Stereotactic MR-guided Adaptive Radiation Therapy Research Articles

Widening the therapeutic window for central and ultra-central thoracic oligometastatic disease with stereotactic MR-guided adaptive radiation therapy (SMART)

Background/PurposeCentral/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. Materials/Methods26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35–60) between 10/2019–10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were ≤ 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. ResultsTumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. ConclusionIsotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Dosimetric comparison of stereotactic MR-guided radiation therapy (SMART) and HDR brachytherapy boost in cervical cancer

The standard of care in locally advanced cervical cancer (LACC) is concomitant chemoradiotherapy followed by high-dose-rate brachytherapy (HDR-BT). Although previous studies compared HDR-BT with stereotactic body radiotherapy (SBRT), there is scarce data regarding the dosimetric outcomes of stereotactic MR-guided adaptive radiation therapy (SMART) boost in lieu of HDR-BT. In this single-institutional in-silico comparative study, LACC patients who were definitively treated with external beam radiotherapy followed by HDR-BT were selected. Target volumes and organs at risk (OARs) were delineated in MRI and HDR-planning CT. An HDR-BT and a SMART boost plan were generated with a prescribed dose of 28 Gy in four fractions for all patients. The HDR-BT and SMART boost plans were compared in regard to target coverage as well OARs doses. Mean EQD2 D90 to HR-CTV and IR-CTV for HDR-BT plans were 89.7 and 70.5 Gy, respectively. For SMART, the mean EQD2 D90 to HR-PTV, HR-CTV, and IR-CTV were 82.9, 95.4, and 70.2 Gy, respectively. The mean D2cc EQD2 of bladder, rectum, and sigmoid colon for HDR-BT plans were 86.4, 70.7, and 65.7 Gy, respectively. The mean D2cc EQD2 of bladder, rectum, and sigmoid colon for SMART plans were 81.4, 70.8, and 73.6 Gy, respectively. All dose constraints in terms of target coverage and OARs constraints were met for both HDR-BT and SMART plans. This dosimetric study demonstrates that SMART can be applied in cases where HDR-BT is not available or ineligible with acceptable target coverage and OAR sparing. However, prospective clinical studies are needed to validate these results.

Volumes Changes in Adrenal Metastases during Delivery of 5-Fraction Stereotactic Magnetic Resonance-Guided Adaptive Radiotherapy

Stereotactic MR-guided adaptive radiotherapy (SMART) improves adrenal target coverage and reduces organ at risk doses. Changes in adrenal tumor volumes were observed during contouring for daily-adaptive planning. We hypothesized that such changes in GTV may correlate with long-term outcomes. An Ethics approved institutional database was accessed for details of 5-fraction adrenal SABR treatments on a 0.35T MR-Linac between 2016-2023. Volumetric MR-scans were acquired at baseline, and prior to each of 5 fractions. Manually contoured GTVs were accessed. Volume changes between simulation and first fraction (ΔPF1), as well as between first and subsequent fractions (ΔF1F2 to ΔF1F5) were computed. Daily relative adrenal volume change (DRVC) and the absolute volume change (DAVC) before treatment, were calculated by dividing ΔPF1 by the number of days between simulation and F1. Paired Wilcoxon tests were used to compare volumes at different timepoints. Univariate linear regression (LinR) models were created to study per-treatment volume changes. A logistic regression (LogR) analysis explored associations between baseline characteristics and volumetric changes with radiological complete response (CR) at the date of last news. Adrenal SMART in 5 fractions of either 8 or 10Gy was delivered to 70 patients. The median interval between simulation and F1 was 13 days (range, 2-35), and 13 days between F1-F5 (range, 9-31). Solitary metastasis comprised 44%; metastases were mainly from non-small cell lung (64%) or renal (9%) primaries. Concurrent systemic therapy (± 3 months) was delivered in 41% of patients. Mean baseline GTV at simulation and F1 were respectively 38.5 and 41.4cc (p<0.001). Mean ΔPF1 was +9.1% (-10.2% to +50.1%) or +2.9cc (-4.4 to +27.4cc). Mean DRVC was +0.8% per day (-1.0% to +8.4%), and did not correlate with histology, GTV or concurrent systemic treatment. Mean DAVC was +0.26cc per day (-0.31 to +2.4cc), and was associated with GTV size (p = 0.04). In total, 47% of adrenal GTVs decreased in volume at F5 compared to F1. A ≥10% increase in GTV was observed in 39% of patients during SMART. GTV variations of ≥20% occurred in 36% patients at some point during SMART. At a median follow-up of 20.3 months, radiological CR was seen in 23% of 64 evaluable patients. Radiological CR was significantly associated with baseline GTV (p = 0.03) and ΔF1F5 (p = 0.03), but not DRVC (p = 0.6) or ΔF1F3 (p = 0.3). Local relapses were seen in 6% of patients. Changes in adrenal volumes during SMART were common, with variations ≥20% occurring in 36% patients. The probability of a radiological CR correlated with both baseline GTV size and median relative volume decline between fractions 1 and 5. These changes support use of daily SABR plan adaptation.

