Non-metastatic Pancreatic Ductal Adenocarcinoma Research Articles

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

Abstract 7615: Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida-positive pancreatic ductal adenocarcinoma

Abstract Candida are commonly found in bile collected during surgery in pancreatic ductal adenocarcinoma (PDAC) patients. However, their significance in tumor biology and oncological outcome is unclear. PDAC patients receiving neoadjuvant therapy and pancreatectomy with intraoperative bile fungal culture were identified (N=40) in a prospective single-institution cohort. Tumor regression scores (TRS) were abstracted from pathology reports and correlated with bile fungal cultures. Bulk tumor RNASeq data were obtained from the Oncology Research Information Exchange Network (ORIEN). Tumor microbiome data of non-metastatic PDAC patients with upfront surgery were extracted using the {exotic} tool (Hoyd et al. Cancer Res. Commun., 2023). Gene expression profiles were compared between Candida+ and Candida- tumors, defined by a cutoff microbial count of 0. Overall survival (OS) of resected PDAC patients with Candida+ and Candida- tumors was compared using Kaplan Meier survival analysis. From the single-institution PDAC cohort, Candida+ bile was associated with poor pathological response to neoadjuvant therapy (Table 1). Using the ORIEN cohort, Candida were detected in 67% (106/158) of the PDAC tumors. Patients with Candida+ tumors had worse OS (median 28 vs. 56 months, Log-Rank p&amp;lt;0.008). Gene Set Enrichment Analysis (GSEA) using Hallmark gene sets showed an enrichment of epithelial-mesenchymal-transition (EMT) gene set and a reduction of metabolic and DNA repair gene sets in Candida+ tumors. GSEA for Immune signature and Tumor Immune Microenvironment Deconvolution (TIMEx) cell types showed an enrichment of Stromal-Fibroblast and EMT signature in Candida+ tumors. Further investigations are underway to determine the causal and metabolic relationship between Candida and this tumor microenvironment with EMT and stromal fibroblasts which is a well-known contributor to poor chemotherapy response and oncological outcome of PDAC. Table 1: Pathological Response to Neoadjuvant Therapy for PDAC Bile Culture TRS0/1 TRS2 TRS3 Candida - 5 (25%) 15 (75%) 0 (0%) Candida + 1 (5%) 11 (55%) 8 (40%) TRS: Tumor Regression Score (TRS0: complete response; TRS1: near-complete response; TRS2: partial response; TRS3: no response). Chi-Square Test, P=0.0035. Citation Format: Po Hien Ear, Min Hu, Jonathan S. Shilyansky, Naomi H. Fei, Sam Coleman, Rebecca Hoyd, Caroline E. Wheeler, Kelsey L. Steckly, Michelle L. Churchman, Nicholas Denko, Rebecca D. Dodd, Sheetal Hardikar, Ning Jin, Qin Ma, Martin D. McCarter, Abdul Rafeh Naqash, Afaf E. Osman, Gregory Riedlinger, Lary A. Robinson, Bryan P. Schneider, Eric A. Singer, Ahmad A. Tarhini, Gabriel Tinoco, Cornelia M. Ulrich, Yousef Zakharia, Daniel Spakowicz, Aik Choon Tan, Carlos H. Chan. Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida-positive pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7615.

Abstract 2393: Development of a novel implantable drug-eluting product for the local treatment of pancreatic adenocarcinoma

