baseline shifts corrected for using the Adapt-to-Position (ATP-of-ATS) workflow. A post treatment MRI (MRIpost) was acquired after delivery. Men in the 2-fraction arm received each fraction in 2 sub-fractions sequentially on the same day, to mitigate intrafraction motion. The plans of 5 men receiving 2 fraction SBRT were analyzed. The targets, urethra, bladder and rectum were recontoured on the MRIverif and MRIpost. Delivered plans were recalculated on the corresponding MRIverif and MRIpost. The percentage of optimal and mandatory target dose constraints met were calculated. Accumulated OAR doses were calculated by averaging their respective dose statistics across all sub-fractions, conservatively assuming that the same area of the OAR receives the maximum dose each fraction. Analysis was carried out separately for MRIverif and MRIpost as the true 'delivered dose' most likely lies between these two estimates. There was good coverage across all fractions. The mandatory constraints of CTVpsv V24.0 Gy > 95% and CTVsv V20.0 Gy > 95% were met in 100% of fractions and V2700cGy > 95% in 90% on the MRIpost. Table 3 shows OAR dose. This work demonstrates that target coverage is good, even for the GTV where no margin is applied. With our conservative dose calculation approach, we found dose constraints are exceeded for some patients. However, treatment has been well tolerated, suggesting that that our current dose constraints may be cautious. Once Elekta's True Tracking and automated gating software is implemented at our center we will be able to further improve OAR clinical goal compliance.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT)

BackgroundUltra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT–utilizing potentially fewer treatments–is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment.Methods/DesignA total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10–14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7–10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score.DiscussionFORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa.Trial registrationClinicaltrials.gov identifier: NCT04984343. Date of registration: July 30, 2021.Protocol version: 4.0, Nov 8, 2022.

Proton Single-Energy Bragg-Peak FLASH Using Clinical Systems Can Achieve IMPT-Equivalent Plan Quality for Breast and Prostate Cancers

Most current proton FLASH-RT studies focus on transmission proton techniques. In this study, we propose a novel method for achieving FLASH dose rate in hypofractionated proton radiotherapy using the Bragg peak of a single-energy proton beam. The dosimetric characteristics using this novel technique for proton pencil beam scanning (PBS) stereotactic body radiation therapy (SBRT) of prostate and breast cancers were first investigated based on the clinically available cyclotron beam parameters. This novel approach uses the distal tracking technique that enables PBS Bragg-peak of the highest proton energy to adapt to the target distally. Positioning of the Bragg peak at different depths is achieved using a universal range shifter and range compensator. To investigate the feasibility of this approach, we developed an in-house treatment planning platform for intensity-modulated proton therapy (IMPT) delivery and performed dosimetric studies on prostate and breast SBRT cases previously treated with conventional proton PBS technique. FLASH plans were generated using a similar clinical beam arrangement to deliver 40 Gy (RBE) in 5 fractions. Dose metrics were compared between the clinical and FLASH plans. Dose-rate volume histograms (DRVH) were also calculated to investigate the 40 Gy/s coverage (V40 Gy/s) of organs-at-risk (OARs) for FLASH plans. The distal tracking can precisely stop the Bragg peak at the target distal edge, and Bragg peak plans achieved tumor coverage and dose conformality equivalent to IMPT plans. The clinical IMPT plans yielded slightly superior target dose uniformity -CTV Dmax of FLASH plans was 10% higher for prostate and 2% higher for breast. There was no significant difference between the clinical and FLASH plans in dose metrics for major OARs, including rectum, large bowel, heart, and lung. Higher maximal doses to femoral heads (∼2 Gy) and urethra (∼6 Gy) were observed in prostate FLASH plans than in the clinical plans but were still within clinically accepted dose limits. The V40 Gy/s for OARs were >90% for prostate FLASH plans and >76.5% for breast FLASH plans. The proposed single-energy Bragg-peak FLASH technique eliminates exit dose associated with transmission proton FLASH and can still yield comparable plan quality and OAR sparing while preserve sufficient FLASH dose rate coverage for prostate and breast proton SBRT. This study demonstrates the potential application of Bragg peaks for highly conformal FLASH-RT using clinical cyclotron systems to treat prostate and breast cancer patients, which moves towards clinical application.

