Background Fiducial markers are frequently used before treatment for image‐guided patient setup in radiation therapy (RT), but can also be used during treatment for image‐guided intrafraction motion detection. This report describes our implementation of automatic marker detection with periodic kV imaging (TrueBeam v2.5) to monitor and correct intrafraction motion during prostate RT. Methods We evaluated the reproducibility and accuracy of software fiducial detection using a phantom with 3 implanted fiducial markers. Clinical implementation for patients with intraprostatic fiducials receiving volumetric modulated arc therapy (VMAT) utilized periodic on‐board kV imaging with 10 s intervals during treatment delivery. For each image, the software automatically identified fiducial locations and determined whether their distance relative to planned locations were within a 3 mm tolerance. Motion was corrected if either ≥2 fiducials in a single image or ≥1 fiducial in sequential images were out of tolerance. Results Phantom studies demonstrated poorer performance of linear fiducials compared to collapsible fiducials, and wide variability to accurately detect fiducials across eight software settings. For any given setting, results were relatively reproducible and precise to ~0.5 mm. Across 17 patients treated with a median of 20 fractions, the software recommended a shift in 44% of fractions, and a shift was actually implemented after visual confirmation of movement greater than the 3 mm threshold in 20% of fractions. Adjustment of our approach led to improved accuracy for the latter (n = 7) patient subset. On average, table repositioning added 3.0 ± 0.3 min to patient time on table. Periodic kV imaging increased skin dose by an estimated 1 cGy per treatment arc. Conclusions Periodic kV imaging with automatic detection of motion during VMAT prostate treatments is commercially available, and can be successfully implemented to mitigate effects of intrafraction motion with careful attention to software settings.
Immune checkpoint inhibitors, such as pembrolizumab (pembro), have been shown to be efficacious in improving survival. However, there is only an overall response rate of 5% after 3 rd /4 th line therapy with pembro alone. Our initial trial combining SBRT with pembro (NRG BR001) was shown to be safe (<9% grade 3 toxicity) with promising local control and overall survival using a biologically effective dose (BED) of roughly 100 Gy. One strategy to increase the response rate is to increase the BED. However, SBRT doses are limited by dosimetric constraints of surrounding organs at risk (OARs). The purpose of this work was to determine if ultra-high radiation (BED >200) could be delivered while still respecting OAR tolerances for patients receiving SBRT + pembro. Materials/Methods: Five patients enrolled on an institutional phase I trial investigating the safety of SBRT + pembro were analyzed. Disease sites included liver (3/5), inguinal region (1/5) and pelvis (1/5). The trial dictated that gross tumor volumes (GTVs) >65 cc were contracted to a 65cc subvolume for planning target volume (PTV) definition (3 mm margin). Volumetric modulated arc therapy (VMAT) was used to plan treatments prescribing 90Gy in 3 fractions (BED 10 Z 360 Gy). Plans utilizing both 6FFF and 10FFF beams were created and compared to the clinical plans delivering 45 Gy in 3 fractions (BED 10 Z 112.50 Gy). The target coverage primary goal was V100% > 95% with a secondary goal of V70% > 99%. OAR tolerances were prioritized. OAR objectives followed the trial protocol. To demonstrate deliverability, plans were delivered to a quality assurance phantom containing a diode array and evaluated for fidelity using gamma analysis. Results: Using 6FFF, all liver tumors and the pelvic mass met the primary coverage goal and the inguinal mass met the secondary coverage goal. Using 10 FFF, the inguinal, pelvis and one liver mass met the primary coverage goal and the remaining two liver masses met the secondary coverage goal. Most importantly, for all plans, OAR dose constraints were met. GTV D 100% ranged from BEDs of 167-504 Gy using 6FFF and 106-470 Gy using 10FFF. Target coverage was generally degraded in the 10FFF vs. 6FFF plans; however, the 10FFF allowed for improved skin sparing and provides a logistical advantage of 2x faster dose rate. Gamma analysis of delivered plans using 3%/1mm criteria passed with average rate of 98.14%. Conclusion: This study suggests that VMAT approaches are capable of delivering radiation doses in excess of 300 Gy BED 10 to tumors at various body sites, while maintaining safe OAR doses. These plans have been shown to be deliverable using standard QA approaches and will be incorporated into an upcoming clinical trial. In the era of precision image guided radiation therapy, these results argue that we may have the capability to vastly increase SBRT doses safely and improve the efficacy of concomitant SBRT and immunotherapy.
Immune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95-120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra-high doses of radiation (BED 10 > 300) to be used in future clinical trials. Methods and Materials: The radiation plans from 15 patients enrolled on a phase I trial of SBRT + pembro were reanalyzed. Metastatic disease sites included liver (8/ 15), inguinal region (1/15), pelvis (2/15), lung (1/15), abdomen (1/15), spleen (1/15), and groin (1/15). Gross tumor volumes (GTVs) ranged from 80 to 708 cc. Following the same methodology used in the Phase I trial on which these patients were treated, GTVs > 65 cc were contracted to a 65 cc subvolume (SubGTV) resulting in only a portion of the GTV receiving prescription dose. Volumetric modulated arc therapy (VMAT) was used to plan treatments BED 10 = 360 Gy. Plans utilizing both 6FFF and 10FFF beams were compared to clinical plans delivering BED 10 = 112.50 Gy. The target primary goal was V100% > 95% with a secondary goal of V70% > 99% and OAR objectives per the trial. To demonstrate feasibility, plans were delivered to a diode array phantom and evaluated for fidelity using gamma analysis. Results: All 30 plans met the secondary coverage goal and satisfied all OAR constraints. The primary goal was achieved in 12/15 of the 6FFF plans and 13/15 of the 10FFF plans. Average gamma analysis passing rate using criteria of 3% dose difference
4DCTs available. For all patients, the CTV volume and motion were monitored throughout the treatment course. Layered rescanned (5 times) 3D and 4D robust optimized PBS-PT plans were created, and approved clinically. These plans were then delivered in dry runs at our proton facility to obtain machine log files, and subsequently evaluated through our 4D robustness evaluation method (4DREM). The 4DREM assesses the plan robustness for the combination of (1) setup and range errors, (2) machine errors, (3) anatomy changes, (4) breathing motion, and (5) interplay effects. The disturbing effects (2), (3), (4), (5) are considered by calculating subplan doses on particular 4DCT phases and performing 4D dose accumulation in all 4DCTs. The subplans were split from the nominal plan by retrieving log files information. For each evaluated plan, 14 4D accumulated scenario dose distributions were obtained, representing 14 possible full fractionated treatment courses. Results: Only small differences in V 95 (CTV) between nominal and voxelwise worst-case dose distributions were observed for all 3D / 4D robust optimized plans (consistently ! 99.89 %). Similarly, averaged D mean (lungs-GTV) over all scenarios considered within the 4DREM changed only slightly (Table 1). Conclusion: For 6 patients with lung / esophageal cancer, our 3D / 4D PBS-PT planning protocol showed to be clinically suitable. After confirming these results in an extended patient cohort, we will proceed to investigate less conservative, more conformal planning strategies. The experience gained through comprehensive robustness evaluations based on patient and machine specific data is essential for the definition of optimal PBS-PT protocols for patients with thoracic tumors.
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