Abstract Background Local control of non-metastatic pancreatic ductal adenocarcinoma (PDAC) remains a major challenge. Therapies with reduced systemic toxicity are needed as intravenous (IV) infusions are limited by patient tolerance with only small amounts reaching the tumor. PanTher created PTM-101, a novel absorbable drug formulation containing paclitaxel, designed to be locally applied via minimally invasive surgery to provide chemotherapy precisely to the peritumoral area in PDAC. Methods A study was conducted using 3 cadaveric abdomens to evaluate surgical feasibility of delivering PTM-101 via laparoscopy. Prior to insertion of PTM-101 into the peritoneum, the surgeons prepared each product by suturing a 3-0 Vicryl SH (Ethicon) at four evenly spaced locations around the edge of the flat circular product. A periumbilical 10mm Hasson port was placed to insufflate the abdomen, followed by placement of 3 additional working ports (5mm). The liver capsule was carefully surveyed to exclude metastatic disease. The surgeons opened a window into the lesser sac through the greater omentum, lifting the stomach up from the transverse colon to expose the pancreas. PTM-101 (a 1mm thick and 6cm diameter film) was rolled into a tubular shape, inserted through the cannula, and affixed to the peri-pancreatic fat with existing vicryl stitches. Results The estimated total operative time from placement of the first trocar to removal of all equipment was 45 minutes, for the 3 procedures. The operations included 25 minutes for entry, port placement, exposure of the simulated pancreatic tumor location and 20 minutes to place and suture PTM-101. PTM-101 was easy to fit through the cannula and was sutured without difficulty to the peri-pancreatic fat that surrounds the capsule of the pancreas. To simulate a tumor with hepatic artery involvement, the implant was sutured towards the hepatoduodenal ligament in one specimen, near the area of the gastroduodenal artery takeoff, proper hepatic artery, and proximal portal vein. PTM-101 covered the entire head/neck area of the simulated tumor locations without requiring disruption of the tumor area or dissection of the tunnel under the pancreatic neck. Conclusion PTM-101 is flexible and conforms easily to the underlying topography, both in a concave (i.e., with the tumor intact) and convex (i.e., after resection) scenario. Although human anatomy does not allow for PTM-101 to completely wrap around the pancreas, the size and flexibility of the product enables it to “drape” over the edges covering areas near the superior mesenteric vein and artery (SMV/SMA). This placement could hypothetically increase the amount of drug reaching the area behind the pancreas to target tumors which abut or encase the mesoportal vasculature. A decrease in the tumor-vessel interface could downsize pancreatic tumors, with the goal of increasing resection rates and post-resection local control. Citation Format: Margaret Lashof-Sullivan, Leslie S. Sloan, Michael P. Kim, Laura Indolfi, Ching-Wei D. Tzeng. Development of a novel implantable drug-eluting product for the local treatment of pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2393.

KRAS mutation status in the prediction of pancreatic tumor response after neoadjuvant systemic therapy and magnetic resonance-guided SBRT.

709 Background: Stereotactic body radiotherapy (SBRT) has been incorporated into multi-modality treatment of locally advanced and borderline resectable pancreatic ductal adenocarcinoma (PDAC). For non-metastatic inoperable PDAC patients (pts) who receive magnetic resonance-guided SBRT (MRgSBRT), baseline features that predict for treatment response remain unsettled. In localized PDAC, multiple studies have investigated the KRAS oncogene as a prognostic factor with mixed findings. In this single institution retrospective study of PDAC pts treated with MRgSBRT, we hypothesized that KRAS mutation status would be predictive of meaningful clinical outcomes. Methods: From an IRB approved dataset of PDAC pts treated with MRgSBRT between 2016 and 2022, 39 pts with non-metastatic inoperable pancreatic cancer, known KRAS mutation status, ≥ 3 months of neoadjuvant systemic therapy (NST), and at least 3 months post-RT follow up were extracted for analysis. Baseline demographics, tumor and treatment characteristics, and clinical endpoints including conversion to resectability, best imaging response per RECIST v1.1, pathologic response (PR) per TRG-CAP, and overall survival (OS) after MRgSBRT were collected. Objective response (ORR) on both imaging and pathology was defined as complete response (CR) + partial response (PR); disease control (DC) was defined as CR + PR + stable disease (SD). Logistic regression was used to assess correlation between baseline variables and ORR. Cox proportional hazard models were utilized to determine association with OS. Results: Out of 39 pts, 21 (53%) were KRAS-mutated (KRAS-mt) and 18 (47%) were KRAS wild-type (KRAS-wt). Median age was 62, 54% were male, only 1 pt had ECOG &gt; 1, and CA 19-9 at diagnosis was 197. Median duration of NST was 9 cycles, and common agents included Gemcitabine and Abraxane (21%); FOLFIRINOX (28%); a combination of the two regimens (41%); or other NSTs (10%). Median MRgSBRT dose fractionation was 50 Gy (range 35 – 50) in 5 fractions; all fractions underwent adaptive optimization. Thirty pts (77%) experienced DC on imaging, 16 (43%) had ORR, and 12 (31%) were converted to resectable following MRgSBRT. Cohort median OS was 12.3 months, and pts who had surgery had a non-significant median OS advantage (18 vs 12 months; p=0.19). KRAS-mt was associated with worse ORR (p=0.04; AUC=0.73) and decreased OS (HR: 2.15; p=0.03). In a clinical model incorporating baseline characteristics (age, ECOG, radiographic staging, CA 19-9 level, and KRAS), only KRAS predicted OS (HR: 3.02 for KRAS-mt; p=0.01). KRAS-mt status was also predictive of OS among pts who underwent surgery (HR: 5.24 for KRAS-mt; p=0.04). Conclusions: For localized PDAC pts inoperable at diagnosis who received NST followed by MRgSBRT, KRAS was the only significant predictor of ORR and OS, highlighting the need for further treatment intensification in KRAS-mt pts.

