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Stent has often been used as an internal surrogate to monitor intrafraction tumor motion during pancreatic cancer radiotherapy. Based on the stent contours generated from planning CT images, the current intrafraction motion review (IMR) system on Varian TrueBeam only provides a tool to verify the stent motion visually but lacks quantitative information. The purpose of this study is to develop an automatic stent recognition method for quantitative intrafraction tumor motion monitoring in pancreatic cancer treatment.A total of 535 IMR images from 14 pancreatic cancer patients were retrospectively selected in this study, with the manual contour of the stent on each image serving as the ground truth. We developed a deep learning-based approach that integrates two mechanisms that focus on the features of the segmentation target. The objective attention modeling was integrated into the U-net framework to deal with the optimization difficulties when training a deep network with 2D IMR images and limited training data. A perceptual loss was combined with the binary cross-entropy loss and a Dice loss for supervision. The deep neural network was trained to capture more contextual information to predict binary stent masks. A random-split test was performed, with images of ten patients (71%, 380 images) randomly selected for training, whereas the rest of four patients (29%, 155 images) were used for testing. Sevenfold cross-validation of the proposed PAUnet on the 14 patients was performed for further evaluation.Our stent segmentation results were compared with the manually segmented contours. For the random-split test, the trained model achieved a mean (±standard deviation) stent Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), the center-of-mass distance (CMD), and volume differenceWe developed a novel deep learning-based approach to automatically segment the stent from IMR images, demonstrated its clinical feasibility, and validated its accuracy compared to manual segmentation. The proposed technique could be a useful tool for quantitative intrafraction motion monitoring in pancreatic cancer radiotherapy.

Supplementary Figure from Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice

Supplementary Data from Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice

Purpose:Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated.Results:Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (18, 3–55) or ovarian (25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC.Conclusions:ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

OBJECTIVE We sought to compare overall survival (OS) and disease control for patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with ablative dose radiotherapy (A-RT) versus resection. SUMMARY BACKGROUND DATA Locoregional treatment for PDAC includes resection when possible or palliative RT. A-RT may offer durable tumor control and encouraging survival. METHODS This was a single-institution retrospective analysis of patients with PDAC treated with induction chemotherapy followed by A-RT [≥98 Gy biologically effective dose (BED) using 15-25 fractions in 3-4.5 Gy/fraction] or pancreatectomy. RESULTS One hundred and four patients received A-RT (49.8%) and 105 (50.2%) underwent resection. Patients receiving A-RT had larger median tumor size after induction chemotherapy [3.2 cm (undetectable-10.9) vs 2.6 cm (undetectable-10.7), P < 0.001], and were more likely to have celiac or hepatic artery encasement (48.1% vs 11.4%, P

Background and Purpose Stereotactic body radiation therapy delivered using MR-guided radiotherapy (MRgRT) and automatic breathold gating has shown to improve overall survival for locally advanced pancreatic cancer (LAPC) patients. The goal of our study was to evaluate feasibility of treating LAPC patients using abdominal compression (AC) and impact of potential intrafraction motion on planned dose on a 1.5T MR-linac. Methods & Materials Ten LAPC patients were treated with MRgRT to 50 Gy in 5 fractions with daily online plan adaptation and AC. Three orthogonal plane cine MRI were acquired to assess stability of AC pressure in minimizing tumor motion. Three sets of T2w MR scans, pre-treatment (MRIpre), verification (MRIver) and post-treatment (MRIpost) MRI, were acquired for every fraction. A total of 150 MRIs and doses were evaluated. Impact of intrafraction organ motion was evaluated by propagating pre-treatment plan and structures to MRIver and MRIpost, editing contours and recalculating doses. Gross tumor volume (GTV) coverage and organs-at-risk (OARs) doses were evaluated on MRIver and MRIpost. Results Median total treatment time was 75.5 (49–132) minutes. Median tumor motion in AC for all fractions was 1.7 (0.7–7), 2.1 (0.6–6.3) and 4.1 (1.4–10.0) mm in anterior-posterior, left–right and superior-inferior direction. Median GTV V50Gy was 78.7%. Median D5cm3 stomach_duodenum was 24.2 (18.4–29.3) Gy on MRIver and 24.2 (18.3–30.5) Gy on MRIpost. Median D5cm3 small bowel was 24.3 (18.2–32.8) Gy on MRIver and 24.4 (16.0–33.6) Gy on MRIpost. Conclusion Dose-volume constraints for OARs were exceeded for some fractions on MRIver and MRIpost. Longer follow up is needed to see the dosimetric impact of intrafraction motion on gastrointestinal toxicity.

Beam gating with deep inspiration breath hold (DIBH) usually depends on some external surrogate to infer internal target movement, and the exact internal movement is unknown. In this study, we tracked internal targets and characterized residual motion during DIBH treatment, guided by a surface imaging system, for gastrointestinal cancer. We also report statistics on treatment time.We included 14 gastrointestinal cancer patients treated with surface imaging-guided DIBH volumetrically modulated arc therapy, each with at least one radiopaque marker implanted near or within the target. They were treated in 25, 15, or 10 fractions. Thirteen patients received treatment for pancreatic cancer, and one underwent separate treatments for two liver metastases. The surface imaging system monitored a three-dimensional surface with ± 3 mm translation and ± 3° rotation threshold. During delivery, a kilovolt image was automatically taken every 20° or 40° gantry rotation, and the internal marker was identified from the image. The displacement and residual motion of the markers were calculated. To analyze the treatment efficiency, the treatment time of each fraction was obtained from the imaging and treatment timestamps in the record and verify system.Although the external surface was monitored and limited to ± 3 mm and ± 3°, significant residual internal target movement was observed in some patients. The range of residual motion was 3-21 mm. The average displacement for this cohort was 0-3 mm. In 19% of the analyzed images, the magnitude of the instantaneous displacement was 5 mm. The mean treatment time was 17 min with a standard deviation of 4 min.Precaution is needed when applying surface image guidance for gastrointestinal cancer treatment. Using it as a solo DIBH technique is discouraged when the correlation between internal anatomy and patient surface is limited. Real-time radiographic verification is critical for safe treatments.

