Radiotherapy For Pancreatic Cancer Research Articles

A pilot study on interobserver variability in organ-at-risk contours in magnetic resonance imaging-guided online adaptive radiotherapy for pancreatic cancer.

Differences in the contours created during magnetic resonance imaging-guided online adaptive radiotherapy (MRgOART) affect dose distribution. This study evaluated the interobserver error in delineating the organs at risk (OARs) in patients with pancreatic cancer treated with MRgOART. Moreover, we explored the effectiveness of drugs that could suppress peristalsis in restraining intra-fractional motion by evaluating OAR visualization in multiple patients. This study enrolled three patients who underwent MRgOART for pancreatic cancer. The study cohort was classified into three conditions based on the MRI sequence and butylscopolamine administration (Buscopan): 1, T2 imaging without butylscopolamine administration; 2, T2 imaging with butylscopolamine administration; and 3, multi-contrast imaging with butylscopolamine administration. Four blinded observers visualized the OARs (stomach, duodenum, small intestine, and large intestine) on MR images acquired during the initial and final MRgOART sessions. The contour was delineated on a slice area of ±2 cm surrounding the planning target volume. The dice similarity coefficient (DSC) was used to evaluate the contour. Moreover, the OARs were visualized on both MR images acquired before and after the contour delineation process during MRgOART to evaluate whether peristalsis could be suppressed. The DSC was calculated for each OAR. Interobserver errors in the OARs (stomach, duodenum, small intestine, large intestine) for the three conditions were 0.636, 0.418, 0.676, and 0.806; 0.725, 0.635, 0.762, and 0.821; and 0.841, 0.677, 0.762, and 0.807, respectively. The DSC was higher in all conditions with butylscopolamine administration compared with those without it, except for the stomach in condition 2, as observed in the last session of MR image. The DSCs for OARs (stomach, duodenum, small intestine, large intestine) extracted before and after contouring were 0.86, 0.78, 0.88, and 0.87; 0.97, 0.94, 0.90, and 0.94; and 0.94, 0.86, 0.89, and 0.91 for conditions 1, 2, and 3, respectively. Butylscopolamine effectively reduced interobserver error and intra-fractional motion during the MRgOART treatment.

Evaluation of Helium Ion Radiotherapy in Combination with Gemcitabine in Pancreatic Cancer In Vitro.

Pancreatic cancer is one of the most aggressive and lethal cancers. New treatment strategies are highly warranted. Particle radiotherapy could offer a way to overcome the radioresistant nature of pancreatic cancer because of its biological and physical characteristics. Within particles, helium ions represent an attractive therapy option to achieve the highest possible conformity while at the same time protecting the surrounding normal tissue. The aim of this study was to evaluate the cytotoxic efficacy of helium ion irradiation in pancreatic cancer in vitro. Human pancreatic cancer cell lines AsPC-1, BxPC-3 and Panc-1 were irradiated with photons and helium ions at various doses and treated with gemcitabine. Photon irradiation was performed with a biological cabin X-ray irradiator, and helium ion irradiation was performed with a spread-out Bragg peak using the raster scanning technique at the Heidelberg Ion Beam Therapy Center (HIT). The cytotoxic effect on pancreatic cancer cells was measured with clonogenic survival. The survival curves were compared to the predicted curves that were calculated via the modified microdosimetric kinetic model (mMKM). The experimental relative biological effectiveness (RBE) of helium ion irradiation ranged from 1.0 to 1.7. The predicted survival curves obtained via mMKM calculations matched the experimental survival curves. Mainly additive cytotoxic effects were observed for the cell lines AsPC-1, BxPC-3 and Panc-1. Our results demonstrate the cytotoxic efficacy of helium ion radiotherapy in pancreatic cancer in vitro as well as the capability of mMKM calculation and its value for biological plan optimization in helium ion therapy for pancreatic cancer. A combined treatment of helium irradiation and chemotherapy with gemcitabine leads to mainly additive cytotoxic effects in pancreatic cancer cell lines. The data generated in this study may serve as the radiobiological basis for future experimental and clinical works using helium ion radiotherapy in pancreatic cancer treatment.

EUS-guided hydrogel injection to separate pancreatic head carcinoma from duodenum for enhanced radiotherapy: multi-site feasibility study

Background and study aims: The proximity of a pancreas head tumor to the duodenum often limits delivery of an ablative dose of radiation therapy. This study evaluated the feasibility and safety of using an injectable polyethylene glycol (PEG) hydrogel between the head of the pancreas and duodenum. Patients and methods: In a multi-site feasibility cohort study of patients with localized pancreatic cancer, PEG hydrogel was injected under endoscopic ultrasound guidance to temporarily position the duodenum away from the pancreas. Procedure characteristics were recorded, including hydrogel volume and space created. Patients were monitored for adverse events (AEs) and radiotherapy toxicity. Results: In all six intent-to-treat patients (four with borderline resectable, two with locally advanced disease), the ability to place and visualize PEG hydrogel and create space between the duodenum and head of pancreas was successful. There were no procedure-related AEs resulting in radiotherapy delay. There were no device-related AEs and no reports of pancreatitis. Conclusions: PEG hydrogel was successfully placed, created space between the duodenum and the head of the pancreas, and was not associated with major toxicity. Enhancing radiotherapy for pancreatic cancer by using PEG hydrogel to create peri-duodenal space could have beneficial implications for treatment and warrants more exploration.

Enhancing Image-Guided Radiation Therapy for Pancreatic Cancer: Utilizing Aligned Peak Response Beamforming in Flexible Array Transducers.

To develop ultrasound-guided radiotherapy, we proposed an assistant structure with embedded markers along with a novel alternative method, the Aligned Peak Response (APR) method, to alter the conventional delay-and-sum (DAS) beamformer for reconstructing ultrasound images obtained from a flexible array. We simulated imaging targets in Field-II using point target phantoms with point targets at different locations. In the experimental phantom ultrasound images, image RF data were acquired with a flexible transducer with in-house assistant structures embedded with needle targets for testing the accuracy of the APR method. The lateral full width at half maximum (FWHM) values of the objective point target (OPT) in ground truth ultrasound images, APR-delayed ultrasound images with a flat shape, and images acquired with curved transducer radii of 500 mm and 700 mm were 3.96 mm, 4.95 mm, 4.96 mm, and 4.95 mm. The corresponding axial FWHM values were 1.52 mm, 4.08 mm, 5.84 mm, and 5.92 mm, respectively. These results demonstrate that the proposed assistant structure and the APR method have the potential to construct accurate delay curves without external shape sensing, thereby enabling a flexible ultrasound array for tracking pancreatic tumor targets in real time for radiotherapy.

Feasibility of proton dosimetry overriding planning CT with daily CBCT elaborated through generative artificial intelligence tools

Radiotherapy commonly utilizes cone beam computed tomography (CBCT) for patient positioning and treatment monitoring. CBCT is deemed to be secure for patients, making it suitable for the delivery of fractional doses. However, limitations such as a narrow field of view, beam hardening, scattered radiation artifacts, and variability in pixel intensity hinder the direct use of raw CBCT for dose recalculation during treatment. To address this issue, reliable correction techniques are necessary to remove artifacts and remap pixel intensity into Hounsfield Units (HU) values. This study proposes a deep-learning framework for calibrating CBCT images acquired with narrow field of view (FOV) systems and demonstrates its potential use in proton treatment planning updates. Cycle-consistent generative adversarial networks (cGAN) processes raw CBCT to reduce scatter and remap HU. Monte Carlo simulation is used to generate CBCT scans, enabling the possibility to focus solely on the algorithm’s ability to reduce artifacts and cupping effects without considering intra-patient longitudinal variability and producing a fair comparison between planning CT (pCT) and calibrated CBCT dosimetry. To showcase the viability of the approach using real-world data, experiments were also conducted using real CBCT. Tests were performed on a publicly available dataset of 40 patients who received ablative radiation therapy for pancreatic cancer. The simulated CBCT calibration led to a difference in proton dosimetry of less than 2%, compared to the planning CT. The potential toxicity effect on the organs at risk decreased from about 50% (uncalibrated) up the 2% (calibrated). The gamma pass rate at 3%/2 mm produced an improvement of about 37% in replicating the prescribed dose before and after calibration (53.78% vs 90.26%). Real data also confirmed this with slightly inferior performances for the same criteria (65.36% vs 87.20%). These results may confirm that generative artificial intelligence brings the use of narrow FOV CBCT scans incrementally closer to clinical translation in proton therapy planning updates.

Targeted irradiation in an autochthonous mouse model of pancreatic cancer.

The value of radiotherapy in the treatment of pancreatic cancer has been the subject of much debate but limited preclinical research. We hypothesise that the poor translation of radiation research into clinical trials of radiotherapy in pancreatic cancer is due, in part, to inadequate preclinical study models. Here, we developed and refined methods for targeted irradiation in autochthonous mouse models of pancreatic cancer, using a small animal radiotherapy research platform. We tested and optimised strategies for administration of contrast agents, iohexol and the liver imaging agent Fenestra LC, to enable the use of computed tomography imaging in tumour localisation. We demonstrate accurate tumour targeting, negligible off-target effects and therapeutic efficacy, depending on dose, number of fractions and tumour size, and provide a proof of concept that precise radiation can be delivered effectively to mouse pancreatic tumours with a clinically relevant microenvironment. This advance will allow investigation of the radiation response in murine pancreatic cancer, discovery of mechanisms and biomarkers of radiosensitivity or resistance, and development of radiosensitising strategies to inform clinical trials for precision radiotherapy in this disease.

Stereotactic body radiotherapy for pancreatic cancer – A systematic review of prospective data

PurposeThis systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT). MethodsFollowing PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies. Results and conclusion31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.

Impact of facility volume on outcomes in patients with pancreatic cancer treated with radiotherapy.

644 Background: The impact of facility volume on overall survival (OS) outcomes in patients with pancreatic cancer (PC) treated with radiotherapy (RT), both standard chemoradiation (CRT) and stereotactic body radiation therapy (SBRT) is not well-defined. Methods: This retrospective study analyzed 16,315 patients with locally advanced (LA) or borderline resectable (BR) PC from the National Cancer Database (2004-2019) who received neoadjuvant RT or RT without surgery across RT facilities with low- (<10 cases/yr), intermediate- (10-20 cases/yr), and high-volumes (>20 cases/yr) of PC cases. Log rank and cox regression were used for univariable and multivariable survival analysis, and Kaplan-Meier curves were generated. Results: Patients were largely treated at low (n=8055) volume centers, followed by intermediate (n=3783), and high (n=4477). Approximately half of the cohort were male (51.4%), and predominantly white (82.5%), and non-Hispanic (92%). On univariable analysis (Table), high-volume centers had improved survival outcomes in the overall population, as well as in both SBRT and CRT subsets (p<0.0001). On multivariable analysis, treatment during the most recent time period: 2016-2019 (HR 0.646, p<0.001), receiving care at a high-volume center (HR 0.844, p<0.001), use of SBRT (HR 0.915, p<0.001), administration of multiagent chemotherapy (HR 0.706, p<0.001) and undergone surgical resection (HR 0.405, p<0.001) were associated with improved OS. In a subgroup analysis of patients receiving SBRT, median OS was 22.6 months for high-volume, 20.0 for intermediate-volume and 18.4 months at low-volume centers (p<0.001). Conclusions: Patients receiving RT for LAPC or BRPC at high-volume centers had longer OS compared to those receiving radiation at intermediate- or low-volume centers. In those undergoing SBRT, treatment at high-volume centers had improved OS compared to intermediate- and low-volume centers. These findings suggest that radiation oncologists’ expertise is critical for providing high-quality RT in PC, especially for SBRT.[Table: see text]

Palliative radiotherapy for pancreatic cancer.

Palliative radiotherapy for pancreatic cancer.

Systematic review and meta-analysis on safety and efficacy of immune checkpoint inhibitors and radiotherapy for advanced pancreatic cancer

Objective: The aim of this study is to assess the safety and efficacy of stereotactic body radiotherapy (SBRT) in combination with immune checkpoint inhibitors (ICIs) in patients with advanced pancreatic cancer. Method: A PRISMA selection protocol was used to identify studies across electronic databases such as; PubMed, Google scholar, Cochrane, Embase, and web of science from inception until November 23, 2022, where data from SBRT studies were compared to data from a combination of SBRT and ICIs for advanced pancreatic cancer. The endpoints recorded after therapy were overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), progression-free survival (PFS) and treatment-related adverse effect (TRAE) were collected in each study. Results: The primary endpoint (OS) retrieved from five studies following SBRT disclosed OS at the rate of one year at 44% as compared to the combination studies of SBRT+ICI with 42%. PFS recorded at the rate of 1 year revealed an outcome of 46% following SBRT. In contrast, PFS in the combination studies recorded SBRT+ICI of 86%. The risk of grade >3 TRAE in the SBRT was 21.5% as compared to the combination studies of 75%. This risk of grade>3 TRAE was reduced as compared to any grade in two studies (Heterogeneity: Chi² = 2.78, df = 1 (P = 0.10); I² = 64%). Conclusion: The Combination of SBRT and ICIs demonstrate modest treatment efficiency and acceptable safety profile in patients with advanced pancreatic cancer. However, combination trials are fewer, and further studies are warranted.

The Role of Radiation Therapy in Pancreatic Cancer

The Role of Radiation Therapy in Pancreatic Cancer

Immune profiling of pancreatic cancer for radiotherapy with immunotherapy and targeted therapy: Biomarker analysis of a randomized phase 2 trial

PurposeImmunotherapy alone offered limited survival benefits in pancreatic cancer, while the role of immunotherapy-centric combined therapy remains controversial. Therefore, it is required to develop biomarkers to precisely deliver immunotherapy-based multimodality for pancreatic cancer. MethodsThis is a secondary analysis of an open label, randomized, phase 2 trial, whereas patients with locally recurrent pancreatic cancer after surgery were enrolled. Eligible patients with mutant KRAS and positive immunohistochemical staining of PD-L1 were randomly assigned to receive stereotactic body radiation therapy (SBRT) plus pembrolizumab and trametinib (SBRT + K + M) or SBRT and gemcitabine (SBRT + G). Meanwhile, patients were classified into PD-L1+/tumor infiltrating lymphocytes [TIL(s)]- and PD-L1+/TIL + group for each arm. ResultsA total of 170 patients were enrolled and randomly assigned to receive SBRT + K + M (n = 85) or SBRT + G (n = 85). The improved outcomes have been reported in patients with SBRT + K + M in the previous study. In this secondary analysis, the median overall survival (OS) was 17.2 months (95% CI 14.6–19.8 months) in patients with PD-L1+/TIL + and 12.7 months (95% CI 10.8–14.6 months) in patients with PD-L1+/TIL- (HR 0.62, 95% CI 0.39–0.97, p = 0.036) receiving SBRT + K + M. In SBRT + G group, the median OS was 13.1 months (95% CI 10.9–15.3 months) in patients with PD-L1+/TIL- and 12.7 months (95% CI 9.2–16.2 months) in patients with PD-L1+/TIL+ (HR 0.97, 95% CI 0.62–1.52, p = 0.896). Grade 3 or 4 adverse events were found in 16 patients (30.8%) and 10 patients (30.3%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + K + M group respectively; whereas 9 (16.7%) and 8 patients (25.8%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + G group. ConclusionPD-L1, TILs and mutant KRAS may be a biomarker to guide clinical practice of radiotherapy and immunotherapy-based regimens in pancreatic cancer if further combined with MEK inhibitors as targeted therapy.

Development and Validation of a Deep Learning-Based Auto-Delineation of Target Volume and Organs at Risk in Pancreatic Cancer Radiotherapy.

The delineation of the clinical target volume (CTV), gross target volume (GTV) and organs at risk (OARs) is a crucial and laborious in pancreatic cancer radiotherapy. In this work, we propose and evaluate a three-dimensional (3D) novel convolutional neural network (CNN) for automatic and accurate CTV, GTV and OARs in pancreatic cancer. A total of 120 computed tomography (CT) scans patients with pancreatic cancer were collected. A novel 3D CNN network, called ResUNet3D, was developed to achieve auto-delineation. 96 patients chosen randomly were used for training, 12 patients for validation, and 12 patients for testing. Meanwhile, the Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (HD95%) were used to assess the performance. The DSC values for the test data were 80.9±8.6%, 77.5±5.6%, 94.5±1.3%, 66.2±13.4%, 73.6±7.6%, 79.0±8.7%, 94.1±1.9%, 94.6±1.4%, 87.3±5.8% for CTV, GTV, liver, duodenum, spinal cord, bowel, kidney left, kidney right, stomach. The corresponding HD95% values were 10.7±6.9mm, 7.8±5.7mm, 11.6±5.6mm, 18.6±5.6mm, 2.7±0.7mm, 17.7±8.6mm, 3.9±1.4mm, 3.7±1.9mm, 13.4±5.7mm, respectively. The average delineation time for one patient's CT images was within 5 seconds. The experimental results demonstrate that the CTV, GTV and OARs delineated for pancreatic cancer by ResUNet3D achieved a close agreement with the ground truth. ResUNet3D could significantly reduce the radiation oncologists' contouring time.

Novel Deep Learning Segmentation Models for Accurate GTV and OAR Segmentation in MR-Guided Adaptive Radiotherapy for Pancreatic Cancer Patients.

MR-guided adaptive radiotherapy (MRgART) improves target coverage and organ-at-risk (OAR) sparing in pancreatic cancer radiation therapy (RT). Inter-fractional changes in patients undergoing RT require time intensive re-delineation of gross tumor volume (GTV) and OARs prior to adaptive optimization. Accurate automatic segmentation has the potential to significantly improve efficiency of the adaptive workflow. We hypothesized that state-of-the-art deep learning (DL) segmentation models could adequately segment GTV and OARs in both planning and daily fractional MR scans. The study included 21 patients with pancreatic cancer treated with MRgART (10 Gy x 5 fractions). The planning MR as well as all daily MR images and registrations were collected (6 image sets per patient and a total of 126 image sets). The planning MR and fraction 1-4 image sets were used as the training set (N = 105), while the test set (N = 21) comprised images for fraction 5, to simulate the last step of incremental learning from planning to final fraction. Evaluated contours included the GTV, Small Bowel, Large Bowel, Duodenum, Left and Right Kidney, Liver, Spinal Cord, and Stomach. To mimic clinical conditions, contour accuracy was evaluated within the ring structure surrounding the PTV, inside of which daily adaptive re-contouring is applied (2 cm expansion in the cradio-caudal direction, 3 cm expansion otherwise). We evaluated three DL model architectures: SegResNet, SegResNet 2D, and SwinUNETR to autosegment GTV and OARs. The segmentation models were trained on the training set using 5-fold cross-validation (CV) and quantitatively analyzed by comparing against clinically used contours with DICE scores. Qualitative analysis was performed by a radiation oncologist using a scoring scale: 1 = perfect, 2 = minor discrepancy, 3 = moderate discrepancy, and 4 = rejected. Overall, the DL segmentations were in acceptable agreement with clinical contours. The best performing model was the SwinUNETR model with overall training DICE = 0.88±0.06, test DICE = 0.78±0.11, and qualitative score of 1.6±0.8. The agreement between the DL model and clinical segmentation for the GTV was 0.79±0.08, with a qualitative score of 2.2±0.9. The highest and lowest OAR DICE scores were for the Left Kidney (DICE = 0.93) and Small Bowel (DICE = 0.68), respectively. The highest qualitative OAR scores were for the Kidney, Liver, and Spinal Cord (score = 1.0) and the lowest qualitative score was for the Duodenum (score = 2.3) CONCLUSION: We report here the most comprehensive work on DL segmentation for pancreatic cancer MRgART, including quantitative and clinically-pertinent qualitative evaluations of 126 image sets and 3 DL architectures. Our data show good quantitative agreement between DL and clinical contours, and acceptable clinician evaluations for the majority of GTVs and OARs. The current work has great potential to significantly reduce a major bottleneck in the MRgART workflow for pancreatic cancer patients.

Patterns of Locoregional Failure After Ablative 5-Fraction Stereotactic MR-Guided on-Table Adaptive Radiation Therapy for Pancreatic Cancer

SBRT for pancreatic ductal adenocarcinoma (PDAC) is routinely delivered with non-ablative dose to only gross disease resulting in locoregional failure (LRF) rates of >50%, most commonly near the celiac artery (CA) and/or superior mesenteric artery (SMA). It is unclear whether an alternative approach of prescribing ablative dose to gross disease plus elective coverage prevents and/or delays LRF. The study objective was to describe the incidence and anatomic distribution of LRF using this treatment approach. A single institution retrospective analysis was performed of non-metastatic PDAC patients who received ablative stereotactic MR-guided on-table adaptive radiation therapy (A-SMART) on a 0.35T MR-Linac from 2018-2022. Median prescribed dose was 50 Gy/5 fractions. Elective coverage (EC), including a margin around the primary tumor, CA, and SMA, to 33-35 Gy/5 fractions became routine in 2019 using a simultaneous integrated boost; the porta hepatis was not routinely covered. LRFs were contoured and defined as out-of-field (OOF), marginal (M), or in-field (IF) if >80%, 20-80%, or <20% of it was outside of the most peripheral prescription isodose line. One hundred four patients were evaluated (87% head tumors). 94% had induction chemotherapy (median 4 months), usually FOLFIRINOX (66%) or gemcitabine/nab-paclitaxel (27%). 88% received EC. Median GTV, CTV, PTVgrosstumor, and PTVelective volumes were 29 cc, 90 cc, 64 cc, and 127 cc, respectively. 16 patients (15%) had LRF after a median of 17 months (range: 2.4-30.8) from A-SMART; 13 had scans available for delineating LRF. Median follow-up from A-SMART for the entire cohort vs. LRF was 12 vs. 24 months. LRF involved the primary tumor (31%), retroperitoneal lymph nodes (25%), SMA (19%), porta hepatis (19%), and CA (6%). LRF was OOF, M, or IF in 30.8% (n = 4), 61.5% (n = 8), and 7.7% (n = 1). Distance from the 3 SMA failures to SMA origin was 10 cm (EC used), 9.3 cm (EC used), and 3 cm (no EC). The 1 CA failure involved the CA origin (no EC). Median mean, maximum, and minimum dose of the contoured LRF region on the original plan was 33.3 Gy (range: 9.7-50.3 Gy), 56 Gy (range: 44.2-71.4 Gy), and 11.4 Gy (range: 1.2-22.7 Gy), respectively. Median V20, V25, V30, V35, and V40 of the contoured LRF was 84.3% (range: 16.1-100%), 69.2% (range: 12.5-99.7%), 57.5% (range: 9.3-95.5%), 41.2% (range: 6.8-84.0%), and 32.7% (range: 4.8-71.8%). This study represents the first patterns of LRF analysis after ablative 5-fraction SBRT for PDAC. Although EC is not currently endorsed by published pancreas SBRT guidelines, our low LRF incidence especially involving the CA/SMA demonstrates that EC should be considered, even when delivering ablative dose. Furthermore, given that nearly all LRF were M or OOF we have considered expanding our institutional elective volumes. While the optimal EC dose is uncertain, 33-35 Gy appears effective in limiting IF LRF and therefore has been standardized within ongoing ablative SBRT trials for PDAC at our institution.

The Outcomes of Neoadjuvant Chemoradiotherapy Using Moderately Hypofractionated Intensity Modulated Radiotherapy for Borderline Resectable Pancreatic Cancer

Complete resection of borderline resectable pancreatic cancer (BRPC) is difficult because of its invasion to the vital vessels. Although neoadjuvant therapy is recommended for BRPC, its optimal regimens remain unclear. Neoadjuvant chemoradiotherapy using moderately hypofractionated intensity-modulated radiotherapy (NAC-MH-IMRT) has potentials to improve the treatment outcomes with shorter treatment periods. Therefore, we evaluated the outcomes for BRPC patients treated with NAC-MH-IMRT. Between February 2013 and June 2021, patients with BRPC treated with NAC-MH-IMRT at our institution were evaluated. All patients were classified as BRPC-A and BRPC-V according to NCCN guidelines. Information regarding patient status, tumor and treatment characteristics, margin-negative resection (R0) rates, histological effects assessed by Evans classification, and outcomes were obtained from the clinical records. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method from the start date of any first treatment for BRPC. Toxicity was evaluated by CTCAE version 5.0. Sixty-eight patients were included in this study (Table). All patients underwent induction chemotherapy, and 67 were treated with IMRT at 42 Gy in 15 fractions with concurrent gemcitabine (for 65) or S-1 (for 2). All patients achieved completion of radiotherapy. Fifty-seven of the 68 patients (83.8%) underwent surgical exploration, and 48 patients (70.6%) had a resection. The R0 resection was achieved in 44 patients, and the R0 resection rate was 91.7% in resected patients. Therapeutic effects by Evans classification showed as below: Grade 1/2a/2b/3/4 = 6 (12.5%)/17 (35.4%)/17 (35.4%)/7 (14.6%)/1 (2.1%). Adjuvant chemotherapy was performed for 41 patients, and S-1 and gemcitabine were used for 40 and 1 patient(s), respectively. The median follow-up time and median survival time (MST) were 23.6 months and 42.7 months, and 2-year OS and PFS were 67.3% and 30.2%, respectively. Recurrence was observed in 54 patients (79.4%), and the first recurrence pattern was as follows: 7 (13.0%)/42 (77.8%)/5 (9.3%) patients had local recurrence, distant metastases, and both of them, respectively. Regarding ≥ Grade 3 gastrointestinal toxicity related NAC-MH-IMRT, grade 3 ileus was observed in 1 patient. NAC-MH-IMRT for BRPC showed preferable outcomes and acceptable toxicities with high completion rate.

Early Assessment of Radiation Treatment at Clinical Field Strength by D2O Administration and Deuterium MRI

An accurate and non-invasive assessment of tumor response following treatment is essential. Traditional anatomical imaging techniques are insufficient before a significant morphological change can be observed. Metabolic imaging of molecular processes in the living body is also used. In recent years, deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field (4-11T) MRI using deuterium-labeled molecules as a contrast agent. The study aim was to evaluate the feasibility of using deuterium MRI 1.5T for tumor visualization and early assessment of the efficacy of three anticancer treatment strategies (radiation and anticancer drugs) in pancreatic cancer model mice given heavy water (D2O) to induce deuterium (2H)-tissue labeling. A MIA PaCa-2 pancreatic cancer model of six BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days after starting free drinking of 30% D2O. We also evaluated 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration of other 20 mice. Additional confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS and histopathology were performed. The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H in the tumor decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments. Deuterium MRI at 1.5T proved feasibility to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for early assessment of radiotherapy and chemotherapy of pancreatic cancer.

Deep Learning and GAN-Synthesis for Auto-Segmentation of Pancreatic Cancer by Non-Enhanced CT for Adaptive Radiotherapy

In conventional adaptive radiotherapy (ART) for pancreatic cancer, contrast-enhanced CT (CECT) helps to more precisely delineate primary gross tumor volume (GTV) than non-enhanced CT (NECT). However, frequent use of contrast medium can damage kidneys and prolong treatment time. Moreover, traditional manual delineation is labor-intensive and highly dependent on the experience of oncologists. Currently, automatic delineation based on deep learning with Generative Adversarial Networks (GAN)-based CT synthesis is one of the most feasible solutions to these problems. A dataset of 35 pancreatic cancer patients was retrospectively collected from May 2021 to December 2022. All patients consist of a pair of NECT and CECT. We designed and developed an automatic delineation framework (Proposed) for GTV of pancreatic cancer based on Trans-cycleGAN and a modified 3D U-Net. TranscycleGAN can not only synthesize CECT from NECT, but can also augment the amount of CT images; then all real and synthesized CT images were used to train the modified 3D U-Net for automatic delineation of GTV; finally, our framework was able to automatically delineate GTV by NECT, but not only by CECT. Our framework was evaluated by dice similarity coefficient (DSC), 95% Harsdorff distance (95HD) and average surface distance (ASD) with oncologists' manual delineation ("gold standard"). The evaluation results were summarized in Table 1. The proposed framework achieved the best automatic delineation results by NECT, which was superior to that of CECT: 0.917 & 0.903 of DSC, 2.498mm & 3.029mm of HD95, 0.481mm & 0.534mm of ASD, p < 0.05 for DSC and HD95. Specifically, it is significantly superior to the automatic delineation results using U-Net by CECT 0.917 & 0.818 of DSC, 2.498mm & 13.228mm of HD95, 0.481mm & 3.633mm of ASD, p < 0.05 for DSC. We proposed an automatic delineation framework for contouring GTV in ART of pancreatic cancer based on deep learning and Trans-cycleGAN network. This framework could automatically delineate GTV and achieve better performance with NECT compared to CECT. Our method could not only reduce the use of contrast medium, but also increase the precision and effectiveness of tumor delineation, which could have a positive impact on precision radiotherapy.

Patient-Reported Adverse Effects in 15-Fraction Pancreatic Cancer Radiation Therapy

Fifteen-fraction radiotherapy (RT) regimens have emerged as a standard option in the treatment of patients with pancreas cancer. Patient-reported outcomes (PROs) during and after pancreas cancer RT have not been well characterized. There is an even greater paucity of data among patients treated with 15-fraction regimens. We aimed to characterize gastrointestinal (GI) PROs in a cohort of patients treated with 15-fraction pancreas RT. This was an IRB-approved retrospective cohort study including patients with primary pancreas tumors treated with pre-operative or definitive 15-fraction RT from 2013 to 2022. PROs, including anorexia, nausea, diarrhea, stool incontinence, and abdominal pain, were prospectively collected and characterized per PRO-common terminology criteria for adverse events (PRO-CTCAE). Acute PROs were defined as occurring during RT through 110 days post-RT but prior to oncological surgery. Grade 3 or 4 PROs were respectively scored as "quite a bit" or "very much" in symptom interference questions, "frequently" or "almost constantly" in symptom frequency questions, and "severe" or "very severe" in symptom severity questions. A total of 330 patients were analyzed. Patient characteristics included a median age of 67 years (IQR: 60 - 72), ECOG 0-1 (96%), and male sex (56%). Most patients had pancreatic ductal adenocarcinoma (96%). Resectability status included resectable (12%), borderline resectable (46%), and locally advanced (42%). 37% had lymph node involvement. 97% of patients received neoadjuvant chemotherapy and 98% received concurrent chemotherapy, most commonly with 5-fluorouracil or capecitabine (88%) or gemcitabine (11%). 99% were treated with intensity modulated RT. Median RT dose was 4500 cGy (IQR 4500 - 4500) to gross disease with margin and 3750 cGy (IQR 3750 - 3750) to elective nodal regions. 59% proceeded with oncologic resection. Grade 3 or higher acute PROs are demonstrated in the table. Often considered more sensitive than physician assessments, PROs provide vital metrics that allow for a better understanding of the patient experience during cancer treatment. We report a comprehensive assessment of prospectively collected PROs per standardized PRO-CTCAE with the goals of raising awareness of the patient experience during 15-fraction pancreas cancer RT and helping guide future clinical trial designs focused on patient quality of life endpoints.

Assessment of interfraction dose variation in pancreas SBRT using daily simulation MR images

Pancreatic Cancer is associated with poor treatment outcomes compared to other cancers. High local control rates have been achieved by using hypofractionated stereotactic body radiotherapy (SBRT) to treat pancreatic cancer. Challenges in delivering SBRT include close proximity of several organs at risk (OARs) and target volume inter and intra fraction positional variations. Magnetic resonance image (MRI) guided radiotherapy has shown potential for online adaptive radiotherapy for pancreatic cancer, with superior soft tissue contrast compared to CT. The aim of this study was to investigate the variability of target and OAR volumes for different treatment approaches for pancreatic cancer, and to assess the suitability of utilizing a treatment-day MRI for treatment planning purposes. Ten healthy volunteers were scanned on a Siemens Skyra 3 T MRI scanner over two sessions (approximately 3 h apart), per day over 5 days to simulate an SBRT daily simulation scan for treatment planning. A pretreatment scan was also done to simulate patient setup and treatment. A 4D MRI scan was taken at each session for internal target volume (ITV) generation and assessment. For each volunteer a treatment plan was generated in the Raystation treatment planning system (TPS) following departmental protocols on the day one, first session dataset (D1S1), with bulk density overrides applied to enable dose calculation. This treatment plan was propagated through other imaging sessions, and the dose calculated. An additional treatment plan was generated on each first session of each day (S1) to simulate a daily replan process, with this plan propagated to the second session of the day. These accumulated mock treatment doses were assessed against the original treatment plan through DVH comparison of the PTV and OAR volumes. The generated ITV showed large variations when compared to both the first session ITV and daily ITV, with an average magnitude of 22.44% ± 13.28% and 25.83% ± 37.48% respectively. The PTV D95 was reduced by approximately 23.3% for both plan comparisons considered. Surrounding OARs had large variations in dose, with the small bowel V30 increasing by 128.87% when compared to the D1S1 plan, and 43.11% when compared to each daily S1 plan. Daily online adaptive radiotherapy is required for accurate dose delivery for pancreas cancer in the absence of additional motion management and tumour tracking techniques.