Neoadjuvant chemotherapy vs upfront resection: A challenging choice in resectable pancreatic ductal adenocarcinoma.

620 Background: Pancreatic ductal adenocarcinoma (PDAC) remains an immense challenge within oncology, with only 15-20% of cases initially qualifying as resectable. Based on National Cancer Database analyses there is an increase in neoadjuvant chemotherapy (NACT) use, with potential downstaging effects. Yet, a subset of neoadjuvant-treated patients fail to proceed with curative-intent surgery, leading to worse outcomes. This retrospective analysis aims to uncover factors that predict NACT use and the impact on survival outcomes. Methods: A cohort of 543 consecutive non-metastatic PDAC patients treated at an NCCN-designated comprehensive cancer center between 2015 and 2022 were prospectively enrolled into a REDCap database. Based on NCCN resectability criteria, initial CT staging placed 96 patients as upfront resectable. Survival outcomes were compared using univariate and multivariate cox regression analyses. Results: Within 96 resectable patients, 45 (47%) underwent upfront surgery, 36 (37%) received NACT followed by surgery and 15 (16%) only received chemotherapy. The majority were CA19-9 secretors (94%) with 54% lower values during chemotherapy. While 60% of patients experienced up to 35% tumor size reductions on NACT, 20% had stable disease, and 20% showed progressive disease. The patients who received NACT were significantly younger (p = 0.01), with higher baseline CA19-9 (p &lt; 0.01) and more frequently underwent stent placement (p = 0.01), table 1. Median overall survival for the upfront surgery, NACT+surgery and chemotherapy groups were 32.8, 23.7 and 20.2 months (log-rank test p&lt;0.01) subsequently. On univariate analysis initial presentation with weight loss (p = 0.02, HR = 2.08) and high baseline CA19-9 (log2-scaled, p = 0.01, HR = 1.13) were predictive of worse overall survival. After adjusting for potential confounding variables, patients in chemotherapy group had significantly worse survival compared to the upfront surgery group (P &lt; 0.01, HR = 3.14). These 15 patients failed to undergo surgery due to diverse reasons, including distant progression (7), local progression (3), performance status decline or death during chemotherapy (2), refusal due to chemotherapy side effects (2), and indecision and loss to follow-up (1). Conclusions: These findings underscore the need for more robust selection criteria in resectable PDAC patients to undergo NACT. Leveraging real-world data helps identify predictive factors of treatment decision making and their impact on patient survival outcomes. [Table: see text]

Abstract A071: Definitive radiation therapy for treatment of non-metastatic pancreatic ductal adenocarcinoma: Practice patterns and outcomes