Standardization of Stereotactic MR-Guided Adaptive Radiation Therapy Planning for Prostate Cancer

To assess the impact of a standardized planning class solution (PCS) in stereotactic MR-guided adaptive radiation therapy (SMART) for prostate cancer on efficiency and robustness for daily adaptive radiation therapy treatments. Data collection of 20 previous SMART prostate plans: number of objective structures, number of beam segments, treatment delivery time (TDT) and the plan adaption robustness (PAR). The PAR was scored from 1 to 3 for the robustness of the plan to re-adapt and achieve similar dose metric scores to the baseline plan on all fractions. These scores were, 1: a single re-optimization required, 2: cost-function adjustments required and 3: medical physics advice required. Five medical dosimetrists provided preferences for objective structures and the optimization thresholds used. A PCS was created based on this data and implemented into SMART prostate plans between October 2022 and December 2022. A consecutive sample of 20 patients (PCSpost) were then retrospectively compared with the previous 20 patients prior to the PCS (PCSpre). The PCS showed minimal difference in the TDT and segment number mean ± (standard deviation), 9.5 ± (0.7) mins and 77.8 ± (6.9) segments PCSpost respectively compared to 9.5 ± (0.8) mins and 80.8 ± (5.9) segments PCSpre. However, the PCS resulted in a considerable reduction in PAR, with 11 patients requiring only a single re-optimization for each fraction to achieve dose metric targets compared to 7 PCSpre patients. Also, the median PAR score was 1 in PCSpost compared to a score of 2 with PCSpre. The PCS had good compliance with the criteria met in 18/20 patient baseline plans. Feedback surveys showed positive results for efficiency saving from multiple disciplines; in therapeutic radiographers from reduced PAR, medical physicists increased automation in plan checking and consistent planning guidelines for medical dosimetrists. The PCS is in clinical use, results have shown improved treatment adaption efficiency and robustness. Fewer re-optimizations per treatment were required onset to achieve similar dose metrics than before its implementation.

Neoadjuvant Stereotactic MR-Guided Ablative Radiation Therapy (SMART) and Surgical Outcomes in Patients with Pancreatic Cancer

The benefit of neoadjuvant radiation therapy for patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC) remains unclear. Stereotactic MR-guided adaptive radiation therapy (SMART) treatment to ablative doses is a newer technique that is well tolerated and has increased local control in unresectable pancreatic cancer. For resectable pancreatic cancer, neoadjuvant SMART has the potential to decrease local recurrence risk and positive margin rates. However, there is concern for perioperative risks associated with ablative dose treatments. We report the efficacy and safety of surgical resection in patients who have received neoadjuvant SMART at our institution. We conducted a retrospective analysis of all consecutive patients diagnosed with PDAC who had noted vascular involvement of the celiac axis, superior mesenteric, and/or portal vessels between January 2016 and December 2022 at a single, high-volume, academic institution. Perioperative events were defined according to the Clavien-Dindo classification. The Kaplan Meier method was applied to estimate disease free survival (DFS) and overall survival (OS). Seventeen patients with PDAC and vessel involvement at time of diagnosis who received SMART were included. Median follow-up time was 14.3 months; all patients underwent surgery, at a median time after radiation of 28 days (range: 15 - 90). Median length of postoperative stay was 7 days (range: 3 - 15). Five patients (29%) underwent vascular resection. Fifteen patients (88%) achieved R0 resection, with two R1 resections noted at the SMA and pancreatic neck respectively. Seven patients (41%) had adverse events attributable to surgery, with the majority being defined as abscess or infection (n = 5; 29%). One (6%) Clavien-Dindo grade III or higher toxicity was observed - a cortical cerebrovascular event following surgery. No major bleeding events requiring surgical intervention were noted. At time of event censorship, there were no observable locoregional failures. The median DFS and OS were not reached; however, 1-year DFS and OS were 62% and 87%, respectively. Neoadjuvant SMART appears to be safe, with low rates of surgical complications and promising outcomes. Further identification of patients for this approach requires additional investigation.

Online adaptive radiotherapy: Assessment of planning technique and its impact on longitudinal plan quality robustness in pancreatic cancer

Background and PurposePlanning on a static dataset that reflects the simulation day anatomy is routine for SBRT. We hypothesize the quality of on-table adaptive plans is similar to the baseline plan when delivering stereotactic MR-guided adaptive radiotherapy (SMART) for pancreatic cancer (PCa). Materials and MethodsSixty-seven inoperable PCa patients were prescribed 50 Gy/5-fraction SMART. Baseline planning included: 3–5 mm gastrointestinal (GI) PRV, 50 Gy optimization target (PTVopt) based on GI PRV, conformality rings, and contracted GTV to guide the hotspot. For each adaptation, GI anatomy was re-contoured, followed by re-optimization. Plan quality was evaluated for target coverage (TC = PTVopt V100%/volume), PTV D90% and D80%, homogeneity index (HI = PTVopt D2%/D98%), prescription isodose/target volume (PITV), low-dose conformity (D2cm = maximum dose at 2 cm from PTVopt/Rx dose), and gradient index (R50%=50% Rx isodose volume/PTVopt volume).A novel global planning metric, termed the Pancreas Adaptive Radiotherapy Score (PARTS), was developed and implemented based on GI OAR sparing, PTV/GTV coverage, and conformality. Adaptive robustness (baseline to fraction 1) and stability (difference between two fractions with highest GI PRV variation) were quantified. ResultsOAR constraints were met on all baseline (n = 67) and adaptive (n = 318) plans. Coverage for baseline/adaptive plans was mean ± SD at 44.9 ± 5.8 Gy/44.3 ± 5.5 Gy (PTV D80%), 50.1 ± 4.2 Gy/49.1 ± 4.7 Gy (PTVopt D80%), and 80%±18%/74%±18% (TC), respectively. Mean homogeneity and conformality for baseline/adaptive plans were 0.87 ± 0.25/0.81 ± 0.30 (PITV), 3.81 ± 1.87/3.87 ± 2.0 (R50%), 1.53 ± 0.23/1.55 ± 0.23 (HI), and 58%±7%/59%±7% (D2cm), respectively. PARTS was found to be a sensitive metric due to its additive influence of geometry changes on PARTS’ sub-metrics. There were no statistical differences (p > 0.05) for stability, except for PARTS (p = 0.04, median difference −0.6%). Statistical differences for robustness when significant were small for most metrics (<2.0% median). Median adaptive re-optimizations were 2. ConclusionWe describe a 5-fraction ablative SMART planning approach for PCa that is robust and stable during on-table adaption, due to gradients controlled by a GI PRV technique and the use of rings. These findings are noteworthy given that daily interfraction anatomic GI OAR differences are routine, thus necessitating on-table adaptation. This work supports feasibility towards utilizing a patient-independent, template on-table adaptive approach.

