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Background: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior., Methods: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC., Results: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P  =  0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size., Conclusions: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies., (© 2024. Society of Surgical Oncology.)

Background: Standard lymphadenectomy for pancreatoduodenectomy is defined for pancreatic ductal adenocarcinoma and adopted for patients with non-pancreatic periampullary cancer (NPPC), ampullary adenocarcinoma (AAC), distal cholangiocarcinoma (dCCA), or duodenal adenocarcinoma (DAC). This study aimed to compare the patterns of lymph node metastases among the different NPPCs in a large series and in a systematic review to guide the discussion on surgical lymphadenectomy and pathology assessment., Methods: This retrospective cohort study included patients after pancreatoduodenectomy for NPPC with at least one lymph node metastasis (2010-2021) from 24 centers in nine countries. The primary outcome was identification of lymph node stations affected in case of a lymph node metastasis per NPPC. A separate systematic review included studies on lymph node metastases patterns of AAC, dCCA, and DAC., Results: The study included 2367 patients, of whom 1535 had AAC, 616 had dCCA, and 216 had DAC. More patients with pancreatobiliary type AAC had one or more lymph node metastasis (67.2% vs 44.8%; P < 0.001) compared with intestinal-type, but no differences in metastasis pattern were observed. Stations 13 and 17 were most frequently involved (95%, 94%, and 90%). Whereas dCCA metastasized more frequently to station 12 (13.0% vs 6.4% and 7.0%, P = 0.005), DAC metastasized more frequently to stations 6 (5.0% vs 0% and 2.7%; P < 0.001) and 14 (17.0% vs 8.4% and 11.7%, P = 0.015)., Conclusion: This study is the first to comprehensively demonstrate the differences and similarities in lymph node metastases spread among NPPCs, to identify the existing research gaps, and to underscore the importance of standardized lymphadenectomy and pathologic assessment for AAC, dCCA, and DAC., (© 2024. The Author(s).)

Despite the advances made in treatment, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal, even in the locoregional and locally advanced stages, with high relapse rates after surgery. PDAC exhibits a chemoresistant and immunosuppressive phenotype, and the tumor microenvironment (TME) surrounding cancer cells actively participates in creating a stromal barrier to chemotherapy and an immunosuppressive environment. Recently, there has been an increasing use of interventional radiology techniques for the treatment of PDAC, although they do not represent a standard of care and are not included in clinical guidelines. Local approaches such as radiation therapy, hyperthermia, microwave or radiofrequency ablation, irreversible electroporation and high-intensity focused ultrasound exert their action on the tumor tissue, altering the composition and structure of TME and potentially enhancing the action of chemotherapy. Moreover, their action can increase antigen release and presentation with T-cell activation and reduction tumor-induced immune suppression. This review summarizes the current evidence on locoregional therapies in PDAC and their effect on remodeling TME to make it more susceptible to the action of antitumor agents.

Background: In metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment., Methods: Randomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3-4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes., Results: A NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21-2.75 and HR = 0.74, 95%CI 0.31-1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied., Conclusions: According to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients., (© 2023. The Author(s).)

Background: Information about the adherence to scientific societies guidelines in the 'real-world' therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM)., Patients and Methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented., Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine + capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel + gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nab-paclitaxel + gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months)., Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing., Competing Interests: Disclosure RM declares grants or contracts from AstraZeneca and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly, PANAVANCE, Celgene, AstraZeneca, Viatris, Merck Sharp & Dohme, Servier, SOTIO, and Baxter. BF declares payment for consulting fees from Servier and AAA Novartis and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Eli Lilly, MSD, EISAI, and Bayer. MM declares grants or contracts from Roche and Novartis, payment for consulting fees from Viatris, AstraZeneca, MSD, and Merck; payment for participation on a Data Safety Monitoring Board or Advisory Board from Novartis. CL declares payment for consulting fees from Astrazeneca e Merck and support for attending meetings and/or travel from Pfizer, Ipsen and Celgene. DMMC declares payment for participation on a Data Safety Monitoring Board or Advisory Board from OncoSil and Olaparib and for Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Editorial Board Future Oncology. SM declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Eli Lilly, Roche, Pfizer, Janssen, Italfarmaco, and BMS and for participation on a Data Safety Monitoring Board or Advisory Board from Eli Lilly, Merck, Pfizer, Janssen, and BMS; payment or has a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from AIOM Sicilia. GE declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Viatris, Amgen, and AstraZeneca and support for attending meetings and/or travel from Ipsen and Viatris. SC declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Merk, Servier, Bayer, and Sanofi and support for attending meetings and/or travel from Amgen, Merk, and Servier. GGC declares payment for attending meetings and/or travel from Incyte, Eli Lilly, Amgen, and MSD and for the participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly, MSD, and AstraZeneca. ME declares payment for consulting fees from MSD. GM declares consulting fees from Italfarmaco, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Merck, Eli Lilly, Servier, and Amgen. PL declares consulting fees from Ipsen and Italfarmaco. CP declares institutional grants from Ely Lilly, Bayer, and Roche; consulting fees from BMS, Ely Lilly, Novartis, and Merck and for the participation on a Data Safety Monitoring Board or Advisory Board for BMS, Amgen, and Novartis. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

