Pancreatic Stereotactic Body Radiation Therapy Research Articles

Abstract B078: A comprehensive spatial atlas of neoadjuvant chemoradiation therapy in resected pancreatic cancer identifies cellular & microenvironmental determinants of persister populations

Abstract Background The molecular pathways involved in the response to radiation therapy (RT) in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. Despite extensive molecular stratification efforts, improvements in molecularly informed RT-based therapeutic strategies in the neoadjuvant setting have been limited. This study aims to elucidate the adaptive mechanisms and interactions within PDAC to identify new combinatorial therapeutic targets with RT. MethodsWe constructed a high-resolution molecular landscape of the cellular subtypes and spatial communities that constitute PDAC. Single-cell RNA sequencing (scRNA- seq) was performed on 16 PDAC biopsies of matched pre- and post-treatment samples from a Phase I/II dose-escalation clinical trial of pancreatic stereotactic body radiation therapy (SBRT). Additionally, Visium spatial transcriptomics (ST) was conducted on biopsies from primary PDAC patients collected at the time of surgery. These patients received either no neoadjuvant therapy (n = 8) or neoadjuvant chemoradiation (chemoRT) (n = 20). Cell type profiles were determined from scRNA-seq to compare changes in cell type proportions and signatures before and after RT. From these profiles, we employed robust cell type decomposition to analyze cell type signatures in our ST dataset. ResultsChemoRT induced several significant effects compared to controls within the tumor microenvironment, including an increase in the proportion of myofibroblasts, specifically senescent cancer-associated fibroblasts (CAFs), with signatures consistent with immune cell dysfunction. We observed an increase in CD8 and CD4 effector memory cells with RT; however, this occurred alongside a rise in immunosuppressive alternatively activated tumor-associated macrophages. Additionally, RT upregulated pathways related to HIF, cytokine production, B cell proliferation, and negative regulation of lymphocytes. Patients with increased infiltration of NK, memory B, and CD8 effector memory cells demonstrated improved overall survival outcomes. Inference of copy number variations enabled us to identify cancer subclones as either responsive or resistant in matched pre and post RT biopsies. Resistance was characterized by augmented hypoxia, KRAS activation, epithelial- mesenchymal transition, and interferon-gamma response signaling. Conversely, responders exhibited increased oxidative phosphorylation signaling and pathway enrichment associated with cell proliferation and cell cycle progression. Interestingly, RT induced a decrease in cancer cells characterized as harboring a chemoresistant basal-like molecular subtype. ConclusionThrough both longitudinal and therapy stratified tumor biopsies, we were able to observe significant selection pressures on stromal and cancer cells following RT. This includes upregulation of innate and adaptive immune pathways with a compensatory immunosuppressive response driven by myeloid cells and CAFs. This may provide opportunities for development of clinical trials to therapeutically target specific cellular phenotypes and their interactions. Citation Format: Vincent Bernard, Galia Jacobson, Kimal Rajapakshe, Jimin Min, Guangsheng Pei, Daniel Lin, Ayush Suresh, Dadi Jiang, Ching-Wei Tzeng, Manoop S Bhutani, Linghua Wang, Paola A Guerrero, Ethan B Ludmir, Albert C Koong, Anirban Maitra, Cullen M Taniguchi, Eugene J Koay. A comprehensive spatial atlas of neoadjuvant chemoradiation therapy in resected pancreatic cancer identifies cellular & microenvironmental determinants of persister populations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B078.

Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol

Background and purposeTreatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methodsA consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. ResultsIn the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 – 53.7 Gy for case 1, 22.6 – 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9–53.6 Gy for case 1, 33.9–36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2–50.9 Gy for case 1, 33.5–36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. ConclusionA global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Clinical experience with adaptive MRI-guided pancreatic SBRT and the use of abdominal compression to reduce treatment volume.

This work presents a method to treat stereotactic body radiation therapy (SBRT) for pancreatic cancer on a magnetic resonance-guided linear accelerator (MR-linac) using daily adaptation, real-time motion monitoring, and abdominal compression. The motion management and treatment planning process involves a magnetic resonance imaging (MRI) simulation with cine and 3D images, a computed tomography (CT) simulation with a breath-hold CT and a 4DCT, pre-treatment verification and planning MRI, and intrafraction MRI cine images. The results from 26 patients were included in this work. Our motion management process results in consistent motion analysis on the CT simulation, MRI simulation, and each treatment fraction. The liver dome was found to be an overestimate of tumor superior/inferior (SI) motion for most patients. Adding compression reduced SI liver dome motion by 6.2 mm on average. Clinical outcomes are similar to those observed in the literature. In this work, we demonstrate how pancreatic SBRT can be successfully treated on an MR-linac using abdominal compression. This allows for an increased duty cycle compared to gating and/or breath-hold techniques.