Abstract Background: Advances in radiation therapy (RT) have allowed for increased biologically effective doses, or ablative RT, to be safely administered to pancreatic tumors. Pancreatic ductal adenocarcinoma (PDA) is diagnosed as local disease without metastasis in roughly 45% of patients (pts) however only 20-25% of pts are candidates for upfront surgical resection, and many are medically unfit to undergo surgery. In such patients, ablative RT can be given with curative intent, termed definitive RT (dRT). Defining practice patterns and outcomes of dRT is needed. Methods: A retrospective chart review was performed on pts with non-metastatic PDA who underwent dRT, defined as &amp;gt; = 100Gy BED over a protracted hypofractionation course, for treatment at our institution. Data collected included: age, gender, primary tumor location, resectability status, surveillance scan frequency and modality, chemotherapy (chemo) used, site of recurrence, cancer antigen (CA) 19-9 levels pre and post dRT, adverse events, and vital status. Neoadjuvant (NA) and adjuvant chemo was defined as chemo received within 6 weeks prior to dRT and 6 weeks after dRT, respectively. Time from diagnosis and dRT until death (OS and dRT-OS, respectively) and time from diagnosis and dRT until progression (PFS and dRT-PFS, respectively) was calculated. Time from diagnosis and dRT until metastasis (MFS and dRT-MFS, respectively) was also calculated. Results: A total of 25 pts who received dRT were identified. Median dose of RT given was 6750 cGY (range 3750-6750) in 15 fractions. Median age at receipt of dRT was 71.5 years (range 50-91), 50% were female. 76% of pts had pancreatic head mass and 24% of pts were considered resectable at time of diagnosis. 2 patients received dRT after isolated local recurrence after surgical resection. 80% of pts received chemo of any kind prior to dRT and 65% of those patients as NA chemo. 35% of patients received 2 chemo regimens prior to dRT; 55% and 65% of patients received mFOLFIRINOX and gemcitabine-based therapy, respectively. 12% of pts received adjuvant chemo. 43% of patients had at least 1 surveillance PET scan. 80% of patients had progression of any kind; of which 85% and 40% experienced distant and local recurrence, respectively. The median OS and dRT-OS was 17.3 months (95% CI 12.2-NA) and 10.1 months (95% CI 6.5-NA), respectively. The median PFS and dRT-PFS was 14.7 months (95% CI 10.3-17.9) and 5.1 months (95% CI 3.6-9.3), respectively. The median MFS and dRT-MFS was 14.7 months (95% CI 10.3-18.0) and 5.6 months (95% CI 3.6-11.3), respectively. Median CA 19-9 pre dRT was 85 (range 4.3-1790) and post-dRT was 42 (range 1.2-1673). 56% of pts had RT-associated toxicity of any kind. Conclusions: Of a single-institutional cohort of 25 patients with non-metastatic PDA who received dRT, more than half of patients received NA chemo; adjuvant chemo was rarely given. dRT provided high rates of local control while MFS was nearly identical to PFS, emphasizing the importance of systemic therapy to reduce distant recurrence in pancreatic cancer treated with dRT. Citation Format: Michael M. Caplan, Brian W. Labadie, Hope Choy, Albert Lee, Weijia Fan, David P. Horowitz. Definitive radiation therapy for treatment of non-metastatic pancreatic ductal adenocarcinoma: Practice patterns and outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A071.

Abstract A116: A machine learning-derived transcriptomic-based biomarker identifies low grade pancreatic ductal adenocarcinoma tumors and may help in treatment decision making

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive and highly lethal malignancy. The majority of cases present with locally advanced unresectable or metastatic disease, which precludes surgical resection and makes cure virtually impossible. However, a subset of tumors with more indolent biology may be candidates for aggressive cytoreduction. Further, synchronous resection of oligometastatic disease is being investigated in prospective trials. We sought to develop a prognostic biomarker that could identify patients with low grade tumors. Methods: The Pancreatic Adenocarcinoma TCGA dataset was analyzed on the cBioPortal platform, comparing 173 patients with non-metastatic PDAC, known tumor grade, and available mRNAseq data. Well-differentiated (G1) tumors were compared to moderately (G2) or poorly differentiated (G3) patients to identify differentially expressed (ΔE) genes. The patients were split into training (n=138) and testing sets (n=35). Low-importance genes were eliminated using a combination of LASSO regression, recursive feature elimination, random forest (RF), and Boruta algorithms. SMOTE was employed to address minority class imbalance. Support vector machine (SVM), RF, and k-nearest neighbors (kNN) were independently trained for the binary classification of G1 vs G2/3 PDAC. The best model and hyperparameters were selected using the mean bootstrapped nested k-fold cross-validation F1-score and evaluated on the held-out test set. Lastly, the model predictions of grade were used to divide patients into two cohorts for Results: There were 1335 ΔE genes between G1 and G2/3 tumors. A panel of 7 genes were unanimously selected by the four low importance gene-elimination algorithms, and used for generation of predictive algorithms. In bootstrapped nested k-fold cross-validation of the training dataset, mean sensitivity and specificity were 0.98 and 0.91 for G1, respectively, and 0.91 and 0.97 for G2/3 PDAC. The kNN model performed best, with a mean F1-score of 0.942 (95% CI: [0.941, 0.943]) on the training set and 0.781 (95% CI: [0.776, 0.786]) for the test set. Conclusion: This study presents a novel machine learning-generated transcriptomic-based tool that predicts PDAC grade with good accuracy, and has the potential to identify less aggressive variants of PDAC that may be more amenable to aggressive cytoreductive approaches. Further testing and validation of the algorithm in larger datasets and using prospectively collected needle biopsy-acquired material is a worthwhile next step, to refine this into a potent clinical risk assessment tool. Citation Format: Daniel Fu, Constantinos P. Zambirinis. A machine learning-derived transcriptomic-based biomarker identifies low grade pancreatic ductal adenocarcinoma tumors and may help in treatment decision making [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A116.

