Faculty Bibliography

OBJECTIVE:To establish a novel method for evaluating carbohydrate antigen 19-9 (CA19-9) during neoadjuvant therapy (NAT) and assess its role in predicting overall (OS) and disease-free (DFS) survival in borderline resectable pancreatic adenocarcinoma (BR-PC). SUMMARY BACKGROUND DATA/BACKGROUND:Static CA19-9 values or percentage changes often fail to capture therapeutic responses in patients with BR-PC undergoing NAT. Improved evaluation methods are essential for guiding the treatment. METHODS:This was a retrospective multicenter study of patients who underwent BR-PC surgery. Two parameters were developed: slope coefficient (SC, change in CA19-9 divided by therapy duration) and mean δf (mδf, calculated as the sum of CA19-9 values over therapy intervals divided by the number of 15-day periods). The main objective was to correlate mδf with OS thresholds derived using a maximally selected log-rank statistic and validated in independent cohorts. RESULTS:Overall, 991 patients (median age 65 [59-71] years; 49% male) were included. The thresholds for mδf were defined as U.mL-1. month-1 (negative SC) and U.mL-1. month-1 (positive SC). Patients with mδf below these thresholds had significantly better prognoses, with hazard ratios (HR) for OS (95% CI) of 0.6 (0.4-0.8; P<0.01) and 0.4 (0.2-0.9; P=0.04) for negative and positive SC, respectively. Both thresholds were validated for mOS, with 29 vs 22 months (P=0.015) and 32 vs 16 months (P=0.0034) for negative and positive SC, respectively. Similarly, the mDFS was 13 vs 10 months (P=0.011) and 12 vs 7 months (P=0.0018), respectively. CONCLUSION/CONCLUSIONS:This CA19-9 evaluation approach accurately predicts survival outcomes, offering a valuable tool for optimizing treatment strategies. An mδf calculator is available at https://www.pancpals.com/tools.

BACKGROUND:The National Comprehensive Cancer Network guidelines consider pancreatic cancer with celiac axis (CA), proper hepatic artery (PHA), and superior mesenteric artery (SMA) involvement unresectable. Thus, technical reports and video illustrations of these operations are rare. We report the stepwise management of multivascular reconstruction for Mayo Clinic class IIIb CA resections at New York University Langone Health, a dedicated center of excellence in pancreatic surgery. METHODS:We illustrated the management of a 56-year-old patient with biopsy-confirmed pancreatic ductal adenocarcinoma arising from the pancreatic body and involving the CA, PHA, SMA, and mesentericoportal venous axis. PERIOPERATIVE MANAGEMENT/UNASSIGNED:The preoperative stepwise considerations include: 1) mandatory patient selection; 2) planning vascular reconstructability; 3) tailoring risk assessment while carefully considering the need for total pancreatectomy, total gastrectomy, and mesenteric/hepatic revascularization; and 4) 3D-reconstruction for arterial evaluation. The key intraoperative considerations include: 1) selective and sequential clamping for vascular reconstruction in a "domino" fashion, to minimize warm ischemic time 2) a combined multi-surgeon approach to comprehensively tackle vascular reconstructions; 3) a low threshold for total pancreatectomy to avoid pancreatic leak; and 4) two-stage surgery to reassess the blood supply to the liver and stomach for on-demand gastric preservation instead of a theoretically advised total gastrectomy. CONCLUSION/CONCLUSIONS:Liver, stomach, and bowel vascularization present life-threatening risks that require an extensive preoperative evaluation and a multidisciplinary approach. Our stepwise management for these extensive operations includes total pancreatectomy, "domino" vascular reconstruction, and two-stage surgery.