Assessment of Daily Target Motion to Optimize ITV Margins in Online Adaptive Plan for Liver and Pancreatic SBRT on MR-LINAC

Accurate measurement of daily target motion on online plan adaptation is essential for re-optimizing the internal target volume (ITV) margins. In this study, by analyzing 2D cine MR images acquired in a 1.5T MR-Linac, we assessed daily target motion and its inter-fractional variations, which is then used to customize ITV margins for MR-based online adaptive plan of liver and pancreatic stereotactic body radiotherapy (SBRT). Twenty-threepatients, enrolled in this study, underwent MR-guided online adaptive SBRT on 1.5 T MR-Linac: liver (n = 12 without compression belt (CB), n = 2 with CB) and pancreas (n = 9 with CB). Target motion in a 2D coronal and sagittal MR images (> 200 cine images to cover multiple breathing cycles), as well as a set of 4D-CT images during the simulation, was analyzed to determine patient specific ITV margins for a reference plan. On every fraction of online adaptive SBRT, the 2D MR images were exported to commercially available software along with a planning MR images: a T1-wighted MR image set for pancreas and or a navigated T2-wighted MR image set for liver. Daily target motion was then measured by overlaying the orthogonal cine image set on the T1- or T2-wighted image set. The ITV margin was adjusted when required prior to online plan optimization RESULTS: Thisstudy successfully assessed the daily target motion and inter-fractional variations in 23 liver or pancreatic cancer patients. We found a discrepancy of daily target motion of orthogonal 2D cine MR images from that of 4D-CT, required to adjust the ITV margin for online plan adaptation. In liver SBRT without CB, 15 out of 45 fractions from 12 patients (33.3 %) went through adjusted ITV margin. The tumor motion was large up to a 2.2 cm along the inferior direction in a patient without CB and thus the patient was treated on a conventional Linac with the active breathing control (ABC) unit for breath-hold. On the other hand, no adjustments were necessary for 2 liver patients with CB. In 9 patients with pancreatic cancers, we found the inter-fractional ITV variations in 3 out of 45 fractions (6.7 %) adjusted the ITV margin. The daily target motion in the pancreatic patients with CB was more stable and relatively smaller than that of the liver patients. Theorthogonal 2D cine MR images are evidently essential for assessing daily target motion to evaluate the inter-fractional variation and achieve daily ITV-customized liver and pancreatic SBRT in the 1.5 T MR-Linac. The customized ITV approach will improve the treatment outcome of the MR-guided online adaptive therapy.

Inter-Breath-Hold Geometric and Dosimetric Variations in Organs at Risk during Pancreatic Stereotactic Body Radiotherapy: Implications for Adaptive Radiation Therapy.

Pancreatic cancer is the fourth leading cause of cancer-related death, with nearly 60,000 cases each year and less than a 10% 5-year overall survival rate. Radiation therapy (RT) is highly beneficial as a local-regional anticancer treatment. As anatomical variation is of great concern, motion management techniques, such as DIBH, are commonly used to minimize OARs toxicities; however, the variability between DIBHs has not been well studied. Here, we present an unprecedented systematic analysis of patients' anatomical reproducibility over multiple DIBH motion-management technique uses for pancreatic cancer RT. We used data from 20 patients; four DIBH scans were available for each patient to design 80 SBRT plans. Our results demonstrated that (i) there is considerable variation in OAR geometry and dose between same-subject DIBH scans; (ii) the RT plan designed for one scan may not be directly applicable to another scan; (iii) the RT treatment designed using a DIBH simulation CT results in different dosimetry in the DIBH treatment delivery; and (iv) this confirms the importance of adaptive radiation therapy (ART), such as MR-Linacs, for pancreatic RT delivery. The ART treatment delivery technique can account for anatomical variation between referenced and scheduled plans, and thus avoid toxicities of OARs because of anatomical variations between DIBH patient setups.

Impact of Dosimetric Parameters on Local Control after SBRT for Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) for pancreatic cancer is an emerging modality to provide local control (LC) in patients deemed to have borderline resectable or locally advanced disease. Given the possibility for significant heterogeneity in dose distributions between SBRT plans, our objective was to determine if there were dosimetric variables associated with improved LC for pancreatic cancer patients. We hypothesized that higher gross tumor volume (GTV), internal target volume (ITV), and planning tumor volume (PTV) doses covering 90% of the volume (D90) as well as minimum (Dmin) and maximum (Dmax) doses would be associated with improved local control. <h3>Materials/Methods</h3> This was a retrospective cohort study including patients who received SBRT for pancreatic adenocarcinoma at a single institution, initially diagnosed as borderline resectable or locally advanced unresectable disease between 2015-2021. Baseline and treatment characteristics were collected including age, gender, performance status, tumor location, staging, CA 19-9 at diagnosis, and use of chemotherapy and/or surgery. Dosimetric parameters included target volume sizes as well as Dmin, Dmax, and D90 for the GTV, ITV, and PTV. These were then converted to BED using the linear/quadratic model based on an alpha/beta of 10Gy. The primary endpoint was LC. The secondary endpoint was overall survival (OS). The Cox proportional hazards model was used for univariate regression analyses (UVA) and the Kaplan-Meier method was utilized to estimate local control. <h3>Results</h3> A total of 55 patients were included in the study. Median follow-up was 9.5 months. All but two patients received 3300cGy in 5 fractions. 49 patients received chemotherapy non-concurrently. 8 patients underwent surgery following RT. On UVA, the Dmin was found to be significantly associated with LC for GTV (p=0.028), ITV (p=0.028), and PTV (p=0.037). D90 for ITV (p=0.010) and PTV (p=0.025) were also associated with LC. Dmax was not significantly associated for any target volume. Other variables significantly associated with LC were performance status (p=0.039), chemotherapy (p=0.008), GTV (p=0.019), and ITV (p=0.028). Patients receiving > 53Gy compared to those receiving ≤ 53Gy had a median time to local recurrence of 15.1 months vs 6.6 months, respectively (p=0.031). No variables on UVA were associated with OS. <h3>Conclusion</h3> This comprehensive dosimetric analysis demonstrates that local control after SBRT for pancreatic cancer is significantly associated with dosimetric factors despite our cohort's relative uniformity in prescription dose. Specifically, an ITV D90 with a BED_α/β10Gy> 53Gy was associated with better LC. This likely reflects the large impact that critical organs-at-risk may have on pancreatic SBRT plans and highlights the need for dosimetric parameter specifications in future studies. Further investigation is warranted for lesions amenable to dose escalation with SBRT to improve LC.

Effect of stomach size on organs at risk in pancreatic stereotactic body radiotherapy

BackgroundIn clinical practice, the organs at risk (OARs) should be carefully determined when performing pancreatic stereotactic body radiotherapy (SBRT). We conducted a simulation study to examine the effect of the stomach size on the radiation dose to the OARs when performing pancreatic SBRT.MethodsTwenty-five cases were included in this study. Pancreatic head and body tumors were 2-cm-sized pseudotumors, which were included as gross target volume (GTV) contours. The stomach, pancreas, small intestine, liver, kidneys, and spinal cord were considered as the OARs. The prescription dose for planning target volume (PTV) was 40 Gy/5fx, and the dose limit for the OARs was determined. The dose to X% of the OAR volume at X values of 0.1, 5.0, and 10.0 cc (DX) and the percentage of the OAR volume that received more than X Gy were recorded.ResultsIn terms of the radiation dose to the pancreatic body tumors, the stomach size was positively correlated with a dose of D10cc [correlation coefficient (r) = 0.5516) to the stomach. The r value between the radiation dose to the pancreatic head tumor and the stomach size was 0.3499. The stomach size and radiation dose to the head and body of the pancreas were positively correlated (pancreatic head D10cc: r = 0.3979, pancreatic body D10cc: r = 0.3209). The larger the stomach, the larger the radiation dose to the healthy portion of the pancreas outside the PTV.ConclusionsWhen performing pancreatic SBRT, the dose to the OARs depends on the stomach size. Reducing the dose to the stomach and pancreas can be achieved by shrinking the stomach.

Machine learning for tracking planned versus delivered dose in pancreas SBRT.

561 Background: Cone-beam CT (CBCT) used for daily image guidance in pancreatic stereotactic body radiotherapy (SBRT) is fraught with imaging artifacts leading to poor visualization of target and avoidance structures. Machine learning methods can be used to generate synthetic CT (sCT) images from CBCT to eliminate imaging artifacts. We sought to compare planned versus delivered radiation dose to luminal GI organs at risk (OARs) during pancreas SBRT using sCT. Methods: Previously treated patients from a single institution were eligible if treated with 5 fractions of pancreas SBRT using daily CBCT and inspiration breath hold. CBCT-based sCT was generated for each treatment fraction using our previously reported cycleGAN technique. Physicians manually contoured GI OARs (stomach, duodenum, and bowel [remaining small bowel and large bowel]) on sCTs. Rigid online registration from treatment was used to re-calculate the delivered dose on each sCT. Fractional delivered dose to OARs was compared to planned dose and dose constraints with descriptive statistics. Max dose to 1cc or 20cc of an OAR was defined as D1cc and D20cc respectively. Results: 7 patients and 35 cumulative SBRT CBCT datasets were included. The median SBRT cumulative dose was 8 Gy x 5 fractions (40 Gy total). Each GI OAR was constrained per fraction to D1cc &lt; 7 Gy (cumulative D1cc &lt; 35 Gy) and D20cc &lt; 4 Gy (cumulative D20cc &lt; 20 Gy) during SBRT planning. Table shows the estimated OAR delivered doses on each sCT compared to planned doses and dose constraints. Each patient had at least 1 fraction that exceeded a planned GI OAR dose; 2 patients had delivered dose to 1cc of duodenum exceeding constraint for all 5 fractions. After a median follow-up of 9 months (range 5-34), there were 2 CTCAE Grade 1 and no Grade 2+ GI toxicity events possibly or likely related to SBRT. Conclusions: Physician contouring and dose calculation using CBCT-based sCT was feasible. Estimated delivered doses of pancreas SBRT generally exceed planned doses. Further study of sCT in pancreas SBRT is warranted for improved localization, dose calculation, and adaptive radiotherapy.[Table: see text]

Pathologic Response and Locoregional Control After Preoperative Pancreatic Stereotactic Body Radiation Therapy