In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.

Arachidonate 15-lipoxygenase-mediated production of Resolvin D5n-3 DPA abrogates pancreatic stellate cell-induced cancer cell invasion.

Activation of pancreatic stellate cells (PSCs) to cancer-associated fibroblasts (CAFs) is responsible for the extensive desmoplastic reaction observed in PDAC stroma: a key driver of pancreatic ductal adenocarcinoma (PDAC) chemoresistance leading to poor prognosis. Specialized pro-resolving mediators (SPMs) are prime modulators of inflammation and its resolution, traditionally thought to be produced by immune cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid mediator profiling PSCs as well as primary human CAFs express enzymes and receptors to produce and respond to SPMs. Human PSC/CAF SPM secretion profile can be modulated by rendering these cells activated [transforming growth factor beta (TGF-β)] or quiescent [all-trans retinoic acid (ATRA)]. ATRA-induced nuclear translocation of arachidonate-15-lipoxygenase (ALOX15) was linked to increased production of n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA), among other SPMs. Inhibition of RvD5n-3 DPA formation increases cancer cell invasion, whereas addback of this molecule reduced activated PSC-mediated cancer cell invasion. We also observed that circulating concentrations of RvD5n-3 DPA levels were decreased in peripheral blood of metastatic PDAC patients when compared with those measured in plasma of non-metastatic PDAC patients. Together, these findings indicate that RvD5n-3 DPA may regulate cancer-stroma cross-talk and invasion.

Tumor Size Reduction and Serum Carbohydrate Antigen 19-9 Kinetics After Neoadjuvant FOLFIRINOX in Patients With Pancreatic Ductal Adenocarcinoma

BackgroundChanges in tumor size and serum carbohydrate antigen 19-9 are commonly reported markers used to assess response to neoadjuvant therapy in pancreatic ductal adenocarcinoma. We evaluated the impact of the percentual tumor size reduction and carbohydrate antigen 19-9 kinetics on resectability and response to neoadjuvant FOLFIRINOX. MethodsThis was an institutional analysis of patients with non-metastatic (upfront resectable, borderline resectable, and locally advanced) pancreatic ductal adenocarcinoma who underwent neoadjuvant FOLFIRINOX. Resectability, pathologic response, disease recurrence, and overall survival were evaluated. ResultsAmong 193 patients who completed FOLFIRINOX, 60% underwent resection, and 91% were R0. Pathologically, complete, and near-complete responses were achieved in 4% and 40% of patients, respectively. Tumor size reduction (odds ratio 1.02 per 1%, P = .024) and normalization of carbohydrate antigen 19-9 (odds ratio 2.61, P = .035) were associated with increased odds of resectability. Concerning pathologic response, tumor size reduction (odds ratio 1.03 per 1%, P = .018) was associated with increased odds of a complete and near-complete response. Lastly, in resected patients, a postoperative increase in carbohydrate antigen 19-9 after prior normalization after neoadjuvant therapy were at an increased risk of recurrence (hazard ratio 9.58, P < .001) and worse survival (hazard ratio 10.4, P < .001) compared to patients who maintained normalization. ConclusionIn patients with non-metastatic pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy, tumor size reduction was a significant predictor of resectability and pathologic response, including complete and near complete responses, whereas serum carbohydrate antigen 19-9 normalization predicted resectability, disease recurrence, and survival. Patients with a postoperative carbohydrate antigen 19-9 rise after prior normalization after administration of neoadjuvant therapy were at an increased risk of recurrence and worse overall survival.

Feasibility, Safety, and Efficacy of Aggressive Multimodal Management of Elderly Patients with Pancreatic Ductal Adenocarcinoma.

