Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results From an International Multicenter Study.

PURPOSE: 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: In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .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: 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.

Total Venous Control and Vein-to-the-Right Superior Mesenteric Artery Approach in Robotic Pancreatoduodenectomy.

BACKGROUND: Robotic pancreatoduodenectomy is an increasingly accepted alternative for the treatment of pancreatic ductal adenocarcinoma (PDAC).1 However, the ability to perform a meticulous robotic-assisted superior mesenteric artery (SMA) dissection to obtain a margin-negative resection remains unknown.2 PDAC within the head of the pancreas (HOP) that involves the superior mesenteric vein (SMV) and portal vein (PV) requires total venous control (TVC) and a 'vein-to-the-right' (or anterior artery-first) approach to SMA dissection to minimize venous congestion and operative blood loss.3-5 Here, we demonstrate a robotic pancreatoduodenectomy with TVC and a 'vein-to-the-right' approach. METHODS: A 70-year-old woman with cT2N0M0 HOP PDAC with lateral SMV involvement and right gastroepiploic vein occlusion underwent robotic pancreatoduodenectomy after neoadjuvant chemotherapy. After transecting the pancreas, we achieved TVC by dividing the small venous tributaries and encircling the SMV, splenic vein, and PV. We then proceeded with a 'vein-to-the-right' approach. The inferior pancreatoduodenal arteries were divided to minimize HOP inflow and decrease specimen bleeding. Once the specimen was dissected off the periadventitial plane of the distal SMA, the SMV dissection was carefully performed using a partial side-wall vein resection using a vascular stapler. RESULTS: Total operative time was 7.5 h and estimated blood loss was 25 mL. The patient recovered well postoperatively and was discharged on postoperative day 3. Final pathology exhibited a 2.4 cm, moderately to poorly differentiated adenocarcinoma with negative margins (ypT2N1, 2/38 lymph nodes positive). CONCLUSION: For tumors with lateral vein involvement, robotic pancreatoduodenectomy can be safely performed via TVC and a 'vein-to-the-right' approach.

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Assessing Surgeon Familiarity with the Commission on Cancer Operative Standards for Cancer Surgery.

BACKGROUND: In response to growing evidence that proper performance of operative techniques during cancer surgery is associated with improved patient outcomes, the American College of Surgeons (ACS) implemented six operative standards as part of Commission on Cancer (CoC) accreditation. This study aimed to assess surgeon familiarity with these standards when first introduced and 2 years after their adoption. METHODS: The ACS Cancer Surgery Standards Program distributed an anonymous 36-question survey to CoC-accredited cancer programs in 2021 and 2023. Questions specific to operative techniques determined the Surgery Score, and those specific to the accreditation standards determined the Standards Score. Mean scores were compared using one-way analysis of variance (ANOVA) and t tests. RESULTS: The survey was completed by 376 surgeons in 2021 and 380 surgeons in 2023. The Surgery Scores were higher than the Standards Scores in 2021 and 2023. The surgeons who practiced at institutions with CoC accreditation had significantly higher Standards Scores than the surgeons at non-accredited institutions in 2021 (p = 0.005) and 2023 (p = 0.004), but not significantly different Surgery Scores. CONCLUSIONS: The baseline survey in 2021 demonstrated significant knowledge of technical aspects of cancer surgery among a broad surgeon base, but a need for greater understanding of the accreditation standards. The repeat survey distribution 2 years after rollout of the operative standards and associated educational programing showed increased awareness surrounding the operative standards in 2023 and a trend toward improvement in knowledge of the accreditation standards across all specialties. Further evaluation will be directed toward compliance with the accreditation standards.

Surgical Outcome After Distal Pancreatectomy With and Without Portomesenteric Venous Resection in Patients with Pancreatic Adenocarcinoma: A Transatlantic Evaluation of Patients in North America, Germany, Sweden, and The Netherlands (GAPASURG).

