Nonmetastatic Pancreatic Adenocarcinoma Research Articles

Intraoperative Ultrasound guided Palliative Radiofrequency Ablation of Unresectable Nonmetastatic Pancreatic Malignancies: A Pilot Observational Study.

Radiofrequency ablation of unresectable pancreatic tumors represents a palliative method in selected patients. The lack of standardization of the technique used as well as the non-homogeneous immediate and long-term results from the reports in the literature made us evaluate in a pilot study the application of a standardized technique through a surgical approach, with the evaluation of the immediate and long-term results. Ten consecutive patients diagnosed with unresectable nonmetastatic pancreatic adenocarcinoma were referred for radio-frequency ablation by surgical approach. For that, a UniBlate (AngioDinamics®) internal cooled electrode was used, under intraoperative ultrasound guidance. We analysed the morbidity, mortality and survival associated with this procedure. The median follow-up period was 12 months. Intraoperative ultrasound was essential for guiding the procedure. No mortality and no major postoperative complications after intraoperative tumoral ablations were noted. The median survival after the procedure was 7.5 months. Radiofrequency intraoperative ablation of unresectable pancreatic tumors is a feasible procedure, with low morbidity and mortality if standardized, being noninferior to palliative chemotherapy alone in regards with survival. A larger study is necessary to demonstrate the potential benefits in survival, the role of multidisciplinary selection being also mandatory.

Comparative outcomes of treatment modalities in nonagenarians with nonmetastatic pancreatic adenocarcinoma

BackgroundThere has been an increase in the elderly patient population seeking care for pancreatic ductal adenocarcinoma (PDAC). This study aimed to delineate the effectiveness of therapeutic options in nonagenarians (aged 90–99 years) diagnosed with resectable PDAC. MethodsThis study used the National Cancer Database to identify patients with nonmetastatic PDAC (stage I-III) from 2004 to 2021. The study compared median overall survival (mOS) using Kaplan-Meier curves among 5 treatment categories: surgery, surgery along with chemoradiation, chemotherapy alone, radiotherapy alone, and chemoradiation alone. Cox proportional hazards regression was used in multivariate analyses. ResultsOf 459,174 patients, 793 aged ≥ 90 years had nonmetastatic PDAC. Of 793 patients, 245 (30.9 %) underwent chemotherapy alone, 296 (37.3 %) underwent radiotherapy alone, 162 (20.4 %) underwent chemoradiation alone, 58 (7.3 %) underwent curative-intent resection, and 32 (4.0 %) underwent surgery combined with chemoradiation. The mOS estimates in different treatment modalities were 9.5 months (95 % CI, 6.7–14.5) for surgery alone, 19.1 months (95 % CI, 2.4–64.3) for surgery combined with chemoradiation, 8.2 months (95 % CI, 7.2–9.2) for chemotherapy alone, 8.4 months (95 % CI, 7.6–9.6) for radiotherapy alone, and 11.2 months (95 % CI, 8.7–12.9) for chemoradiation alone (P < .001). In multivariate analysis, the odds of survival were better for patients who underwent surgery alone than for those who underwent chemotherapy alone, although the odds of survival did not significantly differ between patients who underwent radiotherapy alone and those who underwent chemoradiation alone. Nonetheless, surgery combined with chemoradiation was associated with decreased mortality risk compared with surgery alone (hazard ratio, 0.46; 95 % CI, 0.25–0.87; P = .02). Operative 30-day mortality rate was 8.8 %, and 90-day mortality rate was 17.8 %. ConclusionSurgery combined with chemoradiation improved the survival of nonagenarians with PDAC compared with other therapies. However, only 1 in 25 patients received all 3 treatment components. Moreover, our study highlights a very high operative mortality rate in nonagenarians.

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.