Treatment Delivery Gating of MRI-Guided Stereotactic Radiotherapy for Prostate Cancer: An Exploratory Analysis of a Phase III Randomized Trial of CT-Vs. MR-Guided Radiotherapy (MIRAGE)

Compared to CT-guided radiotherapy, MRI-guided radiotherapy (MRgRT) has been shown to reduce acute physician-scored and patient-reported gastrointestinal and genitourinary (GU) toxicities associated with prostate stereotactic body radiotherapy (SBRT) in the MIRAGE randomized trial (NCT04384770). We hypothesize that real-time intrafraction tracking/gating is important and is a critical enabler of aggressive margin reduction with MRgRT. 79 patients received MRgRT on the MIRAGE trial with a planning margin of 2mm around the prostate and proximal seminal vesicles, which were treated to 40 Gy in five fractions on an MR-Linac. Tracking was performed at 4 frames/second in the sagittal plane during treatment with a gating boundary of 3mm for automatic beam hold. An in-house tool was developed to extract treatment time and beam gating status based on treatment logs and real-time cine images. The ratio of the time that the target was within the gating window/total time of target inside or outside the gating boundary was defined as the duty cycle (DC). Target contours were extracted from each frame of tracking and overlaid to create a motion-convolved target occupancy map. Minimum isotropic expansions of the prostate to cover 85%, 90% and 95% of the intrafraction motion were calculated with and without gating. Median treatment time per fraction including image guidance procedure and beam delivery was 24.3 min (IQR: 22.2-27.7 min). The median time for image guidance 5.4 min (IQR: 4.2-6.7 min). A total of 391 treatment fractions were analyzed and the median DC per fraction was 0.974 (IQR: 0.926 -0.983). 89 (22.8%) and 35 (9.0%) of fractions had DC<90% and <80%, respectively, corresponding to 50/79 (62.3%) and 24/79 (30.4%) of patients having at least one fraction with a DC<90% and <80%, respectively. The minimum duty cycle of all fractions was lower among patients with grade ≥2 GU toxicity compared to those with grade 0-1 GU toxicity (mean 79.8% vs. 85.9%, p = 0.06). The proportion of patients with grade ≥2 GU toxicity was also greater in patients with a minimum gating cycle <80% (37.5% vs. 18.2%, p = 0.06). Gating significantly decreased the minimum isotropic expansion of the prostate to cover 85%, 90% and 95% of the intrafraction motion (p<0.0001 for all). Prostate intrafraction motion tended to be along the bladder-rectum axis secondary to bladder filling, rectal gas and bulk motion. Fractions with large prostate motion were mostly stochastic. A large fraction (30%) of patients had at least of one treatment fraction with DC<80%, which correlated with increased acute GU toxicity. Gating effectively reduces the expansion needed to cover prostate intrafraction motion, and is necessary for real-time motion management given the unpredictable nature of prostate motion.

The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study

Acute gastrointestinal (GI) and genitourinary (GU) toxicity after prostate radiotherapy (RT) has been shown to be associated with late toxicity with 3D conformal RT. However, whether this association is present with modern approaches, such as stereotactic body radiotherapy (SBRT), remains unclear. We analyzed patients treated within the international phase III non-inferiority randomized control trial, PACE-B, to assess the association between acute and late toxicity following SBRT and conventional/moderately hypofractionated radiotherapy (CRT). We hypothesize that acute toxicity is significantly associated with equivalent late toxicity following prostate SBRT and CRT. We analyzed patients with GI and GU Common Terminology Criteria for Adverse Events (CTCAE) measurements in the acute (≤12 weeks post-RT) and late period (6-24 months post-RT). Using logistic regression, we analyze the association between G2+ acute GI and GU toxicities with equivalent late toxicities. Lasso variable selection was used to determine patient, tumor and treatment variables to include in the multivariable model. The area under the receiver operator characteristics curve (AUC) was used to evaluate the model's predictive performance. Of patients included in this analysis (n = 842), 414 were treated with SBRT and 428 with CRT. In univariable analysis (UVA), G2+ acute GU toxicity was significantly associated with developing G2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), p<0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), p<0.0001). This association remained significant in multivariable analysis (MVA). The models AUC for predicting G2+ late GU toxicity after SBRT was 0.73 (95% CI, 0.67-0.78) and 0.66 (95% CI, 0.59-0.73) following CRT. In UVA, G2+ acute GI toxicity was associated with developing G2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), p <0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), p<0.0001). This association also remained significant in MVA. The models AUC for predicting G2+ late GI toxicity after SBRT was 0.66 (0.95% CI, 0.57-0.75) and 0.64 (95% CI, 0.57-0.72) following CRT. In UVA analysis, G2+ baseline GU symptoms were also associated with developing G2+ late GU toxicity after SBRT (OR 7.59, 95% CI (2.72-21.19, p<0.0001) and CRT (OR 7.98, 95% CI (3.03-20.96), p<0.0001), and this continued to be significant in MVA. Acute toxicity remained associated with persistent late toxicity (≥2 G2+ late events) and late toxicity 12-24 months. Our study demonstrates an independent association between acute and late GU/GI toxicity in patients treated with SBRT and CRT for localized prostate cancer. Recognizing those at risk of late toxicity can provide an opportunity for early intervention to improve outcomes. G2+ acute toxicity should be considered an essential variable for predicting late GI/GU toxicity after prostate RT.

