Cross-Sectional Imaging Characteristics of Pancreatic Intraductal Oncocytic Papillary Neoplasms.

PURPOSE: Pancreatic intraductal oncocytic papillary neoplasms (IOPN) are rare precursors to pancreatic ductal adenocarcinoma. We report cross-sectional computed tomography and magnetic resonance imaging (where available) findings of pancreatic IOPNs. MATERIALS AND METHODS: Consecutive cases of pancreatic IOPNs identified on pathology between 2008 and 2020 at University of Pittsburgh and Johns Hopkins University were included in the study. Cross-sectional imaging of all patients was reviewed by two subspecialty trained abdominal radiologists. Patient demographics, cross-sectional imaging appearances and growth characteristics were evaluated. RESULTS: In this dual-center study, 14 patients with IOPNs were included. Median age was 64 years, and 64% were male. The median size of the lesions was 5.4 cm (range, 1.4-12.3 cm). All patients had either an enhancing mural nodule (93% of patients) and/or thick internal septations (29%). Thin/imperceptible outer wall was seen in 93%. Main duct was involved in 64% of the cases. Only 14% of the cases did not demonstrate abutment of the main duct. Histologic evaluation of surgical specimen showed high-grade dysplasia without invasive carcinoma in 57% and invasive carcinoma in 43% of cases. Lesions with invasive carcinoma were larger (7.1 cm vs 4.3 cm, P = 0.05) and tended to have larger mural nodule (3.7 cm vs 1.8 cm) compared with those without invasive carcinoma. CONCLUSION: Pancreatic IOPNs are rare cystic premalignant lesions, which among resected cases, are predominantly seen in middle aged men, are often large, have enhancing mural nodules and frequently harbor invasive carcinoma.

Learning Curve of a Laparoscopic Pancreaticoduodenectomy Program at a Second Institution.

BACKGROUND: Historically, pancreaticoduodenectomy (PD) has been performed via a laparotomy, but increasingly, laparoscopic and robotic platforms are being employed for PD. Laparoscopic PD has a steep surgeon specific learning curve and programmatic elements that must be optimized. These factors may limit a surgeon who is proficient at laparoscopic PD to develop a program at another institution. We hypothesize that the learning curve for a surgeon transferring a program to a second institution is shorter than the initial laparoscopic PD learning curve for the same surgeon. METHODS: A retrospective review of patients who underwent laparoscopic PD for any indication at the first institution (FI) from 2012 to 2017 and the second institution (SI) from 2018 to 2021 was conducted. Standard statistical analysis was performed. The learning curve was identified using one-sided CUSUM analysis of operative times. RESULT: We identified 110 participants, 90 from the FI and 20 from the SI. More patients at the FI were diagnosed with periampullary adenocarcinoma on final pathology compared to the SI (65.6% vs 40.0%, P = .0132). FI operative times stabilized after the 25th laparoscopic PD and SI operative times stabilized after the 5th operation. No statistically significant difference was identified in postoperative complications. CONCLUSIONS: The learning curve and average operative time of an SI laparoscopic PD program was shorter than the initial learning curve for a single surgeon with comparable outcomes. This suggests that complex minimally invasive surgical programs can be safely transferred to another high-volume institution without significant loss of progress.

Postoperative infectious complications worsen oncologic outcomes following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy (PD) remains the only curative option for patients with pancreatic adenocarcinoma (PDAC). Infectious complications (IC) can negatively impact patient outcomes and delay adjuvant therapy in most patients. This study aims to determine IC effect on overall survival (OS) following PD for PDAC. STUDY DESIGN: Patients who underwent PD for PDAC between 2010 and 2020 were identified from a single institutional database. Patients were categorized into two groups based on whether they experienced IC or not. The relationship between postoperative IC and OS was investigated using Kaplan-Meier and Cox-regression multivariate analysis. RESULTS: Among 655 patients who underwent PD for PDAC, 197 (30%) experienced a postoperative IC. Superficial wound infection was the most common type of infectious complication (n = 125, 63.4%). Patients with IC had significantly more minor complications (Clavien-Dindo [CD] < 3; [59.4% vs. 40.2%, p < 0.001]), major complications (CD ≥ 3; [37.6% vs. 18.8%, p < 0.001]), prolonged LOS (47.2% vs 20.3%, p < 0.001), biochemical leak (6.1% vs. 2.8%, p = 0.046), postoperative bleeding (4.1% vs. 1.3%, p = 0.026) and reoperation (9.6% vs. 2.2%, p < 0.001). Time to adjuvant chemotherapy was delayed in patients with IC versus those without (10 vs. 8 weeks, p < 0.001). Median OS for patients who experienced no complication, noninfectious complication, and infectious complication was 33.3 months, 29.06 months, and 27.58 months respectively (p = 0.023). On multivariate analysis, postoperative IC were an independent predictor of worse OS (HR 1.32, p = 0.049). CONCLUSIONS: IC following PD for PDAC independently predict worse oncologic outcomes. Thus, efforts to prevent and manage IC should be a priority in the care of patients undergoing PD for PDAC.