Prolonged length of stay and omission of adjuvant therapy are associated with early mortality after pancreatic adenocarcinoma resection

BackgroundSurgical resection is the preferred treatment for non-metastatic pancreatic adenocarcinoma, but post-resection survival is highly variable. We use the National Cancer Database Participant Use Files to investigate risk factors associated with early mortality (survival less than one year) after pancreatic adenocarcinoma resection. Methods51,345 cases of pancreatic adenocarcinoma were identified. 16,234 had survival between three months and one year (early mortality), and 35,111 had survival greater than one year. Descriptive analyses and multivariate Cox regression models were performed to identify demographic, perioperative, and tumor biology factors associated with early mortality. A sub-analysis subsequently explored the relationship between the length of stay and chemotherapy utilization. ResultsOf the 51,345 cases of pancreatic adenocarcinoma, 16,234 had early mortality. In multivariate models adjusted for demographic, socioeconomic, facility type, tumor characteristics, and hospital risk factors, patients with early mortality also had longer lengths of stay, more unplanned readmissions. They were more likely to receive treatment at non-academic centers. Adjuvant chemotherapy utilization was lower in patients with early mortality, particularly in those with longer lengths of stay. ConclusionReducing the length of stay, decreasing variability across different forms of health insurance, and increasing access to treatment at academic centers may reduce early mortality. Adjuvant chemotherapy is associated with a reduced risk of early mortality but is highly underutilized, especially in patients with prolonged hospital stays. Given that delays in receiving adjuvant chemotherapy were associated with an increased risk of early mortality, interventions to decrease perioperative complications to ensure timely access to adjuvant chemotherapy may improve survival.

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.

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.

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.

Effect of Interval between Neoadjuvant Chemotherapy and Radiation Therapy on Metastasis Risk for Inoperable Non-Metastatic Pancreatic Adenocarcinoma

In inoperable pancreatic cancer patients requiring radiotherapy (RT) after neoadjuvant chemotherapy (CT), there can be delays in starting radiation due to multiple complications. However, pancreatic cancer can progress rapidly during short intervals without treatment. We hypothesize that longer intervals between neoadjuvant chemotherapy and radiation could expediate the development of metastatic disease. We identified patients with inoperable non-metastatic borderline resectable or locally advanced pancreatic cancer treated with neoadjuvant CT followed by RT from 2011 to 2021 at a single institution. Patients who completed palliative RT as defined by a biologic effective dose (BED) of less than 50 Gy, or those who were lost to follow-up within 3 months after completing RT without documented disease progression were excluded. The interval between RT and CT was defined as the time between last date of CT administration and initiation of RT. The primary endpoint was metastasis-free survival (MFS) after RT completion. Differences in MFS between patients who started RT within or after 4, 6, and 8 weeks of completing CT were examined utilizing log rank analysis of MFS generated via the Kaplan-Meier method. At a median follow-up of 5.45 months, twenty-three patients were included. Most patients were male (61%) with cT4 (61%), cN0 (83%) pancreatic adenocarcinoma. Almost all patients completed combination neoadjuvant CT (91%) followed by either intensity modulated RT to 50.4 Gy in 28 fractions with capecitabine (n = 9) or stereotactic body RT to 33-40 Gy in 5 fractions (n = 14). Eleven (48%) patients received adjuvant CT after radiation therapy. The median time between last CT and RT initiation was 34 days (range 13-142). The MFS of patients who initiated RT within 4 weeks of CT compared to after was higher but not significant (16.8 vs 9.9 months, p = 0.144). Those who received RT within 6 or 8 weeks of completing CT exhibited significantly longer MFS compared to later than 6 (16.0 vs 6.9 mo, p = 0.016) or 8 weeks (15.1 vs 2.1 mo, p = 0.004). There was no statistical correlation between MFS and other variables (CA 19-9 before radiation, T-stage, receipt of adjuvant CT, BED). These results suggest that a longer interval between CT and RT is associated with the risk of developing metastatic disease sooner but requires validation in a prospective cohort. Root causes of delays in starting radiation (e.g., insurance authorization) should be investigated as well.

ASO Visual Abstract: Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Non-metastatic Pancreatic Adenocarcinoma.

ASO Visual Abstract: Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Non-metastatic Pancreatic Adenocarcinoma.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p<0.05). SAS (HR 0.79; CI 0.76-0.81; p<0.001) and GRT (HR 0.67; CI 0.65-0.69; p<0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2years vs 1.1 years; p<0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p<0.001). Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

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.