In light of ALLIANCE02150, the role of preoperative stereotactic body radiotherapy (SBRT) for pancreatic cancer is controversial. We studied patients who had surgery after preoperative SBRT to assess pathologic and clinical outcomes, and evaluate if elective nodal irradiation (ENI) decreases locoregional failure (LRF).Patients with pancreatic cancer who received SBRT at one center from 2007 to 2020 followed by oncologic surgery were reviewed. Local (primary tumor), regional (peripancreatic or perivascular per RTOG consensus), and distant failures were coded. Pathologic treatment response per College of American Pathologists was reviewed. Incidence of LRF with death as competing risk was assessed. Time to overall (OS) and progression-free survival (PFS) from date of pathologic diagnosis was assessed via Kaplan-Meier. Association testing via Cox analysis for OS/PFS and Gray test for LRF was performed.Twenty-eight patients were evaluable. Median (range) ECOG was 1 (0-2). Tumor stage was cT4 in 19 (67.9%) patients. Nodal stage was cN1 in 10 (35.7 %) patients. There were 7 and 21 patients with initially unresectable and borderline resectable disease respectively. Chemotherapy (CT) was given prior to SBRT in 27 (96.4%) patients, with FOLFIRINOX and gemcitabine-paclitaxel in 21 and 4 patients, respectively. Median (range) duration of CT was 5 (0-12) cycles. Median (range) dose, BED10, and fractionation were 40 Gy (25 - 50 Gy), 72 Gy (54.78 - 100 Gy), and 5 (1-5) respectively. The median (range) time between SBRT and surgery was 6.7 (2.6 - 21.9) weeks. Whipple, Appleby, and distal pancreatectomy was performed in 22, 4, and 2 patients respectively. The R0 rate was 23/28 (82.1%). Pathologic complete, near complete, partial, and poor/no treatment response was seen in 1 (3.6%), 10 (35.7%), 15 (53.6%), and 2 (7.1%) patients, respectively. The pN1 rate was 12/28 (42.3%). Median (range) follow up was 21.5 months (6.9 - 67.2 months). The 18-month (95% CI) overall survival (OS) and LRF were 66.6% (50.0 - 88.6%), and 7.8% (0.0 - 48.4%) respectively. Complete or near complete pathologic response was associated with improved OS (HR = 0.21, P = 0.022) and PFS (HR = 0.25, P = 0.021), but not LRC (P = 0.780). Longer (≥8 weeks) time between end of SBRT and surgery was associated with improved complete or near complete response rate (P = 0.024) but not OS, PFS, or LRF. BED10 did not predict for pathologic treatment response or margin status. Sixteen patients received ENI. There were no other statistically significant differences in the above baseline characteristics, OS, PFS, or pathology outcomes, with vs without ENI. The 18-month (95% CI) LRF with vs without ENI was 0.0% (0.0 - 0.0%) vs 12.8% (0.0 - 38.8%), P = 0.29.Our cohort of patients with pancreatic cancer treated with preoperative SBRT and surgery showed good pathologic response and R0 rate. ENI was associated with numerically lower LRF. Increased BED10 was not associated with improved pathologic treatment response.

Impact of Tumor Dosimetry on Clinical Outcomes after Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma

We hypothesized that escalated biological effective dose (BED) via stereotactic body radiation therapy (SBRT) would improve outcomes for patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC).A retrospective review was performed on consecutive patients who received pancreas SBRT from June 2009 to June 2020, were non-metastatic at the time of SBRT, received neoadjuvant chemotherapy, and had available gross tumor volume (GTV) dosimetry. Variables of interest included: age, gender, tumor location (body/tail vs head/neck), chemotherapy type (5-fluorouracil-based vs gemcitabine-based), AJCC V8 stage, pre- and post-radiotherapy (RT) CA19-9, GTV D95, and GTV V55-40 Gy. GTV volume variables were analyzed as continuous (cont) and as binary (+) functions. All patients with BRPC at diagnosis were analyzed by a logistic regression model for variables that predicted a higher likelihood of undergoing surgical resection (Model A). A second model of all patients (BRPC and LAPC) unable to undergo surgery was constructed by Cox regression analysis investigating variables that predicted for improved overall survival (OS), progression free survival (PFS), time to loco-regional failure (TTLRF), and time to distant failure (TTDF; Model B). All clinical time points were calculated from the end of SBRT and data analysis was performed in SAS with backward elimination variable selection.A total of 365 patients had a median follow up from SBRT of 12.1 months and 251 patients (69%) were diagnosed with BRPC. Model A composed of 200 BRPC patients (56% resected) with 3 clinical variables: chemotherapy (P = .39), AJCC stage (OR 0.54, P = 0.01), post-RT CA19-9 (OR 0.27, P = < 0.001); and 3 dosimetric variables: GTV D95 (OR 3.81, P = 0.03), GTV V40+ (OR 2.52, P = 0.07), and GTV V40cont (OR 0.98, P = 0.03). Model B included 168 patients (51% BRPC) unable to undergo surgery. In this group, 5-fluorouracil-based chemotherapy was associated with improved OS (HR 0.51, P = < 0.001), PFS (HR 0.48, P = < 0.001), TTLRF (HR 0.47, P = 0.004), and TTDF (HR 0.54, P = 0.006). GTV V40+ was significantly associated with improved PFS (HR 0.59, P = 0.005) and TTLRF (HR 0.58, P = 0.036), but not with OS (HR 1.06, P = 0.78) or TTDF (HR 0.68, P = 0.113). Pre-RT CA19-9 was associated with worse OS (HR 1.43, P = 0.010) and TTLRF (HR 1.59, P = 0.022). The proportion of patients receiving 5-flurouracil-based chemo and achieving GTV V40+ was evenly distributed across the cohort (χ2 = 0.55, P = 0.45).In the largest series of pancreatic cancer SBRT to date, dose-escalated tumor coverage specifically to 40 Gy (BED10 = 72 Gy) increases the likelihood of surgical resection in patients with upfront BRPC and is associated with improved PFS that is driven by improvement in loco-regional disease control for unresected patients. These data may help to inform the evolving landscape on the use of neoadjuvant and definitive radiotherapy in pancreatic cancer.