Improved Clinical Staging System for Localized Pancreatic Cancer Using the ABC Factors: A TAPS Consortium Study.

PURPOSE: Previous studies suggest that besides anatomy (A: resectable, borderline resectable [BR], or locally advanced [LA]) also biologic (B: carbohydrate antigen 19-9 [CA 19-9]) and conditional (C: performance status) factors should be considered when staging patients with localized pancreatic ductal adenocarcinoma (PDAC). The prognostic value of the combined ABC factors has not been quantitatively validated. METHODS: In this retrospective cohort study, we evaluated patients with localized PDAC treated with initial (modified) fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) at five high-volume pancreatic cancer centers in the United States and the Netherlands (2012-2019). Multivariable Cox proportional hazards analysis was used to investigate the impact of the ABC factors for overall survival (OS). RESULTS: Overall, 1,835 patients with localized PDAC were included. Tumor stage at diagnosis was potentially resectable in 346 (18.9%), BR in 531 (28.9%), and LA in 958 (52.2%) patients. The baseline CA 19-9 was >500 U/mL in 559 patients (32.5%). Performance status was ≥1 in 1,110 patients (60.7%). Independent poor prognostic factors for OS were BR disease (hazard ratio [HR], 1.26 [95% CI, 1.06 to 1.50]), LA disease (HR, 1.71 [95% CI, 1.45 to 2.02]), CA 19-9 >500 U/mL (HR, 1.36 [95% CI, 1.21 to 1.52]), and WHO performance status ≥1 (HR, 1.31 [95% CI, 1.16 to 1.47]). Patients were assigned 1 point for each poor ABC factor and 2 points for LA disease. The median OS for patients with score 0-4 was 49.7, 29.9, 22.0, 19.1, and 14.9 months with corresponding 5-year OS rates of 47.0%, 28.9%, 19.2%, 9.3%, and 4.8%, respectively. CONCLUSION: The ABC factors of tumor anatomy, CA 19-9, and performance status at diagnosis were independent prognostic factors for OS in patients with localized PDAC treated with initial (m)FOLFIRINOX. Staging of patients with localized PDAC at diagnosis should be based on anatomy, CA 19-9, and performance status.

Pancreatic Cancer Multidisciplinary Clinic is Associated with Improved Treatment and Elimination of Socioeconomic Disparities.

OBJECTIVE: To identify the association between multidisciplinary clinic (MDC) management and disparities in treatment for patients with pancreatic cancer. BACKGROUND: Socioeconomic status (SES) predicts treatment and survival for pancreatic cancer. Multidisciplinary clinics (MDCs) may improve surgical management for these patients. METHODS: This is a retrospective cohort study (2010-2018) of all pancreatic cancer patients within a large, regional hospital system with a high-volume pancreatic cancer MDC. The primary outcome was receipt of treatment (surgery, chemotherapy, radiation, clinical trial participation, and palliative care); the secondary outcomes were overall survival and MDC management. Multiple logistic regressions were used for binary outcomes. Survival was analyzed using Kaplan-Meier survival analysis, Cox proportional hazards, and inverse probability of treatment weighting (IPTW). RESULTS: Of the 4141 patients studied, 1420 (34.3%) were managed by the MDC. MDC management was more likely for patients who were younger age, married, and privately insured, while less likely for low SES patients (all p < 0.05). MDC patients were more likely to receive all treatments, including neoadjuvant chemotherapy (OR 3.33, 95% CI 2.82-3.93), surgery (OR 1.39, 95% CI 1.15-1.68), palliative care (OR 1.21, 95% CI 1.05-1.38), and clinical trial participation (OR 3.76, 95% CI 2.86-4.93). Low SES patients were less likely to undergo surgery outside of the MDC (OR 0.47, 95% CI 0.31-0.73) but there was no difference within the MDC (OR 1.10, 95% CI 0.68-1.77). Across multiple survival analyses, low SES predicted inferior survival outside of the MDC, but there was no association among MDC patients. CONCLUSION: Multidisciplinary team-based care increases rates of treatment and eliminates socioeconomic disparities for pancreatic cancer patients.

Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

National adoption of neoadjuvant chemotherapy: paradigm shift in the treatment of pancreatic cancer.

BACKGROUND: The historical standard of care in treating operable pancreatic cancer via upfront surgery has been challenged recently using a neoadjuvant approach. The aim of the study is to examine the national practice patterns in the management of pancreatic cancer with an emphasis on the trends of neoadjuvant systemic therapy use. METHODS: This is a cross-sectional time-series study using the National Cancer Database from 2006 to 2019. Patients who underwent resection for stage I-II pancreatic adenocarcinoma were selected. RESULTS: Overall, 25% of patients had neoadjuvant chemotherapy, 49% had surgery followed by adjuvant chemotherapy and 26% had surgery alone. The rate of neoadjuvant chemotherapy has increased from 11% in 2006 to 43% in 2019. There was a decrease in the rate of surgery followed by chemotherapy from 48% to 38%, and a decrease in the rate of surgery alone from 41% to 19%. The rate of radiation therapy use has decreased over time, as has the resection rate, while median overall survival has steadily improved over the years. CONCLUSIONS: In 2019, the rate of using neoadjuvant systemic therapy overtook the rate of surgery first followed by adjuvant systemic therapy, marking a pragmatic national shift in the clinical management of pancreatic cancer.

The risk of clinically-relevant pancreatic fistula after pancreaticoduodenectomy is better predicted by a postoperative trend in drain fluid amylase compared to day 1 values in isolation.

BACKGROUND: Recent studies support early drain removal after pancreaticoduodenectomy in patients with a drain fluid amylase on postoperative day 1 (DFA1) level of ≤5,000. The use of DFA1 to guide drain management is increasingly common among pancreatic surgeons; however, the benefit of checking additional drain fluid amylases beyond DFA1 is less known. We sought to determine whether a change in drain fluid amylase (ΔDFA) is a more reliable predictor of clinically relevant postoperative fistula than DFA1 alone. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Plan, pancreaticoduodenectomy patients with intraoperative drain placement, known DFA1, highest recorded drain fluid amylase value on postoperative day 2 to 5 (DFA2nd), day of drain removal, and clinically relevant postoperative fistula status were reviewed. Logistic models compared the predictive performance of DFA1 alone versus DFA1 + ΔDFA. RESULTS: A total of 2,417 patients with an overall clinically relevant postoperative fistula rate of 12.6% were analyzed. On multivariable regression, clinical predictors for clinically relevant postoperative fistula included body mass index, steroid use, operative time, and gland texture. These variables were used to develop model 1 (DFA1 alone) and model 2 (DFA1 + ΔDFA). Model 2 outperformed model 1 in predicting the risk of clinically relevant postoperative fistula. According to model 2 predictions, the risk of clinically relevant postoperative fistula increased with any rise in drain fluid amylase, regardless of whether the DFA1 was above or below 5,000 U/L. The risk of clinically relevant postoperative fistula significantly decreased with any drop in drain fluid amylase, with an odds reduction of approximately 50% corresponding with a 70% decrease in drain fluid amylase (P < .001). A risk calculator was developed using DFA1 and a secondary DFA value in conjunction with other clinical predictors for clinically relevant postoperative fistula. CONCLUSION: Clinically relevant postoperative fistula after pancreaticoduodenectomy is more accurately predicted by DFA1 and ΔDFA versus DFA1 in isolation. We developed a novel risk calculator to provide an individualized approach to drain management after pancreaticoduodenectomy.

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms (Pseudomyxoma Peritonei).

BACKGROUND: Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. METHODS: Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). RESULTS: Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). CONCLUSIONS: Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Management of Intra-Operative Hemorrhage and Safe Venous Resection in Robotic-Assisted Pancreaticoduodenectomy: Techniques to Avoid Open Conversion.