Stereotactic MR-guided adaptive radiotherapy (SMART) for primary rectal cancer: evaluation of early toxicity and pathological response.

The purpose of this study is to measure the effects of stereotactic MR-guided adaptive radiotherapy (SMART) for rectal cancer patients in terms of early toxicity and pathological response. For this prospective pilot study, patients diagnosed with locally advanced rectal cancer (LARC) with positive lymph node clinical staging underwent SMART on rectal lesion and mesorectum using hybrid MR-Linac (MRIdian ViewRay). Dose prescription at 80% isodose for the rectal lesion and mesorectum was 40 Gy (8 Gy/fr) and 25 Gy (5 Gy/fr), respectively, delivered on 5 days (3 fr/week). Response assessment by MRI was performed 3 weeks after SMART, then patients fit for surgery underwent total mesorectal excision. Primary endpoint was evaluation of adverse effect of radiotherapy. Secondary endpoint was pathological complete response rate. Early toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). From October 2020 to January 2022, twenty patients underwent rectal SMART. No grade 3-5 toxicity was recorded. Twelve patients were eligible for total mesorectal excision (TME). Mean interval between the completion of SMART and surgery was 4 weeks. Pathological downstaging occurred in all patients; rate of pathological complete response (pCR) was 17%. pCR occurred with a prolonged time to surgery (> 7 weeks). To our knowledge, this is the first study to use stereotactic radiotherapy for primary rectal cancer. SMART for rectal cancer is well tolerated and effective in terms of tumor regression, especially if followed by delayed surgery.

PO-1541 Stereotactic MRguided adaptive radiotherapy in prostate cancer:Real life experience of 180 patients

PO-1541 Stereotactic MRguided adaptive radiotherapy in prostate cancer:Real life experience of 180 patients

Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions.

Stereotactic body radiotherapy (SBRT) is an effective radiation therapy technique that has allowed for shorter treatment courses, as compared to conventionally dosed radiation therapy. As its name implies, SBRT relies on daily image guidance to ensure that each fraction targets a tumor, instead of healthy tissue. Magnetic resonance imaging (MRI) offers improved soft-tissue visualization, allowing for better tumor and normal tissue delineation. MR-guided RT (MRgRT) has traditionally been defined by the use of offline MRI to aid in defining the RT volumes during the initial planning stages in order to ensure accurate tumor targeting while sparing critical normal tissues. However, the ViewRay MRIdian and Elekta Unity have improved upon and revolutionized the MRgRT by creating a combined MRI and linear accelerator (MRL), allowing MRgRT to incorporate online MRI in RT. MRL-based MR-guided SBRT (MRgSBRT) represents a novel solution to deliver higher doses to larger volumes of gross disease, regardless of the proximity of at-risk organs due to the (1) superior soft-tissue visualization for patient positioning, (2) real-time continuous intrafraction assessment of internal structures, and (3) daily online adaptive replanning. Stereotactic MR-guided adaptive radiation therapy (SMART) has enabled the safe delivery of ablative doses to tumors adjacent to radiosensitive tissues throughout the body. Although it is still a relatively new RT technique, SMART has demonstrated significant opportunities to improve disease control and reduce toxicity. In this review, we included the current clinical applications and the active prospective trials related to SMART. We highlighted the most impactful clinical studies at various tumor sites. In addition, we explored how MRL-based multiparametric MRI could potentially synergize with SMART to significantly change the current treatment paradigm and to improve personalized cancer care.

To fly or not to fly: Stereotactic MR-guided adaptive radiotherapy effectively treats ultracentral lung tumors with favorable long-term outcomes

BackgroundStereotactic radiotherapy of ultracentral lung tumors (ULT) is challenging as it may cause overdoses to sensitive mediastinal organs with severe complications. We aimed to describe long-term outcomes after stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) as an innovative treatment of ULT. Patients & methodsWe analyzed 36 patients that received SMART to 40 tumors between 02/2020 – 08/2021 inside prospective databases. ULT were defined by planning target volume (PTV) overlap with the proximal bronchial tree or esophagus. We calculated Kaplan Meier estimates for overall survival (OS) and progression-free survival (PFS), and competing risk estimates for the incidence of tumor progression and treatment-related toxicities. ULT patients (N = 16) were compared to non-ULT patients (N = 20). ResultsBaseline characteristics were similar between ULT and non-ULT, but ULT were larger (median PTV: ULT 54.7 cm3, non-ULT 19.2 cm3). Median follow-up was 23.6 months. ULT and non-ULT showed a similar OS (2-years: ULT 67%, non-ULT 60%, p = 0.7) and PFS (2-years: ULT 37%, non-ULT 34%, p = 0.73). Progressions occurred mainly at distant sites (2-year incidence of distant progression: ULT 63%, non-ULT 61%, p = 0.77), while local tumor control was favorable (2-year incidence of local progression: ULT 7%, non-ULT 0%, p = 0.22). Treatment of ULT led to significantly more toxicities ≥ grade (G) 2 (ULT: 9 (56%), non-ULT: 1 (5%), p = 0.002). Most toxicities were moderate (G2). Two ULT patients developed high-grade toxicities: 1) esophagitis G3 and bronchial bleeding G4 after VEGF treatment, 2) bronchial bleeding G3. Estimated incidence of high-grade toxicities was 19% (3–48%) in ULT, and no treatment-related death occurred. ConclusionOur small series supports SMART as potentially effective treatment of ULT. SMART with careful fractionation could reduce severe complications, but treatment of ULT remains a high-risk procedure and needs careful benefit-risk-assessment.