Impact of Stereotactic MR-Guided Adaptive Radiation Therapy on Early Clinical and Dosimetric Outcomes in Patients With Pancreatic Cancer

Dose escalated stereotactic body radiotherapy (SBRT) may improve both local control and overall survival for patients with pancreatic cancer. However, escalated dose cannot be routinely offered because of the risk of injury to adjacent normal organs. Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) represents an innovation that may achieve safer delivery of ablative doses and improve outcomes. The goal of the present study is to identify specific dosimetric gains that can be achieved with MR-guided adaptive pancreatic SBRT and describe acute clinical outcomes.We performed a single institution IRB approved retrospective analysis of 37 consecutive pancreatic cancer patients treated with 40 Gy in 5 fractions with SMART on a MR-linear accelerator using a light inspiration breath hold. The adaptive workflow starts with an "original" plan which is then adapted daily based on anatomical variation for each fraction. "Predicted" plan dosimetry is generated for each fraction by re-calculating the original plan on the re-contoured pre-treatment anatomy, estimating what would have been delivered without adaptive capabilities. A "re-optimized" plan is developed based on the anatomy of the day to improve target coverage and meet critical organ-at-risk (OAR) metrics, including stomach, duodenum, large bowel and small bowel V33 < 1cc. Acute GI toxicity rates were assessed according to CTCAE v5.The median age of our cohort was 71 (range 35-87) with 23/37 (62%) patients having locally advanced disease and 14/37 (38%) having borderline resectable disease. Adaptive planning was used in all cases with a prescription goal of 40 Gy in 5 fractions prescribed to 90% of the target volume. The median CTV was 80.5 cc (range, 10-180cc) and the PTV was a 3mm expansion. Adaptive planning was required in 156/185 fractions to meet either the stomach (63.8%), duodenum (33.5%), large bowel (12.4%) or small bowel (11.4%) V33 < 1cc metric. Of the plans adapted for OAR sparing, 90 plans required adaptation for one gastrointestinal organ, 50 plans for two, 10 plans for three and 1 plan for four. For predicted plans exceeding the V33 < 1cc metric, the median V33 for duodenum was 2.475cc (range: 1.01-10.68cc), stomach was 2.67cc (range: 1.01-8.21cc), small bowel was 2.71cc (range: 1.14-9.54cc) and large bowel was 1.93cc (range: 1.05-8.36cc). All re-optimized plans met the V33 < 1cc metric. No local failure or acute grade 3 toxicities were observed with a median follow-up of 6 months (range 3-15).Online adaptive re-optimization was necessary for the majority of fractions and improved plan dosimetry was achieved specifically for duodenum, stomach, large and small bowel, achieving low rates of acute toxicity. The clinical benefits of MR-guided adaptive pancreatic SBRT for dose escalation warrant further investigation.

Dosimetric Uncertainties Resulting From Interfractional Anatomic Variations for Patients Receiving Pancreas Stereotactic Body Radiation Therapy and Cone Beam Computed Tomography Image Guidance

PurposeTo estimate the effects of interfractional anatomic changes on dose to organs at risk (OARs) and tumors, as measured with cone beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiation therapy. Methods and MaterialsWe evaluated 11 patients with pancreatic cancer whom were treated with stereotactic body radiation therapy (33-40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR data sets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface, duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms into a single dose-volume histogram for comparison with the original planned dose. ResultsFour patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm3 <35 Gy constraint was violated for at least 1 OAR in 3 patients, with either the duodenum (n = 2) or small bowel (n = 1) D1.0 cm3 being higher on the accumulated dose distribution (P = .01). D100% was significantly lower according to accumulated dose GTV (P = .01) and tumor vessel interface (P = .02), with 4 and 2 patients having accumulated D100% ≥4 Gy lower than the planned value for the GTV and tumor vessel interface, respectively. ConclusionsFor some patients, CBCT image guidance based on fiducial alignment may cause large dosimetric uncertainties for OARs and target structures, according to accumulated dose.

Pancreatic Stereotactic Body Radiation Therapy With or Without Hypofractionated Elective Nodal Irradiation

Pancreatic stereotactic body radiation therapy (SBRT) is limited to gross tumor without elective coverage for subclinical disease. Given a better understanding of recurrence patterns, we hypothesized that the addition of elective nodal irradiation (ENI) to pancreatic SBRT would be tolerable and would decrease locoregional progression. We conducted a retrospective 1:2 propensity-matched cohort study to compare toxicity and locoregional progression among patients treated with pancreatic SBRT with or without ENI. In the SBRT+ENI cohort, an elective target volume was delineated per Radiation Therapy Oncology Group guidelines and treated to 25 Gy in 5 fractions alongside 40 Gy in 5 fractions to gross disease. The primary outcome was the cumulative incidence of locoregional progression, with death as a competing risk. Among 135 candidate controls treated with SBRT alone, 100 were propensity-matched to 50 patients treated with SBRT+ENI. All patients completed SBRT. Median potential radiographic follow-up was 28 months. The incidence of late and serious acute toxicity was similar between matched cohorts. However, SBRT+ENI was associated with a statistically significant increase in acute grade 1 to 2 nausea (60% vs 20%, P < .001). The 24-month cumulative incidences of locoregional progression with and without ENI were 22.6% (95% confidence interval [CI], 10.0%-35.1%) versus 44.6% (95% CI, 34.8%-54.4%; multivariable-adjusted hazard ratio, 0.39; 95% CI, 0.18-0.87; P = .021). This was stable in sensitivity analyses of uniform prescription dose, multiagent chemotherapy, and resectability. There were fewer peripancreatic (0% vs 7%), porta hepatis (2% vs 7%), and peri-aortic/aortocaval (5% vs 12%) recurrences after SBRT+ENI, but no difference in survival. Pancreatic SBRT+ENI was tolerable and did not increase late or serious acute toxicity relative to a matched cohort undergoing SBRT alone, but did increase acute grade 1 to 2 nausea. The addition of ENI to SBRT was associated with decreased locoregional progression but not improved survival. Further studies are warranted to determine whether ENI offers meaningful benefit.