BACKGROUND: Pancreatic adenocarcinoma located in the pancreatic body might require a portomesenteric venous resection (PVR), but data regarding surgical risks after distal pancreatectomy (DP) with PVR are sparse. Insight into additional surgical risks of DP-PVR could support preoperative counseling and intraoperative decision making. This study aimed to provide insight into the surgical outcome of DP-PVR, including its potential risk elevation over standard DP. METHODS: We conducted a retrospective, multicenter study including all patients with pancreatic adenocarcinoma who underwent DP ± PVR (2018-2020), registered in four audits for pancreatic surgery from North America, Germany, Sweden, and The Netherlands. Patients who underwent concomitant arterial and/or multivisceral resection(s) were excluded. Predictors for in-hospital/30-day major morbidity and mortality were investigated by logistic regression, correcting for each audit. RESULTS: Overall, 2924 patients after DP were included, of whom 241 patients (8.2%) underwent DP-PVR. Rates of major morbidity (24% vs. 18%; p = 0.024) and post-pancreatectomy hemorrhage grade B/C (10% vs. 3%; p = 0.041) were higher after DP-PVR compared with standard DP. Mortality after DP-PVR and standard DP did not differ significantly (2% vs. 1%; p = 0.542). Predictors for major morbidity were PVR (odds ratio [OR] 1.500, 95% confidence interval [CI] 1.086-2.071) and conversion from minimally invasive to open surgery (OR 1.420, 95% CI 1.032-1.970). Predictors for mortality were higher age (OR 1.087, 95% CI 1.045-1.132), chronic obstructive pulmonary disease (OR 4.167, 95% CI 1.852-9.374), and conversion from minimally invasive to open surgery (OR 2.919, 95% CI 1.197-7.118), whereas concomitant PVR was not associated with mortality. CONCLUSIONS: PVR during DP for pancreatic adenocarcinoma in the pancreatic body is associated with increased morbidity, but can be performed safely in terms of mortality.

Clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset. MATERIALS AND METHODS: The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed. RESULTS: Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively. CONCLUSION: Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent.

New-onset diabetes is a predictive risk factor for pancreatic lesions in high-risk individuals: An observational cohort study.

Background and Objectives: Pancreatic cancer (PC) is the third cause of cancer-related deaths. Early detection and interception of premalignant pancreatic lesions represent a promising strategy to improve outcomes. We evaluated risk factors of focal pancreatic lesions (FPLs) in asymptomatic individuals at hereditary high risk for PC. Methods: This is an observational single-institution cohort study conducted over a period of 5 years. Surveillance was performed through imaging studies (EUS or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and serum biomarkers. We collected demographic characteristics and used univariate and multivariate logistic regression models to evaluate associations between potential risk factors and odd ratios (ORs) for FPL development. Results: A total of 205 patients completed baseline screening. Patients were followed up to 53 months. We detected FPL in 37 patients (18%) at baseline; 2 patients had lesions progression during follow-up period, 1 of them to PC. Furthermore, 13 patients developed new FPLs during the follow-up period. Univariate and multivariate analyses revealed that new-onset diabetes (NOD) is strongly associated with the presence of FPL (OR, 10.94 [95% confidence interval, 3.01-51.79; P < 0.001]; OR, 9.98 [95% confidence interval, 2.15-46.33; P = 0.003]). Follow-up data analysis revealed that NOD is also predictive of lesions progression or development of new lesions during screening (26.7% vs. 2.6%; P = 0.005). Conclusions: In a PC high-risk cohort, NOD is significantly associated with presence of FPL at baseline and predictive of lesions progression or new lesions during surveillance.

Postoperative Adverse Events Following Neoadjuvant Therapy and Surgery for Borderline Resectable Pancreatic Cancer in a Phase 2 Clinical Trial (Alliance A021501).