Surgical outcomes after neoadjuvant ablative dose radiation among patients with borderline resectable and locally advanced pancreas cancer from the multi-institutional phase 2 Stereotactic MR-Guided Adaptive Radiation Therapy (SMART) trial.

718 Background: Acute grade 3+ toxicity was rare in the multi-institutional phase 2 stereotactic MR-guided on-table adaptive radiation therapy (SMART) trial (NCT03621644) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). Surgery may be considered after ablative SMART although the feasibility and safety of this is not well understood. Postoperative outcomes of the subset of patients in the SMART trial are examined here. Methods: Trial eligibility included BRPC or LAPC without metastases after a minimum of 3 months of induction chemotherapy. All patients received SMART prescribed to 50 Gy in 5 fractions using an integrated 0.35T MR-radiation therapy device equipped with cutting edge soft tissue tracking, automatic beam gating, and on-table adaptive replanning. Surgery was permitted after SMART, often after multi-disciplinary review. Perioperative details and postoperative outcomes, including morbidity, mortality, and overall survival (OS), were analyzed. Results: 136 patients across 13 sites were enrolled between 2019-2022. 44 patients (32.4%) had surgery after SMART (33 BRPC, 11 LAPC). Surgical procedures included pancreaticoduodenectomy (81.8%), distal pancreatectomy with splenectomy (9.1%), total pancreatectomy (6.8%), and distal pancreatectomy with celiac axis resection (2.3%). 52.3% required vascular resection/reconstruction, a majority of which were venous resections (65.2%), with a smaller proportion needing both venous/arterial (21.7%), or arterial (13%). Surgery was performed after a mean 51.4 ± 52.8 days from SMART. Postoperative hospitalization was 10.5 ± 8.9 days. Nine patients (20.5%) had Clavien-Dindo complications of grade III or higher; 3 deaths resulted from post-pancreatectomy hemorrhage in patients who had portal vein resection. One-year OS in patients who had surgery versus no surgery after SMART was 66% vs. 43%, respectively. Conclusions: These are the first prospectively evaluated surgical outcomes after 5-fraction ablative SMART for BRPC/LAPC. The rate of surgery for BRPC compares favorably to radiated patients on the Alliance A021501 trial. Despite the use of ablative radiation dose and frequent need for vascular resection, the incidence of serious surgical complications was similar to what is reported after non-ablative radiation therapy. However, several deaths occurred after surgery and we therefore we urge caution when considering surgery after ablative radiation therapy. Further analysis of other variables such as the time between SMART and surgery, approaches to vascular resections, and discrete events such as delayed gastric emptying, operative duration, and post-operative pancreatic fistula are needed to better understand the surgical morbidity seen in these patients. Clinical trial information: NCT03621644 .

Stereotactic MR-Guided Adaptive Radiotherapy for Pancreatic Tumors: Updated Results of the Montpellier Prospective Registry Study.

Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75-93%), and 68.6% (95% CI: (53-80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88-99%), 86.5 (95% CI: 68-95%), and 80.7% (95% CI: 59-92%). There was no grade &gt; 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70-92%)), and 60.5% (95% CI: (42-75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78-97%)), and 45.8% (95% CI: (27-63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.

Widening the Therapeutic Window for Central and Ultra-Central Thoracic Oligometastatic Disease with Stereotactic MR-Guided Adaptive Radiation Therapy (SMART)

<h3>Purpose/Objective(s)</h3> Central ©/ultra-central (UC) thoracic tumors are challenging to treat with stereotactic radiotherapy due to the narrow therapeutic window. Stereotactic MR guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath hold gating and real-time MR imaging as well as the option for daily online adaptive replanning (ARP) to account for changes in target and/or organ-at-risk (OAR) location. Iso-toxic (OAR constraints-driven plan adaptation) SMART may provide an optimal balance of safety and local control (LC) for C/UC thoracic oligo-metastases (OM) or oligo-progression (OP). Here we report our institutional experience. <h3>Materials/Methods</h3> In this IRB-approved retrospective study, we reviewed the records of patients with C/UC thoracic OM/OP tumors treated with 5-fraction isotoxic SMART in 10/2019-8/2021. Tumor was considered UC if the planning target volume (PTV) abutted/overlapped the proximal tracheobronchial tree (PBT), great vessels, or esophagus. Data collection included dose to targets/OARS, frequency/clinical necessity for ARP, toxicity (CTCAE v5.0), and outcomes. Typical OAR constraints observed were PBT V40, great vessel V52.5, and esophagus V35 <0.03 cc. Local failures were defined as recurrences overlapping the PTV. <h3>Results</h3> 5 C/17 UC thoracic tumors were treated with SMART in 20 patients. Median age was 66 yrs (range 35-77). 73% had OP on systemic therapy and 27% were OM. Histology included non-small cell lung cancer (32%), and 9% each of mesothelioma, colorectal, prostate/bladder, and cervical/uterine. 55% of tumors were located in lung/pleura and 45% in hilum/mediastinum. All PTVs were <2 cm from any mediastinal organ and 59% <2 cm from the PBT. PTV abutted/overlapped the PBT in 32%, great vessel in 36%, heart in 36%, and esophagus in 41%. Median target volume was 10 cc for GTV and 18 cc for PTV (margin 3-5 mm). Median dose prescribed was 50 Gy in 5 fractions (range 35-60 Gy). 104/109 (95%) fractions required ARP, necessary to meet OAR constraints in 79% and target coverage in 21%. Median PTV V95 was 94% (range 53-100). Median follow up was 9 months. 1-yr LC rate was 94% (1/22 local failure for NUT-midline paraesophageal metastasis receiving 40 Gy/5 fx). 1-yr distant failure rate was 83% (n=16). 1-yr OS rate was 64%. 14% had acute G2 toxicities (esophagitis, dysphagia, or anorexia). There were no G3+ acute or late toxicities, and no G2+ pneumonitis. 8 (40%) patients had patient reported outcome measures available pre- and post-SMART with EORTC QLQ-C30 (symptom: median Δ -5 [-15, 15]; functional: median Δ 2 [-36, 13]; global health: median Δ -4 [-42, 17]) and QLQ-LC13 (median Δ 0 [-8, 3]) showing most had minimal negative change. <h3>Conclusion</h3> Iso-toxic 5-fraction SMART, with ARP 95% of the time to ensure OAR sparing and target coverage, resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk OM/OP thoracic tumors; further study in larger cohorts is needed.

Quantifying Gadolinium-Based, Theranostic Nanoparticle Uptake in MR Images of Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Nanomedicines are proving to be a viable option in improving radiotherapeutic benefits by amplifying the effects of radiotherapy. A recently developed, gadolinium (Gd) based theranostic agent has shown promise in the treatment of previously difficult to treat tumors. Here we examine, for the first time, uptake of this agent in patients with pancreatic cancer undergoing MR-guided adaptive radiotherapy. <h3>Materials/Methods</h3> Data have been acquired from four patients with pancreatic cancer enrolled in a stereotactic MR-guided adaptive radiotherapy clinical trial utilizing Gd-based nanoparticles (Nano-SMART). This trial has nanoparticles intravenously infused prior to MR simulation scanning (3T and 0.35T) and again prior to the first fraction (of five daily fractions). Physician-drawn contours were delineated on an MRI-guided real-time on-table adaptive radiotherapy 0.35T planning bSSFP scan. T1 maps of the abdomen were produced on a 3T scanner (a fully-body MRI scanner, from a technology company) before and after nanoparticle administration, using a prototype Look-Locker T1 mapping sequence with 28-30 slices (3 mm thickness, 1 mm spacing) and 244 × 244 pixels (1.56 × 1.56mm). Pre- and post- nanoparticle T1 maps were registered to the 0.35T planning images. Nanoparticle concentrations within contour defined volumes were calculated from T1 maps using the measured change in T1 values and a previously determined relaxivity constant (8.9 mM⁻¹s⁻¹). Average concentrations were compared across patients and anatomical structures. The use of an MR-Linac for adaptive radiotherapy enabled examination of nanoparticle uptake over time. MRI scans (bSSFP) were captured at each fraction, processed for bias field correction and normalized to spinal canal volumes; a region previously determined to not have significant uptake. Adapted contours defined fraction-specific volumes which were examined for patterns in signal intensity (SI) over time. <h3>Results</h3> Average T1 values for all targeted volumes (CTV, GTV) dropped after nanoparticle infusion. The amount of uptake varied significantly amongst patients but similarly amongst structures, with a notable initial concentration in the liver and kidneys. Fraction-specific MR scans indicated an approximate 20% drop in SI after the first fraction, followed by a more gradual loss of SI, suggesting a persistence of tumor uptake after initial administration. <h3>Conclusion</h3> We have demonstrated the ability to quantify nanoparticle uptake in patients with pancreatic cancer. Results indicate significant uptake of this new radiosensitizer agent in the pancreatic lesions as well as in the liver and kidneys. Follow-up scans and control subjects will inform tumor response due to nanoparticle-enhanced adaptive radiotherapy.

Investigation of Isotoxic Dose Escalation and Plan Quality with TDABC Analysis on a 0.35 T MR-Linac (MRL) System in Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy (MRgRT) for Primary Pancreatic Cancer.

This study investigates plan quality generated by an MR-Linac (MRL) treatment planning system (TPS) for 5-fraction stereotactic body radiation therapy (SBRT) of primary pancreatic cancer (PCa). In addition, an isotoxic dose escalation was investigated with the MRL TPS based on stereotactic MR-guided adaptive radiation therapy (SMART) trial constraints. A clinical workflow was developed for adaptive and non-adaptive treatments with the MRL, on which a time-driven activity-based costing (TDABC) analysis was performed to quantify clinical efficacy. Fifteen PCa patients previously treated with a conventional Linac were retrospectively re-planned for this study. Three plans were generated for each patient using the original prescription dose (PD) and organ at risk (OAR) constraints (Plan 1), following SMART trial’s OAR constraints but with the original PD (Plan 2), starting with Plan 2, following an isotoxic dose escalation strategy where the dose was escalated until any one of the SMART trial’s OAR constraints reached its limit (Plan 3). Conformity index (CI) and the ratio of the 50% isodose volume to PTV (R50%) conformity metrics were calculated for all 45 MRL plans, in addition to standard dose-volume indices. Forty-five MRL plans were created which met their respective dosimetric criteria described above. For Plan 1, the MRL TPS successfully achieved equivalent or lower OAR doses while maintaining the prescribed PTV coverage for the 15 plans. A maximum dose to the small bowel was reduced on average by 4.97 Gy (range: 1.11–10.58 Gy). For Plan 2, the MRL TPS successfully met all SMART trial OAR constraints while maintaining equivalent PTV coverage. For Plan 3, the MRL TPS was able to escalate the prescription dose from the original 25–33 Gy by, on average, 36 Gy (range: 15–70 Gy), and dose to the PTV was successfully escalated to at least 50 Gy for all 15 plans. These achievements were made possible, in part, due to the omission of the ITV afforded by the MRL’s real-time target tracking technology and sharper dose penumbra due to its unique dual-focus MLC design. The 0.35T MRL TPS can generate plans that are equivalent to conventional Linac-based plans for SBRT of PCa. Through analyzing Plan 2 and 3 strategies, and due to the real-time target localization capabilities of the MRL system, increased OAR sparing and/or target dose escalation are possible.

Establishing the Aortic Maximum Tolerated Dose (MTD) for Ablative 5-Fraction Stereotactic MR-Guided Adaptive Radiation Therapy (SMART)

Stereotactic MR-guided adaptive radiotherapy (SMART) can facilitate the safe delivery of ablative dose (BED > 100 Gy10) for inoperable pancreas cancer while sparing gastrointestinal (GI) OARs. Initially restricted to small volume pancreatic targets, SMART has now been expanded to provide ablative elective nodal irradiation (ENI). With this evolution, the proximity of the aorta to the ENI region becomes a concern. Given that the aortic maximum tolerated dose (MTD) for an ultra-hypofractioned course is poorly understood, our working hypothesis is that the MTD for aortic toxicities within the first year after a 5 fraction SMART course is > 52.5 Gy (Dmax). We tested this on our in-house clinical datasets.Twenty-nine inoperable pancreatic cancer patients were treated with 50 Gy in 5 fractions daily (QD) SMART course from April 2019 to March 2020. All patients underwent adaptive radiotherapy in which the dose was minimized to GI OARs, but no intentional aortic sparing was undertaken. For this study, the cumulative dose from all 5 SMART fractions was summed onto a TRUFI MR fractional scan (i.e., fraction 1). To this end, a rigid transformation was performed from each fractional scan (fraction 2-5) to fraction 1 frame of reference (FOR) based on alignment of aorta adjacent to the PTV. Fractional dose was transformed to fraction 1 FOR followed by summation. A contouring ring (2 cm in SI, 3 cm in AP/LR from PTV) was delineated. The aorta was segmented within the contouring ring. The aortic wall (AW) was delineated based on reported variable thickness of 1-2.5 mm in the literature on TRUFI MR sequence, and denoted as AW#mm.The median follow-up of patients was 17.4 months from SMART. 90% of patients (27 of 29) received ENI, typically including a 5-10 mm margin around celiac axis and superior mesenteric artery. Using the following maximum aortic dose parameter (Dmax/D0.03cc/D0.05cc/D1cc), the respective mean ± SD values in Gy were 56.7 ± 6.1/55.1 ± 6.6/49.3 ± 7.5/44.2 ± 8.3 (AW1mm), 56.7 ± 6.1/55.2 ± 6.6/51.1 ± 7.6/48.0 ± 8.0 (AW1.63mm), 56.9 ± 6.0/55.5 ± 6.4/51.8 ± 7.3/49.2 ± 7.6 (AW2mm), 56.8 ± 6.2/55.4 ± 6.6/51.8 ± 7.5/49.6 ± 7.8 (AW2.5mm). For D5cc/D10cc the respective mean ± SD dose in Gy was 13.5 ± 8.1/3.1 ± NA (AW1mm), 28.0 ± 8.0/8.1 ± 7.0 (AW1.63mm), 33.0 ± 8.6/14.4 ± 10.2 (AW2mm), 35.9 ± 9.3/21.3 ± 9.6 (AW2.5mm). No grade 3 or higher toxicities were observed during this follow-up period. 83% of patients (24 of 29) had Dmax > 52.5 Gy; 48% of patients (14 of 29) had D1cc > 47.5 Gy; 48% of patients (14 of 29) had D0.5cc > 50.4 Gy for all AW thicknesses. 72% (21 of 29), 59% (17 of 30) and 28% (8 of 29) of patients had aorta Dmax greater than 53.5 Gy, 55 Gy, and 60 Gy, respectively.An aorta Dmax of 53.5 Gy in 5 fractions was found to be safe for pancreatic cancer patients receiving daily SMART (n = 21 patients)-an increase from the RTOG 0813 MTD limit (i.e., 52.5 Gy). For ablative stereotactic pancreatic patients with inclusion of ENI, aorta dose should be tracked for further understanding of the aortic MTD.K.E. Mittauer: Research Grant; ViewRay Inc. Honoraria; ViewRay Inc. Travel Expenses; ViewRay Inc. Partnership; MR Guidance LLC.R. Herera: None. T. Romaguera: None. D. Alvarez: None. M.P. Mehta: None. A. Gutierrez: None. M.D. Chuong: Research Grant; ViewRay, AstraZeneca. Honoraria; ViewRay, Sirtex, Accuray. Speaker's Bureau; ViewRay, Sirtex, Accuray. Advisory Board; ViewRay, Advanced Accelerator Applications. Travel Expenses; ViewRay, AstraZeneca, Accuray; Particle Therapy Cooperative Group. Manages the operations and activities within the proton center; Miami Cancer.