Robotic-assisted pancreaticoduodenectomy (RPD) is increasingly utilized for operable periampullary malignancies with oncologic outcomes compared to the open approach. Indications can be carefully expanded to select borderline resectable tumors, but bleeding remains a significant threat. Moreover, the need for venous resection and reconstructions increases as more complex cases are selected to undergo RPD. Herein, we present a video compilation of our approach to safe venous resections during RPD, followed by several video examples of intraoperative hemorrhage highlighting various techniques and tips that the console and bedside surgeon can utilize to control bleeding. Conversion to an open procedure should not be seen as a failure but rather as a safe and sound intraoperative decision made in the patient's best interest. Nonetheless, with experience and proper technique, many intraoperative hemorrhages and venous resections can be managed in a minimally invasive fashion.

No survival benefit with suboptimal CA19-9 response: defining effective neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer.

BACKGROUND/PURPOSE: Neoadjuvant chemotherapy (NAC) is gaining popularity over a surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, what constitutes effective neoadjuvant chemotherapy is unknown. METHODS: We retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010-2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. We utilized Kaplan-Meier and multivariable-adjusted Cox models and competing risk subdistribution methods for statistical analysis. RESULTS: 586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR = 0.72, p = 0.02), but not from surgery (HR = 0.81, p = 0.1). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3 m vs. 21.5 m, p = 0.005) or the 117 SF patients (39.3 m vs. 19.5 m, p < 0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients. The accumulative incidence of liver metastases (but not other metastases) was significantly reduced only in patients with optimal CA19-9 response to NAC (multivariable-adjusted subdistribution HR = 0.26, p = 0.03). CONCLUSION: CA19-9 response to NAC may serve as the marker for effective NAC. These findings warrant validation in a multi-institutional study.

Impact of Extended Antibiotic Use After Pancreaticoduodenectomy for Patients with Preoperative Metallic Biliary Stenting Treated with Neoadjuvant Chemotherapy.

INTRODUCTION: Pancreaticoduodenectomy (PD) remains a complex surgical procedure with infectious complications affecting nearly 50% of patients. Patients who undergo biliary drainage with stent placement prior to neoadjuvant treatment (NAT) reportedly have higher infection rates following PD. The aim of the current study is to evaluate the differences in postoperative infectious complication rates based on the duration of post operative prophylactic antibiotics in patients with indwelling metal biliary stent who had NAT. METHODS: A retrospective institutional pancreatic cancer database was queried for patients who had a metal biliary stent placed prior to NAT initiation, followed by subsequent PD between 2014 and 2021. Duration of postoperative prophylactic antibiotics was defined as short (SC: ≤ 24 h) or extended (EC: > 24 h-7 days). The primary outcome of interest was surgical site infection (SSI). RESULTS: Two hundred and ninety-five (n = 295) patients were identified of which the majority (n = 205, 69.5%) received a short course of antibiotics postoperatively. Baseline characteristics were similar between the two cohorts including age, sex, BMI, and comorbidity index. EC patients received more NAT cycles (4 vs. 3, p < 0.001) and underwent an open PD more frequently (61.8% vs. 41.0%, p < 0.001). SSI occurred in 64 (21.7%) patients; SC cohort: 54, 26.3% vs. EC cohort:10, 11.1%, (p = 0.003). Additionally, the SC cohort demonstrated a higher incidence of major complications (Clavien-Dindo ≥ 3: 51 [24.9%] vs. 13 [14.4%], p = 0.045). On the logistic regression model examining factors associated with SSI, higher BMI (continuous variable) was associated with increased odds of SSI (OR: 1.05 [95%CI: 1.00, 1.10, p = 0.040), while EC was protective (OR: 0.36 [95%CI: 0.17, 0.75], p = 0.007). CONCLUSIONS: These data suggest that an extended course of perioperative antibiotic correlates with reductions in SSI and major morbidity following PD in patients with a metallic biliary stent placed prior to NAT course. These results require validation in a future randomized clinical trial examining a larger cohort of patients with further emphasis on the types of perioperative antibiotics administered.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients.

BACKGROUND: Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients METHOD: A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. RESULTS: 742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56-0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53-0.86],p = 0.002) for overall survival. CONCLUSION: In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

Evaluation of Adjuvant Chemotherapy Survival Outcomes Among Patients With Surgically Resected Pancreatic Carcinoma With Node-Negative Disease After Neoadjuvant Therapy.

Importance: Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT). Objectives: To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS). Design, Setting, and Participants: A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology. Exposures: Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT. Main Outcomes and Measures: The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis. Results: In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04). Conclusions and Relevance: The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.