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.

Phase I study of PTM-101 as neoadjuvant therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A trial in progress.

TPS775 Background: While there have been tremendous advances in cancer treatment, critical challenges remain including limited ability of drugs to successfully reach the tumor, short half-life, and low retention rate on site. Local control of non-metastatic pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable anatomy, for whom enhanced local downsizing of disease could improve symptoms and increase overall survival (OS). Targeted therapies with reduced systemic toxicity are needed for the treatment of PDAC since current therapies have not provided meaningful advances. PTM-101 is a paclitaxel-impregnated absorbable product which is designed for direct, sustained release of the therapeutic agent at the tumor site. Preclinical animal studies demonstrate that PTM-101 results in enhanced drug levels in the tumor compared with comparable systemic paclitaxel dosing leading to tumor reduction, metastasis inhibition and survival benefit (Indolfi et al, 2016). Large animal (i.e. pigs) and human cadaver studies show that PTM-101 can successfully be deployed to the peritumoral pancreatic surface by a standard laparoscopic procedure. Further, large animal studies show no evidence of neutropenia, pancreatitis, severe fibrosis or scarring, or infection after placement of PTM-101. Methods: This Phase I trial will assess the addition of PTM-101 prior to mFOLFIRINOX in 6 subjects with newly diagnosed borderline resectable or locally advanced PDAC. The primary objective is to assess the safety, toxicity and feasibility of a single administration of PTM-101. It is hypothesized that PTM-101 will be readily implanted during diagnostic laparoscopy and will result in clinically meaningful delivery of paclitaxel directly towards the tumor area with good tolerance and minimal local systemic exposure of drug. Patients enrolled and treated on study will be monitored closely for local and systemic toxicities as well as preliminary signals of efficacy. Enrollment is in progress and 3 patients have been enrolled and completed prospective follow up at the time of abstract submission. Clinical trial information: ACTRN12621000881831 .

Impact of Mediating and Confounding Variables on the Volume-Outcome Association in the Treatment of Pancreatic Cancer.

High-volume centers (HVC), academic centers (AC), and longer travel distances (TD) have been associated with improved outcomes for patients undergoing surgery for pancreatic adenocarcinoma (PAC). Effects of mediating variables on these associations remain undefined. The purpose of this study is to examine the direct effects of hospital volume, facility type, and travel distance on overall survival (OS) in patients undergoing surgery for PAC and characterize the indirect effects of patient-, disease-, and treatment-related mediating variables. Using the National Cancer Database, patients with non-metastatic PAC who underwent resection were stratified by annual hospital volume (< 11, 11-19, and ≥ 20cases/year), facility type (AC versus non-AC), and TD (≥ 40 versus < 40 miles). Associations with survival were evaluated using multiple regression models. Effects of mediating variables were assessed using mediation analysis. In total, 19,636 patients were included. Treatment at HVC or AC was associated with lower risk of death [hazard ratio (HR) 0.90, confidence interval (CI) 0.88-0.92; HR 0.89, CI 0.86-0.91, respectively]. TD did not impact OS. Patient-, disease-, and treatment-related variables explained 25.5% and 41.8% of the survival benefit attained from treatment at HVC and AC, reducing the survival benefit directly attributable to each variable to 4.9% and 6.4%, respectively. Treatment of PAC at HVC and AC was associated with improved OS, but the magnitude of this benefit was less when mediating variables were considered. From a healthcare utilization and cost-resource perspective, further research is needed to identify patients who would benefit most from selective referral to HVC or AC.