Magnetic Resonance Guided Stereotactic Ablative Radiation Therapy vs. Chemoradiation for Borderline and Locally Advanced Pancreatic Cancer: Single Institution Overall Survival Comparison

Several academic institutions have investigated stereotactic MR guided adaptive radiation therapy (SMART) to safely dose escalate for locally advanced and borderline resectable pancreatic cancer with initial favorable toxicity and survival outcomes. In 2018 our institution began to evaluate SMART on trial in borderline and locally advanced patients. We previously presented toxicity outcomes for standard fractionated chemoradiation (chemoRT) and SMART groups with acute grade 3+ GI toxicity in 28% vs 11% (P = 0.18) and late toxicity 43% vs 36% (P = 0.77). The purpose of this abstract was to compare overall survival (OS) between chemoRT and SMART.In this IRB approved analysis, we retrospectively reviewed 115 consecutive patients from 2017-2020 with locally advanced or borderline resectable pancreatic cancer who were treated with neoadjuvant radiation therapy. Initially all patients received chemoRT to a dose of 50.4 Gy in 28 fractions. In September 2018 we began to investigate SMART (50Gy in 5 fractions) for these patients. OS was evaluated by Kaplan-Meier and log-rank test. Univariate and multivariate analysis was also performed on multiple treatment variables.Of the patients included, 30 received chemoRT and 85 received SMART. Median follow up for the chemoRT group was 32.8 months and for SMART was 14.9 months from last day of RT. Groups did not have significant differences in age, gender, tumor location, or initial CA 19-9. Pancreatectomy was performed in 13.3% vs 18.8% of patients in chemoRT and SMART groups. Per NCCN.1.2021 staging in the chemoRT group 33.3% were borderline (BL), 50% were locally advanced (LA), and 16.7% medically unresectable (MU) as compared to 24.7% BL, 49.4% LA, and 25.9% MU in the SMART group. Mean months of neoadjuvant chemo was slightly higher in the SMART group at 3.6 vs 2.3 months. Patients in the chemoRT arm were 36.7% African American vs 15.3% in the SMART group. When evaluated using Kaplan-Meier and log-rank test there was no difference in OS between groups (P = 0.95). Median OS from last day of RT in chemoRT and SMART groups was 10.7 vs 12.1 months. On univariate and multivariate analyses pancreatectomy was associated with improved OS, and both N2 disease at diagnosis and poor performance status (ECOG 2+) were associated with worse OS.Dose escalated SMART for locally advanced, borderline, and medically inoperable pancreatic cancer shows similar OS to standard fractionated chemoRT at a median 14.9 month follow up in our single institution analysis. With similar toxicity and OS between treatment modalities, SMART may be preferred due to the single week treatment course in a disease with overall very poor prognosis.

Long-Term Multi-Institutional Outcomes of 5-Fraction Ablative Stereotactic MR-Guided Adaptive Radiation Therapy (SMART) for Inoperable Pancreas Cancer With Median Prescribed Biologically Effective Dose of 100 Gy10

Randomized trials have shown improved local control (LC) but no overall survival (OS) benefit with the addition of non-ablative radiation therapy (RT) dose compared to chemotherapy (CT) alone for pancreas cancer (PCa). Emerging data suggest that dose-escalated RT may improve LC and OS. A few studies suggest that stereotactic magnetic resonance-guided adaptive RT (SMART) can facilitate the safe delivery of ablative dose for inoperable PCa, although long-term outcomes are not well understood.Inoperable PCa patients who received SMART were identified from the RSSearch Registry. Patients with < 3 months (mo.) follow-up after SMART were excluded. LC, progression free survival (PFS), and OS were estimated using the Kaplan-Meier method. LC was evaluated according to RECIST 1.1 criteria. Acute toxicity was considered within 90 days of SMART and evaluated by CTCAE v4 criteria.A total of 148 PCa patients were treated on a 0.35T MR LINAC across 3 institutions between 2018-2020. Median age was 68 years (range 47-91), and 73.6% had ECOG 0-1 performance status. Patients had locally advanced (57.4%), borderline resectable (29.1%), or medically inoperable (13.5%) disease. Median CA19-9 at diagnosis was 202.1 U/mL (range 0.9-21,281). Induction CT was delivered to 89.2% for a median 3.9 mo (range 0.2-11.3); FOLFIRINOX (52.7%) or gemcitabine/nab-paclitaxel (23.4%) were common. Median prescribed RT dose was 50 Gy (range 40-50) in 5 fractions, mostly in consecutive days (96.6%) and in breath hold (95.3%). Median biologically effective dose (BED10) was 100 Gy10. All patients were treated with real-time tissue tracking and automated beam gating without fiducial markers. An elective target volume was rarely used (25%). Pancreaticoduodenectomy was performed in 23% at a median 46 days (range 34-304) after SMART. Median follow-up was 16 mo. from diagnosis for all patients (range, 4-39). Median, 1-year, and 2-year LC was not reached (NR), 94.6%, and 83%, respectively. Median, 1-year, and 2-year PFS was 18 mo., 72%, and 35.9%, respectively. Median, 1-year, and 2-year OS was 26 mo., 82%, and 52.7%, respectively. Acute and late grade 3 toxicity possibly related to SMART occurred in 4.1% and 12.8%, respectively. There was no reported grade 4+ toxicity.To our knowledge, this is the largest reported analysis of 5-fraction SMART for inoperable PCa. These data add to the evidence that ablative radiation dose may improve long-term outcomes including OS. Prospective evaluation of this novel approach is warranted with attention directed at optimizing patient selection, understanding the clinical significance of cumulative dose delivered across all adapted fractions, and assessing treatment response after the delivery of ablative dose.