BACKGROUND: Postoperative adverse events (AEs) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR-PC) treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. We conducted a preplanned secondary analysis of patients enrolled on the Alliance A021501 clinical trial to quantify perioperative AE rates. METHODS: The A021501 phase 2 trial randomized patients with BR-PC to receive 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX and hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (December 31, 2016 to May 31, 2019). Adverse events were assessed 90 days after pancreatectomy. RESULTS: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n = 32, Arm 1; n = 19, Arm 2) at 28 institutions. Five (10%) patients required reoperation within 90 days; 56% of patients (n = 27/48) experienced at least one grade 3 or higher AE (50% vs. 67%, p = 0.37). Ninety-day mortality was 2.0%. Readmission was less frequent in Arm 1 (16% vs. 42%, p = 0.05), but there were no differences between study arms in rates of reoperation (13% vs. 5%), pancreatic fistula or intra-abdominal abscess requiring drainage (9% vs. 16%), or wound infection (6% vs. 16%). Pancreatic fistula or intra-abdominal abscess requiring drainage was associated with receipt of adjuvant therapy (p = 0.012). No difference in overall survival was observed based on occurrence of postoperative AEs (hazard ratio = 1.1; 95% confidence interval 0.5-2.6). CONCLUSIONS: In this multicenter study, rates of postoperative AEs were consistent with those previously reported. Multimodality trials of preoperative therapy for BR-PC may be performed in the cooperative group setting with careful quality assurance and safety monitoring. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02839343.

Effect of surgical approach on early return to intended oncologic therapy after resection for pancreatic ductal adenocarcinoma.

BACKGROUND: Although robotic pancreatectomy may facilitate an earlier functional recovery, the impact of a robotic pancreatectomy program during its early experience on the timing of return to intended oncologic therapy (RIOT) after surgery is unknown. METHODS: In this retrospective cohort study, we used propensity score matching with a 1:2 ratio to compare patients who underwent robotic or open surgery (distal pancreatectomy or pancreatoduodenectomy) for pancreatic ductal adenocarcinoma (PDAC) during the first 3 years of our robotic pancreatectomy experience (January 2018-December 2021). Generalized estimating equations modeling was used to evaluate the effect of surgical approach on early RIOT, defined as adjuvant chemotherapy initiation within 8 weeks after surgery, and late RIOT, defined as initiation within 12 weeks after surgery. RESULTS: The matched cohort included 26 patients who underwent robotic pancreatectomy and 52 patients who underwent open pancreatectomy. Rates of receipt of adjuvant chemotherapy were 96.2% and 78.9%, respectively. Rate of early RIOT in the robotic group (73.1% was higher than that in the open group (44.2%; P = 0.018). In multivariable analysis, a robotic approach was associated with early RIOT (odds ratio, 3.54; 95% confidence interval 1.08-11.62; P = 0.038). Surgical approach did not impact late RIOT (odds ratio, 3.21; 95% confidence interval 0.71-14.38; P = 0.128). CONCLUSIONS: Compared with open pancreatectomy, robotic pancreatectomy did not delay RIOT. In fact, odds of early RIOT were increased, which supports the oncological safety of our robotic pancreatectomy program during its implementation.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Patient-reported outcome measures in surgical patients with upper gastrointestinal cancers: A qualitative interview study.

BACKGROUND AND OBJECTIVES: Patients with pancreatic and gastroesophageal (PGE) cancers experience high symptom burden, but patient experience throughout multimodality treatment remains unclear. We aimed to delineate the experience and symptom burden of patients throughout their perioperative course. METHODS: Qualitative interviews were performed with 17 surgical patients with PGE cancer. Interview transcripts were analyzed and symptoms were ranked by frequency. An expert panel assessed the relevance of these symptom inventory items. RESULTS: Of the 17 patients included, 35% (n = 6) underwent gastrectomy, 30% (n = 5) underwent esophagectomy, and 35% (n = 6) underwent pancreatectomy; 76% (n = 13) received neoadjuvant systemic chemotherapy and/or chemoradiation. Overall, 32 symptoms were reported, and 19 were reported by over 20% of patients. An expert panel rated nine symptoms to be relevant or very relevant to PGE surgical patients. These symptoms (difficulty swallowing, heartburn/reflux, diarrhea, constipation, flushing/sweating, stomach feeling full, malaise, dizziness, or feeling cold) were added to the core MD Anderson Symptom Inventory (MDASI) if they were commonly reported or reached a threshold relevancy score. CONCLUSIONS: In this qualitative study, we developed a provisional symptom inventory for patients undergoing surgery for PGE cancer. This symptom inventory module of the MDASI for PGE surgical patients will be psychometrically tested for validity and reliability.