Radiation therapy (RT) for anorectal cancer after prior prostate cancer RT is usually avoided due to concern for complications. Data on this topic is scarce. Our aim was to evaluate tolerability, toxicity, and clinical outcomes associated with a second course of pelvic radiation in men withWe conducted a single-institution retrospective study of men treated with RT for rectal or anal cancer after prior prostate RT. Toxicity data were collected. Treatment plans were extracted to assess doses to organs at risk and target coverage. Cumulative incidence was calculated for local and distant progression. Kaplan-Meier curves were used to estimate overall survival (OS) and progression-free survival (PFS).We identified 26 patients who received anorectal RT after prostate cancer RT: 17 for rectal cancer and 9 for anal cancer. None had metastatic disease. Prior prostate RT was delivered using low dose rate brachytherapy (LDR), external beam RT (EBRT), or EBRT + LDR. RT for rectal cancer was delivered most commonly using 50.4Gy/28 fractions (fr) or 1.5 Gy twice-daily to 30-45 Gy. The most used RT dose for anal cancer was 50Gy/25 fr. Median interval between prostate and anorectal RT was 12.3 years (range:0.5 - 25.3). 65% and 89% of rectal and anal cancer patients received concurrent chemotherapy, respectively. There were no reported ≥Grade 4 acute toxicities. Two patients developed fistulae; one was urinary-cutaneous after prostate LDR and 45Gy/25fr for rectal cancer, and the other was recto-vesicular after prostate LDR and 50Gy/25fr for anal cancer. In 11 patients with available dosimetry, coverage for anorectal cancers was adequate. With a median follow up of 84.4 months, 5-yr local progression and OS were 30% and 31% for rectal cancer, and 35% and 49% for anal cancer patients, respectively.RT for anorectal cancer after prior prostate cancer RT is feasible but should be delivered with caution since it poses a risk of fistulae and possibly bleeding, especially in patients treated with prior LDR brachytherapy. Further studies, perhaps using proton therapy and/or rectal hydrogel spacers, are needed to further decrease toxicity and improve outcomes.

Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (18, 3–55) or ovarian (25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. Conclusions: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

10 Background: Interest in organ preservation (OP) strategies for rectal cancer (RC) patients persists. The efficacy of long course chemoradiation (LCRT) vs. short course radiation therapy (SCRT) relative to OP is unknown. We compared OP rates between SCRT and LCRT total neoadjuvant therapy (TNT) strategies. Methods: During the COVID-19 pandemic we established an institutional SCRT mandate with no exceptions. For comparison, we identified RC patients treated with LCRT immediately before and after the mandate period. After completion of TNT, patients were restaged by clinical exam, endoscopy, and MRI. A watch and wait (WW) approach was recommended for patients with a clinical complete response (cCR), defined by the MSK regression schema. Total mesorectal excision (TME) was recommended for non-cCR patients. OP was defined as alive, TME-free, and with no evidence of disease in the pelvis. We performed survival analysis for: local regrowth rate, OP, disease-free survival (DFS), and overall survival (OS). Results: We identified 563 consecutive patients with RC treated with TNT, of whom 231 were excluded due to either metastatic disease, synchronous/metachronous malignancies, or non-adenocarcinoma histology (Jan. 2018-Jan. 2021). Patient and tumor characteristics were similar in the LCRT (n = 256) and SCRT (n = 76) cohorts. No significant differences in high-risk features were noted. Most patients had clinical stage III disease (82% in LCRT vs. 83% in SCRT). Induction chemotherapy followed by consolidative radiation was the most common treatment order (78% (LCRT) vs. 70% (SCRT)). The median interval from end of TNT to clinical restaging was 8 weeks (LCRT) and 9 weeks (SCRT). The cCR rate was 46% in both cohorts. The cCR rate was numerically higher in patients treated with radiation first, as compared to chemotherapy first (53% vs. 44% (LCRT) and 52% vs. 43% (SCRT)). Among patients with a cCR, the likelihood of WW management was similar (98% (LCRT) vs. 94% (SCRT)). From start of TNT, the median follow-up was 32 and 28 months respectively for LCRT and SCRT. The 2-year OS (95% vs. 92%), DFS (78% vs 70%), and distant recurrence (20% vs. 21%) rates were similar. Among all patients, the 2-year OP rate was 40% (95% CI 35-47%) for LCRT and 29% (95% CI 20-42%) with SCRT. In those patients managed by WW, the 2-year local regrowth rate was 20% (95% CI 12-27%) with LCRT vs. 36% (95% CI 16-52%) with SCRT. Conclusions: In this nonrandomized comparison, while cCR rates were similar, we observed a numerically higher OP rate with LCRT-TNT than with SCRT-TNT. The ongoing ACO/ARO/AIO-18.1 trial, hypothesizing that LCRT-TNT will increase OP rates relative to SCRT-TNT, should definitively answer this question.

710 Background: For patients with localized but not immediately resectable pancreatic adenocarcinoma (PDAC), the role for local therapy remains undefined. Phase II MAIBE trial studied ablative radiation (A-RT) followed by consideration of surgery for patients with locally advanced pancreatic cancer (LAPC) who remain unresectable after induction chemotherapy. Methods: Participants with histologically confirmed PDAC judged unresectable by multidisciplinary review using NCCN definition after completing 3-6 months of mFOLFIRINOX (FFX) or Gemcitabine/Nab-paclitaxel (GN) were eligible. They received hypofractionated A-RT (either 67.5Gy in 15 fractions or 75Gy in 25 fractions based on anatomy) with concurrent capecitabine followed by consideration of resection within 1-3 months. Primary endpoints included resectability (80% power to detect resectability improvement from 15% in historical controls to 30% with α = 0.05) and overall survival (OS) from A-RT. Secondary endpoints included safety of surgical resection after ablative RT using 90-day Clavien-Dindo Classification of adverse events (AE). Results: Between 6/2018 and 4/2022, 47 eligible participants underwent A-RT. Median age was 67 (range, 50-80) years, 24 (51%) were male with a median tumor size of 3.95 (1.6 – 8.3) cm and CA19-9 of 92 ( < 1-1601) U/mL. Forty-four patients (94%) received at least 1 cycle of FFX with a median duration of chemotherapy (FFX or GN) of 3.5 months (1.0 – 9.4). Sixteen (34%) underwent a laparoscopy and 12 (26%) underwent a resection (Pancreaticoduodenectomy, N = 11; distal pancreatectomy, N = 1) at a median time of 3.2 months (1.9-16.9 months) from start of A-RT. The rate of resection satisfied our prespecified boundary of 11. R0 rate was 58.3%. Two-year OS from A-RT for the entire cohort was 38.9% (95% CI, 21.9 – 55.6%), including 37.1% (18.5 - 55.8%) in non-surgical and 39.4% (7.0- 72.1%) in surgical groups. There were no deaths within 90 days of surgery and 9 surgical AEs were recorded in 6 participants, including grade 1 (n = 1), grade 2 (n = 5), grade 3 (n = 2) and grade unknown (n = 1). Conclusions: In patients with LAPC and no metastatic disease after 3-6 months of chemotherapy, A-RT results in a favorable rate of resection without excess surgical toxicity. Promising 2-year OS rates were noted in both resected and non-resected patients. Clinical trial information: NCT03523312 .