Cumulative Target Volume Dose and Locoregional Failure in Pancreatic Cancer Patients With Treated With Ablative Stereotactic MR-Guided Adaptive Radiation Therapy (SMART)

<h3>Purpose/Objective(s)</h3> Emerging data suggest that ablative stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) for inoperable pancreas cancer (PCa) achieves favorable local control (LC) and overall survival (OS) compared to non-ablative dose. In the current SMART workflow, each adaptive fraction is reoptimized without accounting for previously delivered dose. Cumulative target volume (TV) dose from all SMART fractions has not previously been evaluated with respect to clinical outcomes. <h3>Materials/Methods</h3> We evaluated 44 inoperable PCa patients who were prescribed 50 Gy in 5 daily fractions on a 0.35T-MR LINAC. 33 patients (75%) were treated with elective nodal irradiation, typically including the celiac axis and superior mesenteric artery. PTV margin was 3 mm. On-table adaptive replanning was performed to primarily satisfy gastrointestinal (GI) organ at risk (OAR) constraints, and secondarily maximize TV coverage. Cumulative dose for all fractions was summed onto a TRUFI MR fractional scan (i.e., fraction 5). A rigid transformation was performed for fractions 1 to 4 scans onto the fraction 5 frame of reference (FOR) based on alignment of gross disease. Each fractional dose was transformed onto fraction 5 FOR and summed cumulatively for all 5 fractions. Locoregional failure (LRF) was delineated on follow-up imaging by a diagnostic radiologist with PCa expertise. Cumulative TV dose metrics (D80, D90, mean, max) were evaluated with respect to LRF. Diagnostic scans were rigidly registered to the fraction 5 FOR based on recurrence region to investigate recurrence characteristics and target dose metrics. A Spearman correlation was used to investigate LRF and (1) ENI vs. no ENI, (2) TV coverage metrics, (3) planning TV (PTV) volume. <h3>Results</h3> The median PTV volume for all patients, with ENI, and without ENI was 125.9 cc (range: 20.6-356.8), 137.3 cc (range: 72.8-356.8, and 55.4 (range: 20.6-280.15), respectively. LRF occurred in 12 patients (27.3%); the median LRF volume was 10.9 cc (range: 1.1-145.5cc). The median Dice similarity coefficient taken to characterize LRF overlap with PTV was 0.05 (range: 0-0.45). Moderate negative correlation coefficients were noted between recurrence to ENI [-0.59 (<i>P</i> < 0.001)], recurrence to PTV volume [-0.41 (<i>P</i> < 0.001)] and recurrence to max PTV dose [–0.47 (<i>P</i> < 0.001)]. No correlation was observed for cumulative D80, D90, mean dose to recurrence. <h3>Conclusion</h3> To our knowledge, this is the first analysis of cumulative TV dose from 5-fraction SMART for PCa. While use of ENI is controversial, moderate and statistically significant correlations were noted between LRF and ENI, in addition to PTV volume and maximum dose. Additional investigation is warranted to better understand whether specific dose thresholds exist for gross disease and electively treated volumes with respect to long-term LC and OS.

Indications for Plan Adaptation in Patients with Adrenal Metastases Treated With Stereotactic MR-Guided Adaptive Radiation Therapy (SMART)

Stereotactic body radiation therapy (SBRT) is increasingly utilized in patients with oligometastatic and oligoprogressive disease; however, concerns about interfractional changes in gastrointestinal (GI) anatomy limit broad adoption and dose-escalation in the context of adrenal metastases. The objective of this study is to evaluate the need and indications for daily adaptive replanning in this patient population.Consecutive patients with adrenal metastases treated using respiratory-gated stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) at a single institution were evaluated. Breath-hold 3D-MRI was acquired prior to each fraction to visualize the anatomy-of-the-day. To quantify the indication for adaptation, dose prediction (i.e., calculation of initial plan on the anatomy of the day) was performed. If adaptation was indicated (i.e., critical organ at risk [OAR] dose constraints were exceeded and/or desired target coverage was not achieved), the plan was reoptimized using the original beam parameters with adjustment of individual beam fluence. Comparisons between the predictive and adaptive dose were performed to evaluate adaptive replanning decision-making based on pre-defined institutional criteria. Dose differences between the predictive and adaptive doses were compared by paired sample t test.16 patients with adrenal metastases underwent a total of 80 SMART fractions to a median dose of 50 Gy in 5 fractions. The median PTV was 58.9 cc (Range: 16.1 - 377.4 cc). Plan adaptation was performed in 15/16 patients at least once during the treatment course due to predefined GI OAR dose constraints being exceeded, after accounting for the anatomy of the day. The indications for adaptation were to improve target coverage in 19/80 fractions (24%), or reduce dose to at least one critical GI OAR in 33 fractions (41%), and for both conditions in 9 fractions (11%). The most commonly affected GI OAR for plan adaptation was the stomach for left-sided metastases (6/7 patients, 86 %) and duodenum for right-sided metastases (3/9 patients, 33 %). Plan adaptation allowed for dose-escalation to the GTV with statistically significant increase in the minimum dose (42 Gy vs. 34 Gy, P < 0.001). No patients experienced acute or late grade ≥3 CTCAE v4.0 treatment-related toxicities.SMART enabled dose-escalation with simultaneous OAR sparing in response to changes in the anatomy-of-the-day for patients with adrenal metastases. SMART using an ablative prescription dose should be explored in future prospective studies for targets in proximity to historically dose-limiting GI OARs.