We aimed to evaluate the safety and efficacy of NAT followed by surgical resection in patients with PDAC aged ≥75 years. Whether administration of neoadjuvant therapy (NAT) followed by surgical resection in elderly patients with pancreatic ductal adenocarcinoma (PDAC) is safe and effective is unknown. The present study is a three-part comparison of older (≥ 75 years) versus younger (< 75 years) patients in different settings throughout the continuum of PDAC care. The first analysis was a comparison of older versus younger consecutive patients with non-metastatic PDAC who were initiated on FOLFIRINOX. The second was a comparison of older vs. younger patients who underwent NAT followed by surgical resection, and the third and final analysis was a comparison of older patients who underwent either NAT followed by surgical resection vs. upfront surgical resection. Postoperative complications, overall survival (OS), and time to recurrence (TTR), were compared. Propensity-score matching (PSM) analysis was performed to adjust for potential confounders. In the first analysis, a lower proportion of older patients (n=40) were able to complete the intended neoadjuvant FOLFIRINOX (8) cycles compared to younger patients (n=214) (65.0% vs. 81.4%, P=0.021). However, older patients were just as likely to undergo surgical exploration as younger patients (77.5% vs 78.5%, P=0.89) as well as surgical resection (57.5% vs 55.6%, P=0.70). In the second analysis, PSM was conducted to compare older (n=54) vs. younger patients (n=54) who underwent NAT followed by surgical resection. There were no significant differences in postoperative complications between the matched groups. While there was a significant difference in overall survival (OS) between older and younger patients (median OS: 16.43 months vs. 30.83 months, P=0.002), importantly, there was no significant difference in time to recurrence (TTR, median: 7.65 months vs. 11.83 months, P=0.215). In the third analysis, older patients who underwent NAT followed by surgical resection (n=48) were compared with similar older patients who underwent upfront surgical resection (n=48). After PSM, there was a significant difference in OS (median OS: 15.78 months vs. 11.51 months, P=0.037) as well as TTR (median TTR: 8.81 months vs. 7.10 months, P=0.046) representing an association with improved outcomes that favored the neoadjuvant approach among older patients alone. This comprehensive three-part study showed that administration of NAT followed by surgical resection appears to be safe and effective among patients ≥ 75 years of age. An aggressive approach should be offered to older adults undergoing multimodal treatment of PDAC.

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.

Impact of network treatment in patients with resected pancreatic cancer on use and timing of chemotherapy and survival

Centralization of pancreatic cancer surgery aims to improve postoperative outcomes. Consequently, patients with pancreatic cancer may undergo pancreatic surgery in an expert centre and adjuvant chemotherapy in a local hospital (network treatment). The aim of this study was to assess whether network treatment has an impact on time to chemotherapy, failure to complete adjuvant chemotherapy, and survival. Second, whether these parameters varied between pancreatic networks was studied. This retrospective study included all patients diagnosed with non-metastatic pancreatic ductal adenocarcinoma who underwent pancreatic surgery and adjuvant chemotherapy, registered in the Netherlands Cancer Registry (2015-2020). Time to chemotherapy was defined as the time between surgery and the start of adjuvant chemotherapy. Completion of adjuvant chemotherapy was defined as the receipt of 12 cycles of FOLFIRINOX or six cycles of gemcitabine. Analysis was performed with linear mixed models and multilevel logistic regression models. Cox regression analyses were performed for survival. In total, 1074 patients were included. Network treatment was observed in 468 patients (43.6 per cent) and was not associated with longer time to chemotherapy (0.77 days, standard error (s.e.) 1.14, P = 0.501), failure to complete adjuvant chemotherapy (odds ratio (OR) = 1.140, 95 per cent c.i. 0.86 to 1.52, P = 0.349), and overall survival (hazards ratio (HR) = 1.04, 95 per cent c.i. 0.88 to 1.22, P = 0.640). Significant variation between the networks was observed for time to chemotherapy (range 40.5-63 days, P < 0.0001) and completion of adjuvant chemotherapy (range 19-52 per cent, P = 0.030). Adjusted for case mix, time to chemotherapy significantly differed between networks. In this nationwide analysis, network treatment in patients with resected pancreatic cancer was not associated with longer time to chemotherapy, failure to complete adjuvant chemotherapy, and worse survival. Significant variation between pancreatic cancer networks was found for time to chemotherapy.

Neoadjuvant therapy for pancreatic cancer.

Patients with localized pancreatic ductal adenocarcinoma (PDAC) are best treated with surgical resection of the primary tumour and systemic chemotherapy, which provides considerably longer overall survival (OS) durations than either modality alone. Regardless, most patients will have disease relapse owing to micrometastatic disease. Although currently a matter of some debate, considerable research interest has been focused on the role of neoadjuvant therapy for all forms of resectable PDAC. Whilst adjuvant combination chemotherapy remains the standard of care for patients with resectable PDAC, neoadjuvant chemotherapy seems to improve OS without necessarily increasing the resection rate in those with borderline-resectable disease. Furthermore, around 20% of patients with unresectable non-metastatic PDAC might undergo resection following 4-6 months of induction combination chemotherapy with or without radiotherapy, even in the absence of a clear radiological response, leading to improved OS outcomes in this group. Distinct molecular and biological responses to different types of therapies need to be better understood in order to enable the optimal sequencing of specific treatment modalities to further improve OS. In this Review, we describe current treatment strategies for the various clinical stages of PDAC and discuss developments that are likely to determine the optimal sequence of multimodality therapies by integrating the fundamental clinical and molecular features of the cancer.

Survival Benefit of Adjuvant Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma Who Underwent Surgery Following Neoadjuvant FOLFIRINOX.

The benefit of adjuvant chemotherapy following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant FOLFIRINOX is unclear. This study aimed to assess the survival benefit of adjuvant chemotherapy in this patient population. This retrospective study included 218 patients with localized non-metastatic PDAC who received neoadjuvant FOLFIRINOX and underwent curative-intent surgery (R0 or R1) between January 2017 and December 2020. The association of adjuvant chemotherapy with disease-free survival (DFS) and overall survival (OS) was evaluated in overall patients and in the propensity score matched (PSM) cohort. Subgroup analysis was conducted according to the pathology-proven lymph node status. Adjuvant chemotherapy was administered to 149 patients (68.3%). In the overall cohort, the adjuvant chemotherapy group had significantly improved DFS and OS compared to the observation group (DFS: median, 13.8 months [95% confidence interval (CI), 11.0 to 19.1] vs. 8.2 months [95% CI, 6.5 to 12.0]; p < 0.001; and OS: median, 38.0 months [95% CI, 32.2 to not assessable] vs. 25.7 months [95% CI, 18.3 to not assessable]; p=0.005). In the PSM cohort of 57 matched pairs of patients, DFS and OS were better in the adjuvant chemotherapy group than in the observation group (p < 0.001 and p=0.038, respectively). In the multivariate analysis, adjuvant chemotherapy was a significant favorable prognostic factor (vs. observation; DFS: hazard ratio [HR], 0.51 [95% CI, 0.36 to 0.71; p < 0.001]; OS: HR, 0.45 [95% CI, 0.29 to 0.71; p < 0.001]). Among PDAC patients who underwent surgery following neoadjuvant FOLFIRINOX, adjuvant chemotherapy may be associated with improved survival. Randomized studies should be conducted to validate this finding.

Exploring optimal therapeutic management of STAGE IA PDAC in the era of neoadjuvant chemotherapy.

712 Background: Neoadjuvant chemotherapy (NAT) is currently recommended for non-metastatic pancreatic ductal adenocarcinoma (PDAC). Data on the optimal NAT duration and the proper post-surgical chemotherapy (PSC) are lacking, especially for patients (pts) who yielded a pathological stage IA. Methods: We retrospectively analyzed the outcome of PDAC pts resected between 2015 and 2020 at our institution after NAT yielding a pathologic stage of PDAC ypT1N0. Pts were analyzed basing on NAT duration (aim 1) and PSC indication (yes/no) and type (aim 2). The primary endpoint was median event-free survival (EFS) for aim 1 and median disease free-survival (DFS) for aim 2. As per secondary endpoints, overall survival (OS) and the prognostic role of clinical and pathological variables was assessed (baseline CA19.9 level; pre-operative Ca19.9 level, basal vascular involvement, grading, perineural invasion, R1 resection). Results: During the study period a total of 756 pts were resected, 363 (48%) after NAT. Of them, 72 pts (20%) achieved a pathological ypT1N0 (ypIA). Among this group 16 pts (22%) showed a T1a-T1b, 62 pts (86%) had a G1/G2 tumor, 60 pts (83%) had a R0, 36 pts (50%) had a perineural invasion and 33 (46%) had a tumor regression grade marked or completed. For aim 1 we compared 34 pts (47%) treated with NAT for not more than 4 months (Group A1) and 38 pts (53%) treated for at least 4 months (Group B1). Baseline, biochemical and radiological variables were similar between the 2 groups. No statistical difference was found in EFS (Group A1: median 46 months/ Group B1: median not reached). For aim 2 we compared 10 pts (14%) who received the same chemotherapy regimen in NAT and PSC (Group A2), 35 pts (49%) who received a different chemotherapy regimen in NAT and PSC (Group B2) and 27 (14%) pts who did not receive any PSC (Group C2). PSC were gemcitabine/nab-paclitaxel (10%) and mFOLFIRINOX (90%) in group A2, whereas gemcitabine/nab-paclitaxel (17%), mFOLFIRINOX (3%), gemcitabine (51.5%), capecitabine (17%), gemcitabine/capecitabine (8.5%), PEXG (3%) in group B2. DFS were 24 months for group B2, whereas median was not reached for group A2 e C2 (p=0.006). No statistical difference was found in OS among the groups. At multivariate analysis only grading (G3) emerged as independent factor for poor prognosis. Conclusions: In ypIA pts NAT duration and or type seem to be unrelated to the outcome. PSC performed with alternative and depotentiated chemotherapy as compared to NAT, seem to be related to a higher rate of disease recurrence. Poor differentiated/G3 tumors is confirmed as independent risk factor for poor survival in this population.

Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART).

Treatment options for pancreatic ductal adenocarcinoma (PDAC) are commonly limited for patients with advanced age due to medical comorbidities and/or poor performance status. These patients may not be candidates for more aggressive chemotherapy regimens and/or surgical resection leaving few, if any, other effective treatments. Ablative stereotactic MRI-guided adaptive radiation therapy (A-SMART) is both efficacious and safe for PDAC and can achieve excellent long-term local control, however, the appropriateness of A-SMART for elderly patients with inoperable PDAC is not well understood. A retrospective analysis was performed of inoperable non-metastatic PDAC patients aged 75years or older treated on the MRIdian Linac at 2 institutions. Clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional (LRC). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE, v5). A total of 49 patients were evaluated with a median age of 81years (range, 75-91) and a median follow-up of 14 months from diagnosis. PDAC was classified as locally advanced (46.9%), borderline resectable (36.7%), or medically inoperable (16.3%). Neoadjuvant chemotherapy was delivered to 84% of patients and all received A-SMART to a median 50Gy (range, 40-50Gy) in 5 fractions. 1Year LRC, PFS, and OS were 88.9%, 53.8%, and 78.9%, respectively. Nine patients (18%) had resection after A-SMART and benefited from PFS improvement (26 vs 6months, P = .01). ECOG PS <2 was the only predictor of improved OS on multivariate analysis. Acute and late grade 3 + toxicity rates were 8.2% and 4.1%, respectively. A-SMART is associated with encouraging LRC and OS in elderly patients with initially inoperable PDAC. This novel non-invasive treatment strategy appears to be well-tolerated in patients with advanced age and should be considered in this population that has limited treatment options.

Tolerability, Attrition Rates, and Survival Outcomes of Neoadjuvant FOLFIRINOX for Nonmetastatic Pancreatic Adenocarcinoma: Intent-to-Treat Analysis.

FOLFIRINOX is increasingly used in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy-related and biliary complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking. Patients with nonmetastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution's pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively. Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration, and 54 (21.3%) did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), or disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an emergency department visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (hazard ratio 7.0; 95% CI 3.8 to 12.8; p < 0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (odds ratio [OR] 0.06; p = 0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p = 0.003), increase in ECOG score (OR 0.2, p < 0.001), and being single or divorced (OR 0.3, p = 0.018). Among 254 patients with nonmetastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration.

Staging CT and Diagnostic Laparoscopy With Cytology Prior to the Treatment of Pancreatic Adenocarcinoma: A Case Series.

Initial staging of pancreatic ductal adenocarcinoma (PDAC) is performed with computed tomography (CT). Laparoscopy with peritoneal cytology at staging can uncover occult disease undetected by CT. This case series assessed clinical course following staging laparoscopy with cytology in patients with PDAC. This single-center study examined patients with non-metastatic PDAC diagnosed from 2017 to 2020. Patients underwent CT and subsequent laparoscopy with cytology prior to treatment. Demographics, clinicopathologic status, treatment course, and survival were compared. Eight patients were identified. All had negative laparoscopies. Five cytologies were negative, two were atypical, and one was positive. Two patients with negative cytology received neoadjuvant chemotherapy and underwent resection, with an average follow-up time of 32.9 months since diagnosis. Of the three remaining patients with negative cytology, none underwent resection. One received delayed chemotherapy, while the others could not due to medical contraindications. The average survival was 3.5 months (n=2). Of two patients with atypical cytology, neither underwent resection. One could not receive chemotherapy due to medical contraindication, while the other was lost to follow-up shortly after diagnosis. The average survival was 1.3 months (n=1). The patient with positive cytology received definitive chemotherapy without resection and survived for 21.6 months. The patient with positive cytology may have been spared non-therapeutic surgery. Remaining unresected patients showed poor survival, though the lack of immediate chemotherapy may contribute to this finding.Further research is needed to determine optimal candidates for invasive staging and implications of atypical cytology.

Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer.

Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4Gy/28 fx and 33Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.