1 Background: We hypothesized that circulating tumor DNA (ctDNA) clearance could provide an early signal for clinical complete response (cCR) and/ or long-term recurrence compared to standard clinical exam modalities in patients with anal squamous cell carcinoma (ASCC) undergoing definitive chemoradiation (CRT). Methods: Since early 2021 patients with ASCC undergoing CRT at 2 institutions were offered ctDNA monitoring with a commercially available tumor-bespoke multiplex PCR assay. All patients provided written informed consent for ctDNA testing. Patients were clinically restaged, 3-4 months post-CRT, by clinical exam, endoscopy, and/ or MRI and annually with CT chest, abdomen, and pelvis. cCR was defined as no tumor by digital exam, endoscopy and/or MRI. Molecular ctDNA response is described according to cCR, tumor recurrence, and survival. Results: From January 2021 to September 2022, 31 patients with ASCC treated with definitive CRT underwent ctDNA response assessment. The majority (68%) of patients had stage III disease. Patients were treated to a median radiation dose of 54Gy in 27 fractions with combinatorial mitomycin and fluoropyrimidine-based chemotherapy in 94%, and fluoropyrimidine-based chemotherapy alone in 6%. The median follow up was 22 weeks. ctDNA testing was performed in 25 of these patients at baseline, 26 patients during CRT, and 20 patients 30-days post-CRT. At baseline 88% of patients had detectable ctDNA. Patients with stage III, as compared to stage I-II, disease had numerically higher baseline ctDNA levels (26 vs 4 mean tumor molecules per milliliter (MTM/mL), p=0.08). ctDNA levels decreased with treatment (19 vs 0.9 MTM/mL, p=0.05) among the 18 patients with detectable ctDNA and ctDNA tested during CRT, with 50% of patients entering molecular remission. Similarly, ctDNA levels decreased (21 vs 0.2 MTM/mL, p=0.05) among the 16 patients with detectable ctDNA and ctDNA tested post-CRT, with 94% entering molecular remission. All patients in molecular remission were confirmed to have a cCR. Time to molecular ctDNA remission was significantly shorter than time to cCR (median 30 vs 135 days, p

725 Background: Immune checkpoint blockade (ICB) has a modest signal in the treatment of patients with genomically unselected pancreatic cancer (PDAC). Synergistic effects of combined radiotherapy and ICB are postulated. Preliminary results of a phase 1/2 trial of anti-PD-L1 antibody durvalumab (D) and SABR in locally advanced (LA) and borderline resectable PDAC (Tuli, AACR; 2019; Abstr B58), noted SABR and D to be safe and tolerable following induction chemotherapy. We sought to further evaluate the tolerability and efficacy of D and SABR, in LA PDAC. Methods: A single-arm, open-label phase 2 trial was conducted at Memorial Sloan Kettering (MSK). Key eligibility: histologically confirmed LA unresectable PDAC, with stable or responding disease following 4-6 months (m) of FOLFIRINOX (FFX), ECOG 0-2. Therapy: D and SABR; D dosed on day 1 750mg x 4 doses Q14 days, and subsequently 1500mg Q 28 days x 11 doses (1 year total), or until progression of disease (POD), or limiting toxicity. All patients received MRI adaptive ablative radiation, 50Gy in 5 fractions between doses 1 and 2 of D. Primary endpoint: 6-m progression free survival (6 m PFS) by RECIST v1.1. Secondary endpoints were Duration of Response, Overall Response Rate (ORR), CA 19-9 response, rates of downstaging/resection, and survival outcomes (overall survival (OS) and progression-free survival (PFS)) calculated from date of enrolment. OS and PFS were estimated using Kaplan-Meier method. Pre- and on-treatment tissue, blood and microbiome samples were collected to evaluate tumor-intrinsic and peripheral immunogenomic correlates of response. Results: Between 09/2020 and 05/2022, N = 18 enrolled. Median age 67.5 years (IQR; 62.5, 71.5), 28% (5/18) female. Baseline Performance Status: N = 8 (44%) ECOG 0; N = 10 (56%) ECOG 1. Tumor location: Head/uncinate N = 9 (50%), body N = 7 (39%), neck N = 2 (11%). Median # doses FFX prior to enrolment: 8.5 (IQR; 8.0- 11.0). At median follow-up of 13.8 m, 6-m PFS: 62% (95% CI 43%, 91%). Median PFS: 10.2 m (95% CI; 5.03, NA) and median OS 17.2 m (95% CI; 12.98, NA). Disease progression (any time) N = 12, of which local POD in N = 7 (58%). N = 3 completed maintenance D; N = 5 on active treatment. ORR: N = 17 (94.4%) stable disease (95% CI; 64.6%, 99.4%). Toxicity endpoints of special interest: Grade 3 ICB-related: in N = 4 patients; diarrhea N = 2; elevated AST/ALT N = 2; G3 lipase elevation N = 1; attribution uncertain. Conclusions: D and SABR following FFX in LA PDAC had an encouraging 6-m PFS of 62% (43-91%) and a tolerable safety profile. Immuno-genomic analyses of correlative biospecimens is underway. Funding support AstraZeneca. Clinical trial information: NCT03245541 .

