Faculty Bibliography

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.

The majority of patients diagnosed with pancreatic cancer already have metastatic disease at the time of presentation, which results in a 5-year survival rate of only 13%. However, multiagent chemotherapy regimens can stabilize the disease in select patients with limited metastatic disease. For such patients, a combination of curative-intent therapy and systemic therapy may potentially enhance outcomes compared to using systemic therapy alone. Of note, the evidence supporting this approach is primarily derived from retrospective studies and may carry a significant selection bias. Looking ahead, ongoing prospective trials are exploring the efficacy of curative-intent therapy in managing oligometastatic pancreatic cancer and the implementation of treatment strategies based on specific biomarkers. The emergence of these trials, coupled with the development of less invasive therapeutic modalities, provides hope for patients with oligometastatic pancreatic cancer.

PURPOSE/OBJECTIVE:Dynamics of carbohydrate antigen 19-9 (CA19-9) often inform treatment decisions during and after neoadjuvant chemotherapy (NAT) of patients with pancreatic ductal adenocarcinoma (PDAC). However, considerable dispute persists regarding the clinical relevance of specific CA19-9 thresholds and dynamics. Therefore, we aimed to define optimal thresholds for CA19-9 values and create a biochemically driven composite score to predict survival in CA19-9-producing patients with PDAC after NAT. METHODS:Patients with PDAC who underwent NAT and surgical resection from 2012 to 2022 were retrospectively identified from three high-volume centers. CA19-9 nonproducers and patients with 90-day mortality, and macroscopically incomplete resections were excluded. A composite score was created on the basis of relative CA19-9 change and newly defined optimal thresholds of pre- and postneoadjuvant values for overall survival (OS) using patients from two centers and validated using data from the third center. RESULTS:< .001). Major serological response (90% decrease of CA19-9) had a positive and negative predictive value of 32% and 88%, respectively. CONCLUSION/CONCLUSIONS:The composite score consisting of CA19-9 levels at diagnosis, after neoadjuvant treatment, and its dynamics demonstrates prognostic discrimination between low and high scores. However, better predictive biomarkers are needed to facilitate treatment decisions during neoadjuvant treatment.

AIM/OBJECTIVE:To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer. SUMMARY BACKGROUND DATA/BACKGROUND:Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients. METHODS:This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS. RESULTS:Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007). CONCLUSION/CONCLUSIONS:Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence.

OBJECTIVE:To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS. SUMMARY BACKGROUND DATA/BACKGROUND:Long-term survival (>5 y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear. METHODS:An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression. RESULTS:3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features. CONCLUSIONS:This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS.

OBJECTIVE:To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section. SUMMARY BACKGROUND DATA/BACKGROUND:The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable. METHODS:Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002-2022) from six international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival (RFS). RESULTS:Overall, 832 patients with IPMN-derived PDAC were included with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared to those with an R1 status (65.8 vs. 26.3 mo P<0.001). Patients without dysplasia at the pancreatic neck margin had similar OS compared to those with low-grade dysplasia (mOS: 78.8 vs. 66.8 months, P=0.344). However, high-grade dysplasia (mOS: 26.1 mo, P=0.001) and invasive cancer (mOS: 25.0 mo, P<0.001) were associated with significantly worse OS compared to no or low-grade dysplasia. Patients who underwent conversion of high-risk margins (high-grade or invasive cancer) to a low-risk margin (low-grade or no dysplasia) after intraoperative frozen section had significantly superior OS compared to those with a high-risk neck margin on final pathology (mOS: 76.9 vs. 26.1 mo P<0.001). CONCLUSIONS:In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible.

PURPOSE/OBJECTIVE:The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS:This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS:> .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION/CONCLUSIONS:Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

BACKGROUND:Little is known about the prognostic significance of pancreatic duct (PD) dilation following pancreatoduodenectomy for intraductal papillary mucinous neoplasms (IPMN). Although PD dilation is typically the hallmark radiographic feature of IPMN, other causes of PD dilation exist, including anastomotic stricture, pancreatitis, senescence, and postsurgical passive dilation. Therefore, PD dilation after pancreatoduodenectomy for IPMN represents a diagnostic and management dilemma. The purpose of this study was to evaluate the significance of PD dilation after pancreatoduodenectomy for noninvasive IPMN. METHODS:All patients who underwent pancreatoduodenectomy for noninvasive IPMN at nine pancreatic academic centers between 2013 and 2018 were included. Variables were entered prospectively into institutional databases and retrospectively reviewed for the purpose of this study. Dilation of the PD remnant was defined as a duct diameter of ≥5 mm, according to international guidelines. RESULTS:Four-hundred and eighty-one patients were included in this study. The mean age of the patients was 66 years (range 30-90). Patients were surveilled for a median of 4.5 (+/-2.3; max 10.6) years. During follow-up, 132 patients (27.4%) developed PD dilation in the remnant tissue after a median of 3.3 years. Multivariable analysis demonstrated that older age at the time of pancreatoduodenectomy (P=0.01) and longer surveillance duration (P=0.002) were predictors of PD dilation. Interestingly, neither the pathological IPMN subtype (branch-duct vs. main duct/mixed, P=0.96) nor the preoperative PD diameter (P=0.14) was associated with an increased risk of PD dilation in the remnant. During follow-up, IPMN recurrence was suspected in the remaining 72 patients (18.4%), solely because of ductal dilation on cross-sectional imaging in 97% (70/72). Completion pancreatectomy was performed in only 16 patients (3.3%), of whom only four (0.8%) had invasive carcinoma. Three of these four patients had high-grade dysplasia in the original pancreatoduodenectomy specimen, whereas only one had a low-grade dysplastic lesion initially. On multivariable analysis, no variable was predictive of IPMN recurrence in the remnant. CONCLUSIONS:New main duct dilation in the pancreatic remnant after pancreatoduodenectomy for IPMN is common, occurring in 27% of the patients. The duration of surveillance is the main factor associated with remnant PD dilation, suggesting that this is likely a physiologic phenomenon. Although recurrence of IPMN in the remnant is often suspected, only 0.8% of patients develop an invasive carcinoma in the pancreatic remnant requiring completion pancreatectomy.

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC.