Faculty Bibliography

BACKGROUND:The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. METHODS:Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022-2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients' healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017-002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. DISCUSSION/CONCLUSIONS:The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. TRIAL REGISTRATION/BACKGROUND:PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

OBJECTIVE:The aim of the study was to investigate prognostic factors in context of neoadjuvant therapy (NAT) and develop tools that can allow for accurate and personalized patient prognostication. SUMMARY OF BACKGROUND DATA/BACKGROUND:NAT might impact the prognostic ability of well-established clinicopathological factors in resected pancreatic ductal adenocarcinoma (PDAC). METHODS:Patients after resection for PDAC were identified from the Dutch Pancreatic Cancer Group Recurrence Database and institutional databases at NYU Langone Health and the Johns Hopkins Hospital (2014-2019). Patients were stratified into NAT and chemo-naïve groups. Overall survival (OS), calculated from the time of resection, was estimated using Kaplan-Meier and compared using log-rank tests. Prognostic factors associated with OS were assessed in both groups using univariable and multivariable Cox-regression analyses and presented using hazard ratios (HR) with corresponding 95% confidence intervals (95%CI). Predictive models were developed and an interactive tool was created to predict survival independently in both groups. RESULTS:Of 2,760 patients with resected PDAC, 778 patients (28%) received NAT. Independent predictors for worse OS in chemo-naïve patients included age ≥65 years, markedly elevated CA19-9 (≥500 U/mL) at diagnosis, higher AJCC-T stage (T3/4 vs T1/2), worsening AJCC N-stage (N2 vs. N1 vs. N0), poor tumor differentiation, perineural invasion, and microscopically positive resection margin (R1 vs. R0). Contrastingly, predictors for worse OS in NAT patients included non-normalization of CA19-9 after NAT (<37 U/mL), presence of nodal disease (N1/2 vs. N0 given no statistical difference between N1 and N2 disease), and grade of treatment response (moderate/poor vs. complete/near complete). CONCLUSION/CONCLUSIONS:Prognostic factors for OS in patients with resected PDAC differ between chemo-naïve and NAT patients. Personalized prediction tools for OS in resected PDAC based on these specific factors are available online (www.pancpals.com/tools).

OBJECTIVE:To investigate whether tangential versus segmental portomesenteric venous resection (PVR) impacts surgical and oncological outcome in patients undergoing pancreatoduodenectomy for pancreatic cancer with portomesenteric vein (PMV) involvement. SUMMARY BACKGROUND DATA/BACKGROUND:Current comparative studies on tangential versus segmental PVR as part of pancreatoduodenectomy for pancreatic cancer include all degrees of PMV involvement, including cases where tangential PVR may not be a feasible approach, limiting the clinical applicability. METHODS:International retrospective study in 10 centers from 5 countries, including all consecutive patients after pancreatoduodenectomy with PVR for pancreatic cancer with ≤180° PMV involvement on cross-sectional imaging at diagnosis (2014-2020). Cox and logistic regression analyses were performed to investigate the association of tangential versus segmental PVR with overall survival (OS) from surgery, recurrence-free survival (RFS), locoregional recurrence, and in-hospital/30-day major morbidity, adjusting for potential confounders. RESULTS:Overall, 357 patients who underwent pancreatoduodenectomy with PVR were included (42% tangential PVR, 58% segmental PVR). The adjusted risk for in-hospital/30-day major morbidity was 23% (95%CI, 17-32) after tangential and 23% (95%CI, 17-30) after segmental PVR (P=0.98). After adjusting for confounders, PVR type was not associated with OS (HR=0.94 [95%CI, 0.69-1.30]), RFS (HR=0.94 [95% CI, 0.69 to 1.28), and locoregional recurrence (OR=0.76 [95%CI, 0.40-1.46]). CONCLUSIONS:In patients undergoing pancreatoduodenectomy for pancreatic cancer with ≤180° PMV involvement, the type of PVR (i.e., tangential vs. segmental) was not associated with differences in surgical and oncological outcome. This suggest that if both procedures are technically feasible, surgeons can choose the type of PVR based on their preference.

BACKGROUND:To improve outcomes for patients with pancreatic ductal adenocarcinoma, a complete resection is crucial. However, evidence regarding the impact of microscopically positive surgical margins (R1) on recurrence is conflicting due to varying definitions and limited populations of patients with borderline-resectable and locally advanced pancreatic cancer. Therefore, we aimed to determine the impact of the resection margin status on recurrence and survival in patients with pancreatic ductal adenocarcinoma stratified by local tumor stage. METHODS:We performed a retrospective cohort study on patients with nonmetastatic pancreatic ductal adenocarcinoma undergoing pancreatectomy at a high-volume academic center (2012-2022). R1 was subclassified into microscopic invasion of the margin (R1 direct) or carcinoma present within 1 mm but not directly involving the margin (R1 <1 mm). Overall survival and time to recurrence were assessed by log-rank test and multivariable Cox regression. RESULTS:Of 472 included patients, 154 (33%) had an R1 resection. Of those 50 (32%) had R1 <1 mm and 104 (68%) R1 direct. The most commonly involved margin was the uncinate (41%) followed by the pancreatic neck (16%) and vascular margins (9%). Overall, a stepwise shortening of time to recurrence and overall survival was observed with an increasing degree of margin involvement (median time to recurrence: R0 39.3 months, R1 <1 mm 16.0 months, and R1 direct 13.4 months, all comparisons P < .05). Multivariable analyses confirmed the independent prognostic value of R1 direct across all surgical stages. CONCLUSION/CONCLUSIONS:The resection margin status portends an independent prognostic value. Moreover, this association persists in patients with borderline-resectable and locally advanced pancreatic cancer. Increasing the R0-resection rate is the most important potentially influenceable prognostic factor for improving surgery-related outcomes.

BACKGROUND:IPMN consensus guidelines make implicit judgments on what cancer risk level should prompt surgery. We used decision modeling to estimate this cancer risk threshold (CRT) for BD-IPMN patients. METHODS:We created a decision model to compare quality-adjusted life years (QALYs) following surgery or surveillance for BD-IPMNs. We simulated treatment decisions for hypothetical patients, varying age, comorbidities and lesion location (pancreatic head/tail). The base case was a 60-year-old patient with mild comorbidities and pancreatic head IPMN. Probabilities, life expectancies, and utilities were incorporated from literature/public datasets. CRT was defined as the level of cancer risk at which the expected value of QALYs for surgery first exceeded that of surveillance. RESULTS:In the base case, surgery was preferred over surveillance, yielding 21.90 vs. 21.88 QALYs. The optimal CRT for a BD-IPMN patient depended on age, comorbidities, and location. CRT in the base case was 20 % and 3 % for an IPMN in the head and tail of the pancreas, respectively. Other drivers of preferred treatment were age and likelihood of postoperative mortality. CONCLUSION/CONCLUSIONS:For BD-IPMNs, the optimal CRT varies depending on patient age and risk of surgical complications. Personalized risk threshold values could guide treatment decisions and inform future treatment consensus guidelines.

BACKGROUND:The existence of sociodemographic disparities in pancreatic cancer has been well-studied but how these disparities have changed over time is unclear. The purpose of this study was to longitudinally assess patient management in the context of sociodemographic factors to identify persisting disparities in pancreatic cancer care. METHODS:Using the National Cancer Database, patients diagnosed with pancreatic ductal adenocarcinoma from 2010 to 2017 were identified. The primary outcomes were surgical resection and/or receipt of chemotherapy. Outcome measures included changes in associations between sociodemographic factors (i.e., sex, age, race, comorbidity index, SES, and insurance type) and treatment-related factors (i.e., clinical stage at diagnosis, surgical resection, and receipt of chemotherapy). For each year, associations were assessed via univariate and multivariate analyses. RESULTS:Of 75,801 studied patients, the majority were female (51%), White (83%), and had government insurance (65%). Older age (range of OR 2010-2017 [range-OR]:0.19-0.29), Black race (range-OR: 0.61-0.78), lower SES (range-OR: 0.52-0.94), and uninsured status (range-OR: 0.46-0.71) were associated with lower odds of surgical resection (all p < 0.005), with minimal fluctuations over the study period. Older age (range-OR: 0.11-0.84), lower SES (range-OR: 0.41-0.63), and uninsured status (range-OR: 0.38-0.61) were associated with largely stable lower odds of receiving chemotherapy (all p < 0.005). CONCLUSIONS:Throughout the study period, age, SES, and insurance type were associated with stable lower odds for both surgery and chemotherapy. Black patients exhibited stable lower odds of resection underscoring the continued importance of mitigating racial disparities in surgery. Investigation of mechanisms driving sociodemographic disparities are needed to promote equitable care.

BACKGROUND:The American Joint Committee on Cancer (AJCC) eighth edition is based on pancreatic intraepithelial neoplasia-derived pancreatic ductal adenocarcinoma (PDAC), a biologically distinct entity from intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer. The role of nodal disease and the AJCC's prognostic utility for IPMN-derived pancreatic cancer are unclear. This study aimed to evaluate the prognostic role of nodal disease and the AJCC eighth-edition N-staging for IPMN-derived pancreatic cancer. METHODS:Upfront-surgery patients with IPMN-derived PDAC from four centers were stratified according to the AJCC eighth-edition N stage. Disease characteristics were compared using descriptive statistics, and both overall survival (OS) and recurrence-free survival (RFS) were evaluated using log-rank tests. Multivariable Cox regression was performed to determine the prognostic value of N stage for OS, presented as hazard ratios with 95 % confidence intervals (95 % CIs). A lowest p value log-rank statistic was used to derive the optimal cutoff for node-positive disease. RESULTS:For 360 patients, advanced N stage was associated with worse T stage, grade, tubular histology, and perineural and lymphovascular invasion (all p < 0.05). The median OS was 98.3 months (95 % CI 82.8-122.0 months) for N0 disease, 27.8 months (95 % CI 24.4-41.7 months) for N1 disease, and 18.1 months (95 % CI 16.2-25.9 months) for N2 disease (p < 0.001). The AJCC N stage was validated and associated with worse OS (N1 [HR 1.64; range, 1.05-2.57], N2 [HR2.42; range, 1.48-3.96]) and RFS (N1 [HR 1.81; range, 1.23-2.68], N2 [HR 3.72; range, 2.40-5.77]). The optimal cutoff for positive nodes was five nodes. CONCLUSION/CONCLUSIONS:The AJCC eighth-edition N-staging is valid and prognostic for both OS and RFS in IPMN-derived PDAC.