Purpose Deep inspiration breath hold (DIBH) and respiratory gating (RG) are widely used to reduce movement of target and healthy organs caused by breathing during irradiation. We hypothesized that accuracy and efficiency comparable to DIBH can be achieved with RG for pancreas treatment. Methods and Materials Twenty consecutive patients with pancreatic cancer treated with DIBH (eight) or RG (twelve) volumetric modulated arc therapy during 2017–2019 were included in this study, with radiopaque markers implanted near or in the targets. Seventeen patients received 25 fractions, while the other three received 15 fractions. Only patients who could not tolerate DIBH received RG treatment. While both techniques relied on respiratory signals from external markers, internal target motions were monitored with kV X‐ray imaging during treatment. A 3‐mm external gating window was used for DIBH treatment; RG treatment was centered on end‐expiration with a duty cycle of 40%, corresponding to an external gating window of 2–3 mm. During dose delivery, kV images were automatically taken every 20◦ or 40◦ gantry rotation, from which internal markers were identified. The marker displacement from their initial positions and the residual motion amplitudes were calculated. For the analysis of treatment efficiency, the treatment time of every session was calculated from the motion management waveform files recorded at the treatment console. Results Within one fraction, the displacement was 0–5 mm for DIBH and 0–6 mm for RG. The average magnitude of displacement for each patient during the entire course of treatment ranged 0–3 mm for both techniques. No statistically significant difference in displacement or residual motion was observed between the two techniques. The average treatment time was 15 min for DIBH and 17 min for RG, with no statistical significance. Conclusions The accuracy and efficiency were comparable between RG and DIBH treatment for pancreas irradiation. RG is a feasible alternative strategy to DIBH.

We aimed to assess longitudinal changes in quantitative imaging metric values obtained from diffusion-weighted (DW-) and dynamic contrast-enhanced magnetic resonance imaging (DCE)-MRI at pre-treatment (TX[0]), immediately after the first fraction of stereotactic body radiotherapy (D1-TX[1]), and 6 weeks post-TX (Post-TX[2]) in patients with pancreatic ductal adenocarcinoma. Ten enrolled patients (n = 10) underwent DW- and DCE-MRI examinations on a 3.0 T scanner. The apparent diffusion coefficient, ADC (mm2/s), was derived from DW imaging data using a monoexponential model. The tissue relaxation rate, R1t, time-course data were fitted with a shutter-speed model, which provides estimates of the volume transfer constant, Ktrans (min−1), extravascular extracellular volume fraction, ve, and mean lifetime of intracellular water protons, τi (seconds). Wilcoxon rank-sum test compared the mean values, standard deviation, skewness, kurtosis, and relative percentage (r, %) changes (Δ) in ADC, Ktrans, ve, and τi values between the magnetic resonance examinations. rADCΔ2–0 values were significantly greater than rADCΔ1-0 values (P = .009). rKtransΔ2–0 values were significantly lower than rKtrans Δ1-0 values (P = .048). rveΔ2-1 and rveΔ2-0 values were significantly different (P = .016). rτiΔ2-1 values were significantly lower than rτiΔ2-0 values (P = .008). For group comparison, the pre-TX mean and kurtosis of ADC (P = .18 and P = .14), skewness and kurtosis of Ktrans values (P = .14 for both) showed a leaning toward significant difference between patients who experienced local control (n = 2) and failed early (n = 4). DW- and DCE-MRI-derived quantitative metrics could be useful biomarkers to evaluate longitudinal changes to stereotactic body radiotherapy in patients with pancreatic ductal adenocarcinoma.

Purpose: Pelvic radiation therapy (RT) is standard of care for patients with locally advanced rectal cancer (LARC). Premature ovarian insufficiency (POI) in premenopausal women is a possible side effect. The purpose of our study was to evaluate factors associated with POI in women younger than 50 years, treated with pelvic RT for LARC, including those who underwent ovarian transposition (OT). Methods and Materials: We retrospectively reviewed the records of women younger than 50 years treated with pelvic RT for LARC at our institution between 2001 and 2019. Clinical and hormonal data were used to determine ovarian function. The ovaries and uterus were contoured and dose volume histograms were generated. Association of clinical and dosimetric factors with POI within 12 months of RT was evaluated using Wilcoxon-rank sum test and Fisher's exact test. Results: We identified 76 premenopausal women at time of RT with median age of 43 years (range, 20-49). Twenty-six women (34%) underwent OT. Neoadjuvant, concurrent, and adjuvant chemotherapy was administered in 56 (74%), 69 (91%), and 26 (34%) women, respectively. Median RT dose was 50 Gy/25 fractions. Among 75 women with 12 months of follow-up, 25% had preservation of ovarian function, all in the OT group. Ovarian function was preserved in 19 (76%) women who underwent OT. The median of ovarian mean dose was 1.7 Gy in the OT group versus 44.8 Gy in the non-OT group (P < .001). OT and age at RT were significantly associated with POI (P < .001). No patient with ovarian mean dose less than 1.36 Gy developed POI. Conclusions: OT was significantly associated with reduced risk of POI by enabling lower radiation doses to the ovaries. OT should be considered in young patients undergoing pelvic RT. Although there appears to be a significant association between ovarian mean dose and POI, larger studies are needed to find a dosimetric threshold. Our results suggest keeping the dose to the ovaries as low as reasonably achievable in patients who undergo OT and pelvic RT.