Non-Adaptive MR-Guided Radiotherapy for Prostate SBRT: Less Time, Equal Results.

Background: The use of stereotactic body radiation therapy (SBRT) is widely utilized for treatment of localized prostate cancer. Magnetic-resonance-guided radiotherapy (MRgRT) was introduced in 2014 and has recently been implemented in SBRT for prostate cancer as it provides an opportunity for smaller margins and adaptive daily planning. Currently, the only publications of MRgRT for prostate SBRT describe European clinical experiences which utilized adaptive planning. However, adaptive planning adds significantly to the time required for daily treatment. Objectives: Since prostate SBRT has demonstrated acceptable toxicity for several years, we did not consider daily adaptation critical to the process of prostate SBRT. After Institutional Review Board approval, we analyzed and now report our experience using MRgRT without adaptation. Methods: Between 25 September 2019 and 21 December 2020, 35 consecutive patients were treated with MRgRT prostate SBRT at our center. Patients treated with MRgRT included favorable intermediate risk (43%) and unfavorable intermediate risk (54%), and only one patient had low-risk prostate cancer. Nine patients (25%) received adjuvant leuprolide for a median of 4.5 months (range 4–6 m). Our clinical pathway allows for a maximum prostate gland volume of 60 cc; median prostate volume of this cohort was 35.0 cc (range 17–58.4 cc). Median pre-treatment PSA was 6.30 (range 2.55–16.77). Each patient was treated with 36.25 Gy delivered in five fractions over 2 weeks with urethral sparing to a maximal dose of 35 Gy. Target volumes included the prostate gland and proximal seminal vesicles with a 3 mm margin. Results: Median follow-up as of 26 May 2021 was 11.97 months (range 4.37–19.80). First follow-up data are available for all patients, with a median of 1.10 month from completion of treatment (0.63–3.40). The median PSA at first visit was 2.75 (range 0.02–9.00) with a median AUA symptom score of 9 (range 1–24). Second follow-up data are available for 34 patients at a median of 4.45 months (range 2.57–8.90). At second follow-up, the median PSA was 1.60 (range 0.02–5.40) with a median AUA symptom score of 6 (range 1–33). Seventeen patients had third follow-up data with a median of 9.77 months (range 4.70–12.33) after SBRT. The median PSA was 1.13 (range 0.02–4.73) with an AUA score of 9 (2–22) at the third follow-up. We observed a statistically significant decrease in PSA between pre-treatment and at first follow-up (p < 0.005). The most common toxicity was grade 2 urethritis, managed in all cases by tamsulosin. One patient developed grade 2 tenesmus relieved by topical steroids. No cases of grade ≥ 3 toxicity were seen in our patient population. Conclusions: By avoiding the extra time required for plan adaptation, MRgRT without daily adaptation allows for successful prostate SBRT with manageable toxicity. We continue to reserve our limited adaptive treatment slots for preoperative pancreatic and ultra-central lung SBRT patients, which require time-intensive respiratory gating and adaptive planning.

Learning-based dose prediction for pancreatic stereotactic body radiation therapy using dual pyramid adversarial network

Treatment planning for pancreatic cancer stereotactic body radiation therapy (SBRT) is very challenging owing to vast spatial variations and close proximity of many organs-at-risk. Recently, deep learning (DL) based methods have been applied in dose prediction tasks of various treatment sites with the aim of relieving planning challenges. However, its effectiveness on pancreatic cancer SBRT is yet to be fully explored due to limited investigations in the literature. This study aims to further current knowledge in DL-based dose prediction tasks by implementing and demonstrating the feasibility of a new dual pyramid networks (DPNs) integrated DL model for predicting dose distributions of pancreatic SBRT. The proposed framework is composed of four parts: CT-only feature pyramid network (FPN), contour-only FPN, late fusion network and an adversarial network. During each phase of the network, combination of mean absolute error, gradient difference error, histogram matching, and adversarial loss is used for supervision. The performance of proposed model was demonstrated for pancreatic cancer SBRT plans with doses prescribed between 33 and 50 Gy across as many as three planning target volumes (PTVs) in five fractions. Five-fold cross validation was performed on 30 patients, and another 20 patients were used as holdout tests of trained model. Predicted plans were compared with clinically approved plans through dose volume parameters and two-paired t-test. For the same sets, our results were compared with three different DL architectures: 3D U-Net, 3D U-Net with adversarial learning, and DPN without adversarial learning. The proposed framework was able to predict 87% and 91% of clinically relevant dose parameters for cross validation sets and holdout sets, respectively, without any significant differences (P > 0.05). Dose distribution predicted by our framework was also able to predict the intentional hotspots as feature characteristics of SBRT plans. Our method achieved higher correlation coefficients with the ground truth in 22/26, 24/26 and 20/26 dose volume parameters compared to the network without adversarial learning, 3D U-Net, and 3D U-Net with adversarial learning, respectively. Overall, the proposed model was able to predict doses to cases with both single and multiple PTVs. In conclusion, the DPN integrated DL model was successfully implemented, and demonstrated good dose prediction accuracy and dosimetric characteristics for pancreatic cancer SBRT.

A survey of the practice of stereotactic body radiotherapy for hepatocellular and pancreatic malignancies in India.