Germline Testing Identifies Pathogenic/Likely Pathogenic Variants in Patients with Pancreatic Neuroendocrine Tumors.

Ten percent of pancreatic neuroendocrine tumors (pNET) are related to inherited syndromes (MEN1, MEN4, VHL, NF1, and TSC). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathologic/likely pathologic (P/LP) germline variants in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center and Johns Hopkins Hospital. The high-risk cohort included (n = 132) patients seen at MD Anderson Cancer Center who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer, and syndromic features) between 2013 and 2019. The unselected cohort included (n = 106) patients seen at Johns Hopkins Hospital who underwent germline testing following their diagnosis of pNETs between 2020 and 2022. In the high-risk cohort (n = 132), 33% (n = 44) had P/LP variants. The majority of the patients had P/LP variants in MEN1 56% (n = 25), followed by DNA repair pathways 18% (n = 8), and 7% (n = 3) in MSH2 (Lynch syndrome). Patients with P/LP were younger (45 vs. 50 years; P = 0.002). In the unselected cohort (n = 106), 21% (n = 22) had P/LP. The majority were noted in DNA repair pathways 40% (n = 9) and MEN1 36% (n = 8). Multifocal tumors correlated with the presence of P/LP (P = 0.0035). MEN1 germline P/LP variants correlated with younger age (40 vs. 56 years; P = 0.0012), presence of multifocal tumors (P < 0.0001), and World Health Organization grade 1 histology (P = 0.0078). P/LP variants are prevalent in patients with clinically sporadic pNET irrespective of high-risk features. The findings support upfront universal germline testing in all patients with pNET. Prevention Relevance: Here, we present germline data from the largest reported cohort of patients with pNET (n = 238), comprising both a high-risk cohort and an unselected cohort. In both cohorts, we identify a high number of P/LPs, including those in the DNA repair pathway. Our findings support universal germline testing in patients with pNET.

The i-gel® supraglottic airway device compared to endotracheal intubation as the initial prehospital advanced airway device: A natural experiment during the COVID-19 pandemic.

Objective: Unlike randomized controlled trials, practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings where there may be reluctance to adopt new practices. We present the results of a natural experiment that was driven by mandated COVID-19 pandemic-driven shift from endotracheal intubation (ETI) to the i-gel® supraglottic airway (SGA) as a primary advanced airway management device in the prehospital setting to reduce emergency medical services (EMS) personnel exposure to potentially infectious secretions. The objective was to compare first-pass success and timing to successful airway placement between ETI and the i-gel® SGA under extenuating circumstances. Methods: This pre/post study compared airway placement metrics in prehospital patients requiring advance airway management for non-trauma-related conditions. Data from EMS records were extracted over 2 years, 12 months pre-pandemic, and 12 months post-pandemic. During the pre-COVID-19 year, the EMS protocols utilized ETI as the primary advanced airway device (ETI group). Post-pandemic paramedics were mandated to utilize i-gel® SGA as the primary advanced airway device to reduce exposure to secretions (SGA group). Results: There were 199 adult patients, 83 (42%) in the ETI group and 116 (58%) in the SGA group. First-pass success was significantly higher with SGA 96% (92%-99%) than ETI 68% (57%-78%) with paramedics citing the inability to visualize the airway in 52% of ETI cases. Time to first-pass success was significantly shorter in the SGA group (5.9 min [5.1-6.7 min]) than in the ETI group (8.3 min [6.9-9.6 min]), as was time to overall successful placement at 6.0 min (5.1-6.8 min) versus 9.6 min (8.2-11.1 min), respectively. Multiple placement attempts were required in 26% of ETI cases and 1% of the SGA cases. There were no statistically significant differences in the number and types of complications between the cohorts. Return of spontaneous circulation (on/before emergency department [ED] arrival), mortality at 28 days, intensive care unit length of stay, or ventilator-free days between the groups were not statistically different between the groups. Conclusion: In this natural experiment, the SGA performed significantly better than ETI in first-pass airway device placement success and was significantly faster in achieving first-pass success, and overall airway placement, thus potentially reducing exposure to respiratory pathogens. Practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings and in systems with a low frequency of tracheal intubations.