Background Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. Materials and methods This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. Results Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. Conclusion Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. Implications for practice Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

PURPOSE A circulating tumor DNA (ctDNA) test to detect plasma Epstein-Barr viral DNA can be used to screen for early nasopharyngeal cancers; however, the reported sensitivity of viral ctDNA tests to detect human papillomavirus (HPV)–associated cancers is modest. We assessed the utility of droplet digital polymerase chain reaction (ddPCR) to detect early-stage HPV-associated cancers using sequential HPV16 and HPV33 assays that account for HPV subtype distribution and subtype sequence variants. PATIENTS AND METHODS We collected plasma specimens from 97 HPV-positive patients with oropharyngeal squamous cell carcinoma and eight patients with HPV-positive anal squamous cell carcinoma, each with locoregionally confined disease. Negative controls included samples from seven patients with HPV-negative head and neck cancers and 20 individuals without cancer. RESULTS Of 97 patients with nonmetastatic, locoregionally confined oropharyngeal squamous cell carcinoma, 90 patients had detectable HPV16 ctDNA and three patients had HPV33 ctDNA, indicating an overall sensitivity of 95.6%. Seven of eight patients with early anal cancer were HPV16 ctDNA positive. No HPV ctDNA was detected in 27 negative controls, indicating 100% specificity. HPV16 ctDNA was detected in 19 of 19 patients with low-volume disease, defined as patients with a single, asymptomatic positive lymph node (N1) or an isolated T1-2 asymptomatic primary tumor. HPV16 ctDNA levels directly corresponded to tumor responses to chemoradiation and surgery. CONCLUSION With an updated understanding of HPV subtypes and sequence variation, HPV ctDNA by ddPCR is highly sensitive and specific, identifying HPV16 and HPV33 subtypes in a similar distribution as reported in major genomic profiling studies. The detection of small tumors indicates that HPV16 and HPV33 ctDNA ddPCR could be readily used in early detection screening trials and in disease response monitoring, analogous to Epstein-Barr virus DNA.

The present study aims to monitor longitudinal changes in simulated tumor interstitial fluid pressure (IFP) and velocity (IFV) values using dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) in pancreatic ductal adenocarcinoma (PDAC) patients. Nine PDAC patients underwent MRI, including DCE-MRI, on a 3-Tesla MRI scanner at pre-treatment (TX (0)), after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation, incorporating the Starling Principle of fluid exchange, Darcy velocity, and volume transfer constant (Ktrans), was solved in COMSOL Multiphysics software to generate IFP and IFV maps. Tumor volume (Vt), Ktrans, IFP, and IFV values were compared (Wilcoxon and Spearman) between the time- points. D2-TX Ktrans values were significantly different from pre-TX and D1-TX (p &lt, 0.05). The D1-TX and pre-TX mean IFV values exhibited a borderline significant difference (p = 0.08). The IFP values varying &lt, 3.0% between the three time-points were not significantly different (p &gt, 0.05). Vt and IFP values were strongly positively correlated at pre-TX (r = 0.90, p = 0.005), while IFV exhibited a strong negative correlation at D1-TX (r = −0.74, p = 0.045). Vt, Ktrans, IFP, and IFV hold promise as imaging biomarkers of early response to therapy in PDAC.

BACKGROUND: More than 70% of patients with hepatocellular carcinoma (HCC) are not candidates for curative therapy or recur after curative-intent therapy. There is growing evidence on the use of ablative radiation therapy (RT) for liver tumors. We aimed to analyze outcomes of HCC patients treated with conventional versus ablative RT. METHODS: We retrospectively analyzed medical records of HCC patients treated with liver RT from 2001 to 2019. We defined ablative RT as biologically effective dose (BED) ≥80 Gy. RECIST 1.1 was used to define early responses at 3–6 months after RT, and local control (LC) at last follow-up (FU). Data was analyzed using Fisher exact test, Kaplan-Meier, cumulative incidence rates, Cox proportional hazards model and Fine-Gray competing risks. RESULTS: Forty-five patients were identified, of whom 14 (31.1%) received ablative RT using a stereotactic technique. With median FU of survivors of 10.1 months, 1-year cumulative incidence of LC was 91.7% for ablative and 75.2% for BED

Standard doses of conventionally fractionated radiation have had minimal to no impact on the survival duration of patients with locally advanced unresectable pancreatic cancer (LAPC). The use of low-dose stereotactic body radiation (SBRT) in 3- to 5-fractionshas thus far produced a modest improvement in median survival with minimal toxicity and shorter duration of treatment, but failed to produce a meaningful difference at 2 years and beyond. A much higher biologically effective dose (BED) is likely needed to achieve tumor ablation The challenge is the delivery of ablative doses near the very sensitive gastrointestinal tract. Advanced organ motion management, image guidance, and adaptive planning techniques enable delivery of ablative doses of radiation (> = 100Gy BED) when more protracted hypofractionated regimens or advanced image guidance and adaptive planning are used. This approach has resulted in encouraging improvements in survival in several studies. This review will summarize the evolution of the radiation technique over time from conventional to ablative and describe the practical aspects of delivering ablative doses near the GI tract using cone beam CT image (CBCT) guidance and online adaptive MRI guidance.

Purpose Multibeam intensity modulated radiation therapy (IMRT) enhances the therapeutic index by increasing the dosimetric coverage of the targeted tumor tissues while minimizing volumes of adjacent organs receiving high doses of RT. The tradeoff is that a greater volume of lung is exposed to low doses of RT, raising concern about the risk of radiation pneumonitis (RP). Methods and Materials Between July 2010 and January 2013, patients with node-positive breast cancer received inverse-planned, multibeam IMRT to the breast or chest wall and regional nodes, including the internal mammary nodes (IMNs). The primary endpoint was feasibility, predefined by dosimetric treatment planning criteria. Secondary endpoints included the incidence of RP grade 3 or greater and changes in pulmonary function measured with the Common Terminology Criteria for Adverse Events version 3.0 scales, pulmonary function tests and community-acquired pneumonia questionnaires, obtained at baseline and 6 months after IMRT. Clinical follow-up was every 6 months for up to 5 years. Results Median follow-up was 53.4 months (range, 0-82 months). Of 113 patients enrolled, 104 completed follow-up procedures. Coverage of the breast or chest wall and IMN was comprehensive (median 48.1 Gy and 48.9 Gy, respectively). The median volume of lung receiving a high dose (V20Gy) and a low dose (V5) was 29% and 100%, respectively. The overall rate of respiratory toxicities was 10.6% (11/104), including 1 grade 3 RP event (0.96%). No differences were found in pulmonary function test or community-acquired pneumonia scores after IMRT. The 5-year rates of locoregional recurrence-free, disease-free, and overall survival were 93.2%, 63.6%, and 80.3%, respectively. Conclusions Multibeam IMRT in patients with breast cancer receiving regional nodal irradiation was dosimetrically feasible, based on early treatment planning criteria. Despite the large volume of lung receiving low-dose RT, the incidence of grade 3 RP was remarkably low, justifying inverse-planned IMRT as a treatment modality for patients with high-risk breast cancer in whom conventional RT techniques prove inadequate.

Purpose Beam gating with deep inspiration breath hold (DIBH) has been widely used for motion management in radiotherapy. Normally it relies on some external surrogate for estimating the internal target motion, while the exact internal motion is unknown. In this study, we used the intrafraction motion review (IMR) application to directly track an internal target and characterized the residual motion during DIBH treatment for pancreatic cancer patients through their full treatment courses. Methods and Materials Eight patients with pancreatic cancer treated with DIBH volumetric modulated arc therapy in 2017 and 2018 were selected for this study, each with some radiopaque markers (fiducial or surgical clips) implanted near or inside the target. The Varian Real‐time Position Management (RPM) system was used to monitor the breath hold, represented by the anterior‐posterior displacement of an external surrogate, namely reflective markers mounted on a plastic block placed on the patient's abdomen. Before each treatment, a cone beam computed tomography (CBCT) scan under DIBH was acquired for patient setup. For scan and treatment, the breath hold reported by RPM had to lie within a 3 mm window. IMR kV images were taken every 20° or 40° gantry rotation during dose delivery, resulting in over 5000 images for the cohort. The internal markers were manually identified in the IMR images. The residual motion amplitudes of the markers as well as the displacement from their initial positions located in the setup CBCT images were analyzed. Results Even though the external markers indicated that the respiratory motion was within 3 mm in DIBH treatment, significant residual internal target motion was observed for some patients. The range of average motion was from 3.4 to 7.9 mm, with standard deviation ranging from 1.2 to 3.5 mm. For all patients, the target residual motions seemed to be random with mean positions around their initial setup positions. Therefore, the absolute target displacement relative to the initial position was small during DIBH treatment, with the mean and the standard deviation 0.6 and 2.9 mm, respectively. Conclusions Internal target motion may differ from external surrogate motion in DIBH treatment. Radiographic verification of target position at the beginning and during each fraction is necessary for precise RT delivery. IMR can serve as a useful tool to directly monitor the internal target motion.

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

Purpose/Objective(s) This prospective multi-institutional study aimed to determine the safety and maximally tolerated dose of 3-fraction stereotactic body radiotherapy (SBRT) for locally advanced pancreatic cancer (LAPC). Materials/Methods Patients with localized, histologically confirmed pancreatic adenocarcinoma deemed unresectable on radiographic multidisciplinary review without distant progression following induction chemotherapy for at least 2 months were eligible. Patients received 3-fraction LINAC-based SBRT at 3 dose levels, 27Gy, 30Gy and 33Gy following a modified 3+3 design, allowing for enrollment of additional patients at the last dose level during the 90-day observation period, provided no dose-limiting toxicities (DLTs) were observed. DLTs were defined as ≥ Grade 3 treatment-related GI toxicity within 90 days of RT as scored by CTCAE v.4. The secondary endpoints were overall survival (OS), local progression-free and distant metastasis-free survival (LPFS and DMFS, respectively), treatment-related toxicity and quality of life. Results Between 3/2016 and 4/2019, 23 consecutive evaluable LAPC patients were enrolled at two academic hospitals (14 and 9 patients, respectively), including 8 patients at 27Gy, 8 patients at 30Gy and 7 patients at 33Gy. The median age was 67 years (range 52 - 79 years), 9 patients (39%) were male, all were stage III, 12 (52%) had a head/uncinate tumor location, with a median tumor size of 3.5cm (range, 1.0 - 6.4cm) and a median CA19-9 of 60U/mL (range, Conclusion For select LAPC patients, dose escalation to the target dose of 33Gy in 3 fractions resulted in no DLTs and disease outcomes comparable to conventional RT. These results warrant further exploration of hypofractionated SBRT schemes to maximize tumor control while enabling efficient integration of RT with systemic therapy for more expedient treatment options for these high-risk LAPC patients.

Purpose/objective(s) RT for rectal and anal cancer after prostate cancer RT is usually avoided due to fear of complications, and data on this topic is scarce. Our aim was to evaluate outcomes and toxicity associated with RT in this group of patients. Materials/methods We conducted a single institution retrospective study of patients treated with RT for rectal or anal cancer after prior prostate RT from 1/1/1995 - 8/1/2019. Acute and long-term toxicities were collected. Treatment plans were extracted to assess doses to organs at risk and target coverage. Wilcoxon rank sum test was used for correlation between dosimetry and toxicities. Estimated cumulative incidence was used for local progression. Results We identified 29 patients who received RT after prostate cancer RT, 19 with rectal cancer and 10 with anal cancer. None of those patients had metastatic disease. Prior prostate RT was delivered using low dose rate brachytherapy (LDR) in 15/29 patients with a median dose of 145 Gy (144-160), external beam RT (EBRT) in 10 patients with 79.2Gy/44 or 81Gy/45 fractions (fr), and EBRT + LDR in 4 patients with 50.4/28 + 80-110 Gy I-125 or Pd-103 LDR. RT for rectal cancer was delivered most commonly with 50.4Gy/28 fr or 1.5 Gy twice daily fractionation to 30-45 Gy (53% of patients). The most commonly used RT dose for anal cancer was 50Gy/25 fr. Brachytherapy was used in 6 (21%) patients: as a boost after EBRT in 2 patients with anal cancer and alone in 4 rectal cancer patients. Median interval between prostate and anorectal RT was 134 months (6-303). 68% and 80% of rectal and anal cancer patients got concurrent chemotherapy. Table 1 summarizes toxicities associated with anorectal re-RT. Two patients developed fistulas, one was urinary cutaneous after prostate LDR and 45Gy/25fr for rectal cancer, and the other recto vesicular after prostate LDR and 50Gy/25fr for anal cancer; both repaired by extensive surgery. Both patients had more than 10 years between the two RT courses. In 21 patients with available dosimetry, coverage was adequate with a GTV V100% of 98% for rectal cancer patients and 96% for anal cancer patients. There was no significant correlation between toxicities and dosimetric values probably due to the small sample size. The estimated 5-year local progression incidence for all patients was 22%: 11% for rectal cancer, and 4% for anal cancer patients. Conclusion RT of anorectal cancer after prior prostate cancer RT is feasible but poses a risk of fistulae. Further studies, possibly using proton therapy and/or rectal hydrogel spacers, are needed to further establish the feasibility of RT in this context, decrease toxicity, and improve outcomes.

Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012–2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0–20 vs 21–40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1–4 vs 5–8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score–matched. After matching, median OS was 26.2 months (95% CI, 24.0–38.4) with RT versus 32.8 months (95% CI, 25.3–42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

PURPOSE Accurate deformable registration between computed tomography (CT) and cone-beam CT (CBCT) images of pancreatic cancer patients treated with high biologically effective radiation doses is essential to assess changes in organ-at-risk (OAR) locations and shapes and to compute delivered dose. This study describes the development and evaluation of a deep-learning (DL) registration model to predict OAR segmentations on the CBCT derived from segmentations on the planning CT. METHODS The DL model is trained with CT-CBCT image pairs of the same patient, on which OAR segmentations of the small bowel, stomach, and duodenum have been manually drawn. A transformation map is obtained, which serves to warp the CT image and segmentations. In addition to a regularity loss and an image similarity loss, an OAR segmentation similarity loss is also used during training, which penalizes the mismatch between warped CT segmentations and manually drawn CBCT segmentations. At test time, CBCT segmentations are not required as they are instead obtained from the warped CT segmentations. In an IRB-approved retrospective study, a dataset consisting of 40 patients, each with one planning CT and two CBCT scans, was used in a fivefold cross-validation to train and evaluate the model, using physician-drawn segmentations as reference. Images were preprocessed to remove gas pockets. Network performance was compared to two intensity-based deformable registration algorithms (large deformation diffeomorphic metric mapping [LDDMM] and multimodality free-form [MMFF]) as baseline. Evaluated metrics were Dice similarity coefficient (DSC), change in OAR volume within a volume of interest (enclosing the low-dose PTV plus 1 cm margin) from planning CT to CBCT, and maximum dose to 5 cm3 of the OAR [D(5cc)]. RESULTS Processing time for one CT-CBCT registration with the DL model at test time was less than 5 seconds on a GPU-based system, compared to an average of 30 minutes for LDDMM optimization. For both small bowel and stomach/duodenum, the DL model yielded larger median DSC and smaller interquartile variation than either MMFF (paired t-test P

552 Background: Dose escalated radiation therapy for localized pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes (Reyngold, JAMA Onc, 2021). Overall survival (OS) and loco-regional failure (LRF) rates with ablative radiation therapy (A-RT) in unresectable PDAC approach those of surgery. Herein, we report outcomes of A-RT as loco-regional salvage after resection. Methods: A prospective database (2016 onward) has been maintained of all patients receiving A-RT at for PDAC. A-RT is defined as a biologically effective dose (BED) ≥96 Gy (α/β = 10). We analyzed consecutive patients from June 2016 through January 2021 who received A-RT for isolated loco-regional recurrences after resection. Survival was calculated using the Kaplan-Meier method. Results: Sixty-nine patients (40 men, 29 women) with median age of 67 received A-RT for loco-regionally recurrent PDAC. At diagnosis of recurrence, median disease-free interval from time of initial resection was 15.6 months (range 6.2–82.7) and median CA 19-9 was 65 U/mL (range < 1–1087). Twenty-one patients (30%) received neoadjuvant chemotherapy prior to surgery: pancreaticoduodenectomy (57 patients, 83%) or distal pancreatectomy (12 patients, 17%). There was a negative resection margin in 55 patients (80%). Most had T1/T2 (61 patients, 88%) and node-positive disease (44 patients, 64%). Radiation fractionation ranged from 5-25 fractions (median 25) to a total dose of 50-75 Gy (median 75). Median follow up was 16.2 months from RT. Median OS was 26.5 months from diagnosis of recurrence and 20.7 months from time of salvage A-RT. Twelve- and 24-month OS were 78.5% (95% CI 66.3–86.7) and 40.3% (25.8–54.3), respectively. In-field local failure was 8.5% (0.3–36.0) at 12 months and 27.5% (5.2–57.0) at 24 months. Respective disease-free survival at 12 and 24 months were 32.9% (21.7–44.1) and 12.3% (5.7–21.6). Grade 3 or greater gastrointestinal bleeding (GIB) occurred in 7 patients (10%), including one grade 4 event while on anticoagulation and one grade 5 event in a patient with portal hypertension. Conclusions: A-RT achieves favorable OS and LRF outcomes in patients with PDAC and an isolated loco-regional recurrence after surgical resection.

613 Background: The optimal dose and fractionation scheme for stereotactic body radiotherapy (SBRT) is unknown. The biologic effects of ultra-high doses per fraction (>8Gy) are theoretical, but may include eliciting an effect on the endothelial cells of the tumor vasculature which could improve treatment response. This study aimed to determine the safety and maximally tolerated dose of 3-fraction SBRT for locally advanced pancreatic cancer (LAPC). Methods: A multi-site phase 1 dose escalation trial was conducted from March 2016 to April 2019 at Memorial Sloan Kettering Cancer Center (NCT02643498) and University of Colorado (NCT02873598). Patients with localized histologically confirmed pancreatic adenocarcinoma deemed unresectable on multidisciplinary review without distant progression following induction chemotherapy for ≥ 2 months were eligible. Patients received 3-fraction LINAC-based SBRT at 3 dose levels, 27Gy, 30Gy and 33Gy following a modified 3+3 design, allowing for enrollment of additional patients at the last dose level during the 90-day observation period, provided no dose-limiting toxicities (DLTs) were observed. DLTs were defined as ≥ Grade 3 treatment-related GI toxicity within 90 days of RT by CTCAE v.4. The secondary endpoints were overall survival (OS), local progression-free and distant metastasis-free survival (LPFS and DMFS, respectively). Univariate analysis using log-rank test was performed to identify factors associated with OS. Results: Twenty-three evaluable patients were enrolled, including 8 patients at 27Gy, 8 patients at 30Gy and 7 patients at 33Gy. The median age was 67 years (range 52 - 79), 9 patients (39%) were male, all were stage IIIwith a median tumor size of 3.5cm (range, 1.0 - 6.4) and CA19-9 of 60U/mL (range, 60U/mL were 80% vs 27% (p=0.0023). Conclusions: For select LAPC patients, dose escalation to the target dose of 33Gy in 3 fractions resulted in no DLTs and disease outcomes comparable to conventional RT. Lower pre-SBRT CA19-9 values were associated with improved OS and could help identify patients most likely to benefit from local therapies. Continued exploration of (ultra)hypofractionated schemes to maximize tumor control while enabling efficient integration of RT with systemic therapy is warranted. Clinical trial information: NCT02643498/NCT02873598.