A safety study of intraoperative radiation therapy following stereotactic body radiation therapy and multi-agent chemotherapy in the treatment of localized pancreatic adenocarcinoma: study protocol of a phase I trial

BackgroundLocalized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED10] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a “Triangle Volume” (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT).MethodsPatients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute (< 90 days) toxicity after IORT measured by Clavien-Dindo classification. Secondary objectives include late (> 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival.DiscussionIf the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach.Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513

Dosimetric Predictors of Acute and Late Gastrointestinal Toxicities in Stereotactic Online Adaptive Magnetic Resonance-Guided Radiotherapy (SMART) for Locally Advanced Pancreatic Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Ablative SBRT is growing in use for non-metastatic pancreatic adenocarcinoma (PAC). Data for organ-at-risk (OAR) constraints have been historically limited by the inability to account for inter-fraction changes in OAR positions and their potential effects on toxicity risk. The purpose of this single institution, retrospective study was to investigate the relationships of dose and volume to OAR during daily stereotactic, MRI-guided online adaptive radiotherapy (SMART). We hypothesized that the daily, dose-volume data for OARs generated through the process of daily adaptation could be leveraged to identify dosimetric drivers of gastrointestinal (GI) toxicities for pancreas SBRT. <h3>Materials/Methods</h3> 147 patients with PAC were treated with five-fraction SMART on a 0.35 MR Linac at our institution from July 2018 to August 2021. All patients met clinical OAR constraints, typically V36Gy <0.5cc to OAR. Patients were reviewed and evaluated using the common terminology criteria for adverse events (CTCAE) V5.0 for possibly, probably, or definitely related to radiation acute (≤3 months) and late (>3 months) toxicities and confirmed by an attending GI radiation oncologist. Each OAR: stomach, duodenum, and small bowel (SB) was matched to a ≥ grade 2 (Gr2+) toxicity endpoint composite group. Due to the high degree of multicollinearity between dose-volumes within OARs, a least absolute shrinkage selector operator (LASSO) regression model was constructed using R 4.1.2 for each. The models were grouped by V15Gy, V20Gy, V25Gy, V30Gy, V33Gy, and V36Gy to OARs. Following identification of dose levels (Gy) associated with each toxicity group, receiver operator curve (ROC) analysis was performed for the combined average SB and duodenum V33Gy across all fractions to identify critical volumes at those dose levels most predictive of risk. <h3>Results</h3> 18 of 147 patients experienced ≥1 Gr2+ acute or late GI toxicity. 17 had duodenal toxicities, including 10 Gr2, 6 Gr3, and 1 Gr4 (duodenal ulcer). Acute Gr2+ occurred in 8.84% of patients. Of the 7 Gr3+ duodenal toxicities, 71% were duodenal ulcers. The most significant predictor of Gr 2+ duodenal and SB toxicity was V33Gy odds ratio of 1.65 (95% CI 1.05-2.72) and 1.60 (95% CI 1.01-2.54) per cc of OAR, respectively. On ROC analyses for duodenum and SB, AUC was 0.72 for each. For duodenum, the optimal cut-point was 1cc, with true positive (TP) and true negative (TN) rates of 17.8% of 94.9% above that volume. For SB, it was 1.75cc (TP: 16.7%; TN: 94.3%). A specific stomach dose that related to toxicities was not identified. <h3>Conclusion</h3> After SMART, the dose-volume threshold of V33Gy was associated with Gr2+ acute and late toxicities for the duodenum and SB. These data provide an evidence-based understanding of dose-constraints to OAR for PAC and are the first to our knowledge to account for inter-fraction motion using daily volumetric on-board MRI. These metrics can be utilized to guide future dose-volume choices for patients undergoing SMART or non-adaptive SBRT.