Stereotactic body radiotherapy (SBRT) is increasingly being performed for hepatocellular cancer and liver metastases. The purpose of this study was to review the practice of SBRT for hepatocellular, pancreatic cancer and liver metastases in India. A survey comprising of 25 questions was designed and served to radiation oncology professionals at two major conferences. The survey consisted of 25 multiple choice questions on SBRT infrastructure and caseload, simulation methods and immobilizations, organ motion control methods, simulation and delivery, indications of liver and pancreatic SBRT and prescribed dose. The responses were analyzed using descriptive statistics. From January to June 2017, about 200 professionals were approached and 71 professionals responded with a response rate of 35.5%. The duration of the SBRT practice among respondents was less than 3 years in 53% with 32% having formal training in SBRT. The most common sites for the use of SBRT were lung and brain followed by liver and spine. Liver SBRT was practiced by 29 (59.2%) for hepatic oligometastases, hepatocellular carcinoma (HCC), and cholangiocarcinoma. The most common fractionation used was 50-60 Gy/6 fractions and 45 Gy/3 fractions. Pancreatic SBRT was practiced by 37%, mostly for medically inoperable or locally advanced pancreatic cancer. SBRT was not practiced by 22 (31%) of the respondents, and the main reasons were lack of infrastructure and structured training. The SBRT for liver has increased with a usage rate of over 50% amongst respondents. Pancreatic SBRT use is infrequent and limited to inoperable or advanced cases. Lack of infrastructure and training are the main challenges in the routine adaptation of SBRT.

Patterns of Regional Failure in Patients with Pancreatic Cancer treated with Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy (SBRT) is a treatment option for locally advanced pancreatic cancer. Current practice is to target the gross tumor volume (GTV) only and omit elective nodal irradiation, which may lead to increased regional failures. In this study, we review the patterns of regional failure of our patients treated with SBRT. We retrospectively reviewed all patients diagnosed with pancreatic cancer treated with SBRT to the GTV only from 2003 to 2019 in our institution with regional nodal failure on at least one follow-up scan. Major blood vessels (celiac artery (CA), superior mesenteric artery (SMA), portal vein (PV), and aorta) were contoured, and the distance of the nodal failures measured. Regional nodal failure was defined as new lymphadenopathy within 1.5 cm of CA, SMA, and PV, and within 2cm of aorta in accordance with RTOG consensus contouring guidelines. Follow-up scans were fused with the treatment planning scan, and doses to the regional failures were computed. They were then drawn to one template CT scan for mapping. Patients were excluded for regional mapping if they had incomplete SBRT plan data or follow-up scan images. Out of 355 patients diagnosed with pancreas cancer treated with SBRT in our institution, 23 patients (6.5%) had identified regional nodal failure in their follow-up. Thirteen (57%) patients had locally advanced disease treated definitively, 4 (17%) were neoadjuvant prior to Whipple, 3 (13%) were treated palliatively and were metastatic at presentation, and 3 (13%) were recurrence after Whipple or conventional radiotherapy. The median prescribed dose to the planning treatment volume (PTV) was 33 Gy (range, 24 – 40 Gy) in 5 (range, 1-5) fractions. The mean PTV dose delivered BED 10 is 66.63 Gy (range, 27.01-121.19Gy) There were 0 isolated regional failures; 17 (74%) regional failures occurred with simultaneous distant failure, 2 (9%) had distant recurrence before they had locoregional failure, 3 (13%) had simultaneous local progression, and 1 (4%) had local progression before regional failure. We identified 30 nodal failures from 23 patients. Nineteen (63%) nodal failures occurred within the para-aortic nodes, followed by 4 SMA nodal failures (17%), 5 CA failures (22%), and 2 PV failures (9%). The mean distance from CA, SMA, aorta, and PV were 0.72, 1.12, 0.80, and 0.58 cm respectively. The median mean, min, and max doses received by the regional nodes were 2.12 Gy (range, 0.07-20.77Gy), 0.87 Gy (range, 0-17.51Gy), and 4.02 Gy (range, 0.07-24.2 Gy) respectively. Regional failures with pancreatic SBRT were overall rare with a crude rate of 6.5%, none of which occurred in isolation as the first site of failure. The most common sites of regional failure were the para-aortic nodes followed by the CA nodes and then SMA nodes. Although this data supports the continued exclusion of elective nodal regions with pancreatic SBRT, the risk of nodal failures may increase with improvements in systemic therapy.

Pancreatic Stereotactic Body Radiation Therapy (SBRT) in the Era of Multi-Agent Chemotherapy for Locally Advanced and Borderline Resectable Pancreatic Cancer: A Prospective Single Institution Study