For positioning a moving target, a maximum intensity projection (MIP) or average intensity projection (AIP) image derived from 4DCT is often used as the reference image which is matched to free breathing cone-beam CT (FBCBCT) before treatment. This method can be highly accurate if the respiratory motion of the patient is stable. However, a patient’s breathing pattern is often irregular. The purpose of this study is to investigate the effects of irregular respiration on positioning accuracy for a moving target aligned with FBCBCT. Nine patients’ respiratory motion curves were selected to drive a Quasar motion phantom with one embedded cubic and two spherical targets. A 4DCT of the phantom was acquired on a CT scanner (Philips Brilliance 16) equipped with a Varian RPM system. The phase binned 4DCT images and the corresponding MIP and AIP images were transferred into Eclipse for analysis. FBCBCTs of the phantom driven by the same respiratory curves were also acquired on a Varian TrueBeam and fused such that both CBCT and MIP/AIP images share the same target zero positions. The sphere and cube volumes and centroid differences (alignment error) determined by MIP, AIP and FBCBCT images were calculated, respectively. Compared to the volume determined by MIP, the volumes of the cube, large sphere, and small sphere in AIP and FBCBCT images were smaller. The alignment errors for the cube, large sphere and small sphere with center to center matches between MIP and FBCBCT were 2.5 ± 1.8 mm, 2.4 ± 2.1 mm, and 3.8 ± 2.8 mm, and the alignment errors between AIP and FBCBCT were 0.5 ± 1.1 mm, 0.3 ± 0.8 mm, and 1.8 ± 2.0 mm, respectively. AIP images appear to be superior reference images to MIP images. However, irregular respiratory pattern could compromise the positioning accuracy, especially for smaller targets.

PURPOSE/OBJECTIVE(S) To report on our early experience of treating patients with pancreas ductal adenocarcinoma (PDAC) with ablative SBRT (50 Gy in 5 fractions) on the Elekta Unity MR-Linac. MATERIALS/METHODS Ten PDAC patients were treated with abdominal compression (AC) and daily online plan adaptation using Adapt-to-Shape (ATS) workflow. AC is the method of choice to reduce breathing motion since automatic breath-hold/gating or other motion management options are not yet available on Unity MR-Linac. Three tumors were located in the head of the pancreas and seven were in the body. Seven patients were considered inoperable per surgeon and six were node positive. Average GTV volume during simulation was 42.5 ± 24.8 cc. Three orthogonal plane cine MRI were acquired to assess AC belt pressure during MR simulation as well as during each treatment fraction to assess stability of AC in minimizing tumor motion. Three sets of 3D T2w MR scans, pre-treatment (MRIpre), verification (MRIver) and post-treatment (MRIpost) MRI, were acquired for online planning. To assess the dosimetric impact of intrafraction organ motion, a post-treatment quality assurance (QA) was performed before the next fraction by propagating pre-treatment plan and structures to both MRIver and MRIpost, editing the contours and recalculating dose. GTV coverage and selected organs-at-risk (OAR) dose constraints (e.g., < 33 Gy to 0.035 cc, < 25 Gy to 2 cc and < 25 Gy to 5cc volume) were evaluated on MRIver and MRIpost. RESULTS Median total treatment time was 75.5(49-132) minutes. Average contouring, planning, physics QA and beam-on time was 25.1 ± 11.9, 12.2 ± 6.0, 1.9 ± 1.5 and 14.1 ± 3.7 mins respectively. Average AP, LR and SI motion in FB and with compression was 0.3 ± 0.1, 0.6 ± 0.2 and 0.7 ± 0.2 and 0.2 ± 0.1, 0.2 ± 0.1, 0.4 ± 0.1 cm respectively, indicating that compression belt was effective in minimizing patient breathing motion. Average tumor motion in AC belt for all fractions was 0.2 ± 0.1, 0.2 ± 0.1 and 0.4 ± 0.2 cm in AP, LR and SI direction. Median GTV coverage was 78.7% of Rx dose for all fractions. Average GTV Dmax and GTV mean dose for all the fractions was 57.4 ± 0.7 and 51.2 ± 1.6 Gy respectively. Average 0.035 cc, D2cc and D5cc stomach dose was 34.4 ± 5.4, 26.7 ± 2.9 and 24.3 ± 2.1 Gy on MRIver and 35.3 ± 6.2, 27.0 ± 3.3 and 24.6 ± 2.5 Gy on MRIpost. Average 0.035 cc, D2cc and D5cc small bowel dose was 35.1 ± 6.3, 27.1 ± 3.6 and 24.4 ± 2.6 Gy on MRIver and 35.5 ± 6.5, 27.3 ± 3.9 and 24.6 ± 2.5 Gy on MRIpost. CONCLUSION MR-guided adaptive RT enables delivery of curative dose to pancreatic tumors by taking into account interfraction motion of gastrointestinal OARs in daily adaptive planning. To manage intrafraction motion in our current clinical workflow, the organ motion is assessed for first two fractions and conservative strategies (e.g., bigger PRV margins or change the directive to keep stomach 0.035 cc dose to < 30 Gy) are employed for later fractions. ATS workflow with AC and the post-treatment QA allow safe delivery of ablative radiation doses for selected cases of PDAC on Unity MR-Linac. AUTHOR DISCLOSURE N. Tyagi: Honoraria; Elekta. Travel Expenses; Elekta; ISMRM.J. Liang: None. S. Burleson: None. E. Subashi: None. P. Godoy Scripes: None. K.R. Tringale: None. P.B. Romesser: Travel Expenses; Elekta. M. Reyngold: None. C.H. Crane: Honoraria; Elekta. Travel Expenses; Elekta.