PURPOSE/OBJECTIVE:Local and distant progression remain common following resection of resectable pancreatic ductal adenocarcinoma (PDAC) despite adjuvant multiagent chemotherapy. We report a prospective institutional phase I trial incorporating adjuvant GVAX vaccine, low-dose cyclophosphamide (Cy) and SBRT followed by FOLFIRINOX (FFX) among patients who underwent resection of high-risk PDAC. PATIENTS AND METHODS/METHODS:The study design was a modified 3+3. Cohort 1 received 5-fraction SBRT to 33 Gy to the tumor bed and 25 Gy to elective nodes followed by 6 cycles of full dose FFX. After toxicity review, cohort 2 had SBRT and were switched to modified FFX (mFFX). Cohort 3 had 1 cycle of Cy/GVAX followed by SBRT, mFFX, and 4 cycles of maintenance Cy/GVAX with 6-month Cy/GVAX boosts until progression. RESULTS:19 patients were enrolled with a median follow-up of 36.2 months. To be eligible, patients were required to have close/positive margins (within ≤1 mm) (71%) and/or lymph node metastasis (79%). Overall, 63% of patients had both. In cohort 1, 67% of patients received 6 cycles of FFX; in cohort 2, 75% received 6 cycles of modified FFX. In cohort 3, 12 patients received the first dose of Cy/GVAX and SBRT with 10 individuals (83%) receiving 6 cycles of mFFX. Cohort 3 had acceptable levels of grade ≥3 thrombocytopenia, neutropenia, and diarrhea after two cycles of mFFX. Median OS/DFS for the overall cohort and cohort 3 was 36.2/18.2 months and 61.3/24.1 months, respectively. 1-year and 2-year OS for cohort 3 was 83%/75%, respectively. At last follow-up (median= x), 5 patients were alive (42%) in cohort 3. CONCLUSION/CONCLUSIONS:This is the first prospective trial to evaluate adjuvant GVAX, Cy, SBRT, and mFFX in resected PDAC patients with high-risk features. This combination regimen was well tolerated with limited toxicity and promising survival outcomes, warranting future studies to validate this regimen in the adjuvant setting.

SUMMARY OF BACKGROUND DATA/BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). OBJECTIVE:To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. METHODS:Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. RESULTS:In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. CONCLUSION/CONCLUSIONS:After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

BACKGROUND:Current guidelines recommend the resection of main duct- (MD) and mixed-type (MT) intraductal papillary mucinous neoplasms (IPMN) based on specific risk criteria to prevent or treat pancreatic cancer in selected patients. This paradigm follows high rates of malignancy observed in published surgical series. The aim of this systematic review and meta-analysis was to provide robust, pooled rates of invasive carcinoma (IC) and high-grade dysplasia (HGD) in resected MD- and MT-IPMNs of the pancreas. METHODS:The PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL databases were systematically searched. Studies that reported rates of IC or HGD, diagnosed by histopathology of surgical specimens, in MD- or MT-IPMNs were included. Pooled prevalence with 95 % confidence interval (95 % CI) was calculated using a random effects model. Galbraith plots were used to evaluate heterogeneity. Risk of bias was assessed using the National Institutes of Health Quality Assessment Tool. RESULTS:Based on 51 studies, 59 % (95 % CI: 54 %, 64 %) of resected MD- and MT-IPMN had IC or HGD, with IC in up to 39 % (95 % CI: 33 %, 44 %) of lesions and HGD in 20 % (95 % CI: 16 %, 25 %). Most studies were deemed to be of good quality and Galbraith plots demonstrated high concordance. CONCLUSIONS:These results confirm the rates of IC and HGD in resected MD/MT-IPMNs. However, a significant proportion of patients have benign lesions, and future research is needed to develop precise diagnostics to distinguish between patients with and without high-risk or cancerous disease.

OBJECTIVE:The ISGPS aims to develop a universally accepted complexity and experience grading system to guide the safe implementation of robotic and laparoscopic minimally-invasive pancreatoduodenectomy (MIPD). BACKGROUND:Despite the perceived advantages of MIPD, its global adoption has been slow due to the inherent complexity of the procedure and challenges to acquiring surgical experience. Its wider adoption must be undertaken with an emphasis towards appropriate patient selection according to adequate surgeon and center experience. METHODS:The ISGPS developed a complexity and experience grading system to guide patient selection for MIPD based on an evidence-based review and a series of discussions. RESULTS:The ISGPS complexity and experience grading system for MIPD is subclassified into patient-related risk factors and provider experience-related variables. The patient-related risk factors include anatomical (main pancreatic and common bile duct diameters), tumor-specific (vascular contact), and conditional (obesity and previous complicated upper abdominal surgery/disease) factors, all incorporated in an A-B-C classification, graded as no, a single, and multiple risk factors. The surgeon and center experience-related variables include surgeon total MIPD experience (cut-offs 40 and 80) and center annual MIPD volume (cut-offs 10 and 30), all also incorporated in an A-B-C classification. CONCLUSION/CONCLUSIONS:This ISGPS complexity and experience grading system for robotic and laparoscopic MIPD may enable surgeons to optimally select patients after duly considering specific risk factors known to influence the complexity of the procedure. This grading system will likely allow for a thoughtful and stepwise implementation of MIPD and facilitate a fair comparison of outcome between centers and countries.