Lymph node yield as a measure of pancreatic cancer surgery quality

Evaluated lymph node (ELN) yield has been established as a promising measure of surgical quality. Research has suggested that an ELN of at least 15 in pancreatic cancer patients is associated with improved survival and staging metrics. The aim of this study was to determine what impact a high ELN yield of ≥15 has in a novel population. A retrospective cohort study was performed of patients with resectable, non-metastatic pancreatic adenocarcinoma who underwent neoadjuvant therapy followed by pancreatectomy using the National Cancer Database (NCDB 2004-2017). Patients who had <15 nodes examined and those who had ≥15 examined (high ELN) were compared. Univariate and multivariate analyses were performed to determine factors associated with ELN yield. A Cox proportional hazards model was used to identify factors associated with overall survival. A total of 5,930 patients were included; 58% of patients had ≥15 lymph nodes examined. High ELN was associated with significant improvement in overall survival rates (p<0.004) and perioperative outcomes including post-operative stay (p<0.0001), 30-day unplanned readmission (p<0.028), and 90-day mortality (p<0.001). Patients who were treated at facilities with a high procedure-specific surgery volume were more likely to receive high ELN surgeries than those treated at facilities with a low volume (HR = 2.86[95% CI = 2.36-3.47]). An ELN yield of ≥15 was a significant measure of surgical quality in this novel population as it was associated with improvements in survival and perioperative outcomes. However, considerable harvest disparities exist at the facility level.

Synoptic CT scan reporting of pancreatic adenocarcinoma to align with international consensus guidelines on surgical resectability: a Victorian pilot.

Non-metastatic pancreatic ductal adenocarcinoma (PDAC) is classified as resectable (R), borderline resectable (BR) or locally advanced (LA). International Consensus Guidelines on these definitions exist, but have not been integrated into everyday Australian practice. The anatomical features on CT imaging lend themselves to synoptic reporting which should enhance completeness, comparability and consistency. We developed and tested a synoptic report for PDAC derived from the International Consensus Guidelines at two metropolitan pancreatic cancer services to standardize CT reporting in the region. Consecutive scans with suspected PDAC discussed at multidisciplinary meetings were reported using the template between October 2020 and September 2021. A purpose-built database captured data regarding resectability and image-quality parameters. Ninety-five scans were reviewed, 57.9% (N= 55) of which conformed to high-quality pancreatic CT protocols. Of suboptimal scans, meaningful synoptic reports were able to be issued for a further 24/40 (due to metastases in 9, and unequivocal resectability status in 15). Of 79 classifiable scans, 20% were metastatic, 51% deemed resectable, 16% locally advanced and 13% borderline resectable. PDAC lends itself to synoptic reporting given the specific anatomical considerations that classify resectability. This relies, however, on high-quality CT imaging and it was surprising that over 40% of scans reviewed were of suboptimal quality. Despite this, resectability status according to the International Consensus Guidelines was designated for 83% of scans. Optimal treatment algorithms for LA, BR and resectable disease vary widely underscoring the critical importance of accurately differentiating these anatomic subtypes of PDAC, and thus support further implementation of a synoptic report of this nature.

Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy.

Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear. Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2months of neoadjuvant chemotherapy or died within 90days from surgery were excluded. A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4months, P = 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 &amp; 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5months, P &lt; 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9months; P = 0.406). Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.

Comparison of survival prediction models for pancreatic cancer: Cox model versus machine learning models

A survival prediction model has recently been developed to evaluate the prognosis of resected nonmetastatic pancreatic ductal adenocarcinoma based on a Cox model using two nationwide databases: Surveillance, Epidemiology and End Results (SEER) and Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP). In this study, we applied two machine learning methods—random survival forests (RSF) and support vector machines (SVM)—for survival analysis and compared their prediction performance using the SEER and KOTUS-BP datasets. Three schemes were used for model development and evaluation. First, we utilized data from SEER for model development and used data from KOTUS-BP for external evaluation. Second, these two datasets were swapped by taking data from KOTUS-BP for model development and data from SEER for external evaluation. Finally, we mixed these two datasets half and half and utilized the mixed datasets for model development and validation. We used 9,624 patients from SEER and 3,281 patients from KOTUS-BP to construct a prediction model with seven covariates: age, sex, histologic differentiation, adjuvant treatment, resection margin status, and the American Joint Committee on Cancer 8th edition T-stage and N-stage. Comparing the three schemes, the performance of the Cox model, RSF, and SVM was better when using the mixed datasets than when using the unmixed datasets. When using the mixed datasets, the C-index, 1-year, 2-year, and 3-year time-dependent areas under the curve for the Cox model were 0.644, 0.698, 0.680, and 0.687, respectively. The Cox model performed slightly better than RSF and SVM.