Few studies have examined the role of stereotactic body radiation (SBRT) after multiagent chemotherapy (ChT) in pancreatic ductal adenocarcinoma (PDAC). This was a prospective study of SBRT after ChT for PDAC. To prospectively assess safety and efficacy of pancreatic SBRT following neoadjuvant multiagent chemotherapy. Eligible pts had locally advanced (LA), borderline resectable (BR), or locally recurrent (LR) PDAC and received either gemcitabine/nab-paclitaxel (GA) or FOLFIRINOX. SBRT was delivered to tumor and tumor-vessel interface and dose escalated from 33 to 36 Gy in 5 fractions. Pts with prior abdominal RT received 25 Gy in 5 fractions. Primary endpoint was severe (≥ grade 3) acute (≤ 6 mos from SBRT) toxicity rate. Kaplan Meier and multivariate Cox regression were used for survival analyses. 35 pts completed treatment on study with an additional 10 treated off study but per protocol (total 45). Median age was 66 yrs; 22, 17 and 6 pts, respectively, had BR, LA, and LR disease. 69% received FOLFIRINOX before SBRT and 24% received GA. Severe acute toxicity rate after SBRT was 4.4% (2/45, both grade 3). 16 patients were resected after SBRT; 12 had partial responses, but none had pathologic complete response. For all pts, at a median follow-up of 15.4 mos, median overall survival (OS) was 22.8 (95% CI 17.6-28.0) mos from diagnosis and 11.8 (10.4-13.1) mos from SBRT. In patients with LA, BR, and LR disease, median OS from diagnosis was 17.6, 25.9, and 36.4 mos, respectively, while median OS from SBRT was 9.6 mos, 19.8 mos, and not reached. Median progression-free survival (PFS) from SBRT was 8.4, 16.1, and 20.3 mos in patients with LA, BR, and LR disease, respectively. Actuarial 1-year local PFS (LPFS) rate was 78.5%, with 1-year LPFS rates of 71.6% and 100% in pts treated with ≤33 Gy and >33 Gy, respectively (p = 0.13). Cox regression showed that resection (p = 0.023), and pre-SBRT CA 19-9 (p = 0.005) were significant predictors of post-SBRT survival, but type of ChT was not (p = 0.75). Median OS from diagnosis was 25.2 mos in resected and 18.4 mos in unresected pts (log-rank p=0.047). SBRT can be performed safely after multiagent ChT for PDAC. There was a trend towards improved local control in patients treated with dose-escalated (36 Gy/5 fractions) SBRT. Patients with BR/LR disease and low baseline CA19-9 benefited the most from SBRT. Further study is needed to define the role of SBRT in PDAC.

Patterns of Failure After Adjuvant Stereotactic Body Radiation Therapy for Pancreatic Cancer With Close or Positive Margins

PurposeThere is no consensus on treatment volumes for adjuvant stereotactic body radiation therapy (SBRT) for pancreatic cancer. Herein, we report patterns of failure after pancreatic SBRT for close/positive margins, which may inform target volume design. Methods and MaterialsAn institutional review board-approved retrospective review of patients with pancreatic adenocarcinoma treated with adjuvant SBRT for close/positive margins from 2009 to 2018 was conducted. Patterns of failure were defined as local (LF) within the tumor bed, regional (RF) within lymph nodes or anastomoses, or distant (DF). The cumulative incidence of locoregional failure was calculated using the cumulative incidence function accounting for the competing risk of death. LFs were mapped to the planning target volume (PTV) and classified as in-field (completely within the PTV), marginal (partially within the PTV), or out-of-field (completely outside the PTV). The location of LFs was compared with the Radiation Therapy Oncology Group 0848 contouring atlas to determine whether standard postoperative radiation therapy volumes would have included the LF. ResultsSeventy-six patients were treated with adjuvant SBRT for close (51.3%) or positive (48.7%) margins. Most (81.6%) received 36 Gy in 3 fractions, with a median PTV volume of 17.8 cc (interquartile range, 12.1-25.6). With a median follow-up of 17.0 months (interquartile range, 7.3-28.4), crude rates of first isolated LF, isolated RF, and DF +/– LF or RF were 9.2%, 6.6%, and 56.6%, respectively. Two-year cumulative incidences of LF, RF, locoregional failure, and DF were 34.9%, 30.8%, 49.2%, and 60.4%, respectively. Of 28 reviewable LFs, 21.4% were in-field while the remainder were completely outside (60.7%) or partially outside (17.9%) the PTV. Most LFs (92.9%) would have been encompassed by the Radiation Therapy Oncology Group consensus target volumes. ConclusionsAfter adjuvant pancreatic SBRT for close/positive margins, the majority of LFs were outside the PTV but within contemporary target volumes for conventional radiation therapy.

Australasian Gastrointestinal Trials Group (AGITG) and Trans-Tasman Radiation Oncology Group (TROG) Guidelines for Pancreatic Stereotactic Body Radiation Therapy (SBRT)

PurposeNonrandomized data exploring pancreas stereotactic body radiation therapy (SBRT) has demonstrated excellent local control rates and low toxicity. Before commencing a randomized trial investigating pancreas SBRT, standardization of prescription dose, dose constraints, simulation technique, and clinical target volume delineation are required. Methods and MaterialsSpecialists in radiation oncology, medical oncology, hepatobiliary surgery, and gastroenterology attended 2 consecutive Australasian Gastrointestinal Trials Group workshops in 2017 and 2018. Sample cases were discussed during workshop contact with specifically invited international speakers highly experienced in pancreas SBRT. Furthermore, sample cases were contoured and planned between workshop contact to finalize dose constraints and clinical target volume delineation. ResultsOver 2 separate workshops, consensus was reached on dose and simulation technique. The working group recommended a dose prescription of 40 Gy in 5 fractions. Treatment delivery during end-expiratory breath hold with triple-phase contrast enhanced computed tomography was recommended. In addition, dose constraints, stepwise contouring guidelines, and an anatomic atlas for pancreatic SBRT were developed. ConclusionsPancreas SBRT is emerging as a promising treatment modality requiring prospective evaluation in randomized studies. This work attempts to standardize dose, simulation technique, and volume delineation to support the delivery of high quality SBRT in a multicenter study.