293 Prostate Stereotactic Body Radiotherapy Treatment Planning and Image Guidance: Initial Experience from Two Institutions

293 Prostate Stereotactic Body Radiotherapy Treatment Planning and Image Guidance: Initial Experience from Two Institutions

Noninvasive inter- and intrafractional motion control in ultrahypofractionated radiation therapy of prostate cancer using RayPilot HypoCath™—a substitute for gold fiducial-based IGRT?

PurposeIn ultrahypofractionated radiation concepts, managing of intrafractional motion is mandatory because tighter margins are used and random errors resulting from prostate movement are not averaged out over a large number of fractions. Noninvasive live monitoring of prostate movement is a desirable asset for LINAC-based prostate stereotactic body radiation therapy (SBRT).MethodsWe prospectively analyzed a novel live tracking device (RayPilot HypoCath™; Micropos Medical AB, Gothenburg, Sweden) where a transmitter is noninvasively positioned in the prostatic urethra using a Foley catheter in 12 patients undergoing ultrahypofractionated intensity-modulated radiation therapy (IMRT) of the prostate. Gold fiducials (Innovative Technology Völp, Innsbruck, Austria) were implanted to allow comparison of accuracy and positional stability of the HypoCath system and its ability to be used as a standalone IGRT method. Spatial stability of the transponder was assessed by analyzing transmitter movement in relation to gold markers (GM) in superimposed kV image pairs. Inter- and intrafractional prostate movement and the impact of its correction were analyzed.ResultsA total of 64 fractions were analyzed. The average resulting deviation vector compared to the GM-based position was 1.2 mm and 0.7 mm for inter- and intrafractional motion, respectively. The mean intrafractional displacement vector of the prostate was 1.9 mm. Table readjustment due to exceeding the threshold of 3 mm was required in 18.8% of fractions. Repositioning reduced the time spent outside the 3‑mm margin from 7.9% to 3.8% of beam-on time. However, for individual patients, the time spent outside the 3‑mm margin was reduced from to 49% to 19%.Conclusionthe HypoCath system allows highly accurate and robust intrafractional motion monitoring. In conjunction with cone beam CT (CBCT) for initial patient setup, it could be used as a standalone image-guided radiation therapy (IGRT) system.

Urethral identification using three-dimensional magnetic resonance imaging and interfraction urethral motion evaluation for prostate stereotactic body radiotherapy.

Prostatic urethra identification is crucial in prostate stereotactic body radiotherapy (SBRT) to reduce the risk of urinary toxicity. Although computed tomography (CT) with a catheter is commonly employed, it is invasive, and catheter placement may displace the urethral position, resulting in possible planning inaccuracies. However, magnetic resonance imaging (MRI) can overcome these weaknesses. Accurate urethral identification and minimal daily variation could ensure a highly accurate SBRT. In this study, we investigated the usefulness of a three-dimensional (3D) T2-weighted (T2W) sequence for urethral identification, and the interfractional motion of the prostatic urethra on CT with a catheter and MRI without a catheter for implementing noninvasive SBRT. Thirty-two patients were divided into three groups. The first group underwent MRI without a catheter to evaluate urethral identification by two-dimensional (2D)- and 3D-T2W sequences using mean slice-wise Hausdorff distance (MSHD) and Dice similarity coefficient (DSC) of the contouring by two operators and using visual assessment. The second group provided 3-day MRI data without a catheter using 3D-T2W, and the third provided 3-day CT data with a catheter to evaluate the interfractional motion using MSHD, DSC, and displacement distance (Dd). The MSHD and DSC for the interoperator variability in urethral identification and visual assessment were superior in 3D-T2W than in 2D-T2W. Regarding interfractional motion, the Dd value for prostatic urethra was smaller in MRI than in CT. These findings indicate that the 3D-T2W yielded adequate prostatic urethral identification, and catheter-free MRI resulted in less interfractional motion, suggesting that 3D-T2W MRI without a catheter is a feasible noninvasive approach to performing prostate SBRT.