One of the historical standard of care for locally advanced rectal adenocarcinoma (LARC) is neoadjuvant fluoropyrimidine-based chemoradiotherapy (FP-based CTRT) followed 6-8 weeks later by surgery. The incorporation of further chemotherapy cycles (CT) before or after CTRT (total neoadjuvant therapy) resulted in better outcomes than CTRT alone. Therefore, we performed a network meta-analysis (NMA) to compare the relative efficacy of different neoadjuvant treatments for LARC. Fixed-or random-effects models were fit using a Bayesian approach to NMA. Between-group comparisons were estimated using hazard ratios (HRs) or risk ratios (RRs) with 95 % credible intervals (95 % CrIs). A total of 23 randomized clinical trials were included. In Bayesian comparisons. FOLFIRINOX followed by capecitabine-based CTRT resulted in better OS than other regimens, including the previous standard, and ranked as the best regimen with a probability of 87 %. This NMA confirms that adopting total neoadjuvant therapy improves outcome compared to other preoperative strategies, including FP-based CTRT., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Patients with initially inoperable non-metastatic pancreatic cancer (PC) have a poor prognosis, often similar to those with metastatic disease. Neoadjuvant chemotherapy (CT) plus concomitant or sequential radiotherapy (RT) may cause tumor shrinkage and allow for radical surgery. We pooled data of studies in which patients with locally advanced (unresectable) or borderline resectable PC were treated with a course of induction (or consolidation) CT followed or preceded by neoadjuvant CTRT regimen., Materials and Methods: We searched articles, including phase 2 or 3 studies, published in English from 2010 up to December 2020 in PubMed, SCOPUS, the Cochrane Library, and EMBASE. The primary outcomes were the pooled radical and R0 resection rates, median PFS and OS of included patients (those included in the intent to treat analysis)., Results: A total of 28 studies were finally considered eligible for inclusion in quantitative analysis for a total of 2446 patients with locally advanced/borderline resectable PC. Overall the pooled rate of resection was 29.7% (95%CI 26.7-32.8%). In patients who completed the CT + CTRT program, the overall resection rate was 31.8% (95% 28.4-35.4%). After exclusion of studies that included resectable PCs, the overall resection rate was 19.9% (95%CI 17.3-22.7%). In studies were all patients had unresectable PC (n = 20 studies), the resection rate was 12.1% (95%CI 10-14.5%). In two studies that enrolled all borderline resectable PCs the resection rate was 59.2% (95%CI 48.9-68.8%). The pooled R0 resection rate was 68.7% (95%CI 64.7-72.3%). The median pooled OS was 15.7 months (95%CI 14-17.2 months) and the median pooled PFS was 10.7 (95%CI 9.3-12.1 months)., Conclusions: Surgery is a treatment option in about one third of patients with initially inoperable PC, following total neoadjuvant therapy. In unresectable cases the resection rate was 12%. Median OS and PFS rates were comparable with historical data of advanced PCs. Optimal integration and sequence of chemo- and radiotherapy in unresectable PC must still be defined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2-9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.

Background: Adjuvant chemotherapy (CT) is the standard of care for patients with resected pancreatic cancer (PC). Overall survival (OS) has traditionally represented the primary endpoint in randomized trials assessing adjuvant therapies for PC. The aim of this study was to assess if disease-free survival (DFS) was an adequate surrogate endpoint for OS in randomized trials of adjuvant therapy in PC., Methods: A systematic literature search was conducted in PubMed, Web of Science, SCOPUS and Embase, Cochrane Library and the World Health Organization International Clinical Trials Registry Platform up to February 2nd, 2017. Surrogacy of DFS with OS was assessed between endpoints and OS through the Spearman rank correlation coefficient, and between the treatment effects on the endpoints using the squared correlation R 2 ., Results: A total of 12 eligible randomized trials that enrolled 4,888 patients where identified for the final analysis. Correlation of DFS with OS was weak at the individual level (Spearman rank correlation coefficient = 0.31) and moderate at the trial level (R 2  = 0.44)., Conclusions: DFS does not represent an appropriate surrogate for OS in randomized trials of adjuvant therapy for resected PC. Hence, OS should remain the primary endpoint of future trials evaluating new agents in postsurgical setting., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6)., Methods: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm., Results: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%., Conclusions: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

Aim: This multicenter study evaluated the association of 11 candidate polymorphisms in eight genes with outcome of pancreatic cancer patients treated with the equivalent polychemotherapeutic regimens: cisplatin/epirubicin/capecitabine/gemcitabine, cisplatin/docetaxel/capecitabine/gemcitabine and gemcitabine/capecitabine plus epirubicin/cisplatin intra-arterial infusion., Patients & Methods: Towards this end, polymorphisms were assessed in DNA from 122 pancreatic cancer stage-III/IV patients, and their associations with toxicity/response and progression-free survival (PFS) and overall survival were evaluated using Pearson-χ(2) and log-rank test., Results: Patients harboring XPD Gln751Gln, XPD Asp312Asn + Asn312Asn or XRCC1 Arg399Gln + Gln399Gln genotypes had a worse prognosis. XPD Gln751Gln (hazard ratio: 1.9; p = 0.003), as well as a combination of over two risk genotypes (hazard ratio: 2.7; p < 0.001), emerged as independent predictors for death risk at multivariate analysis. No correlations were observed with toxicity. Conversely, XPD Gln751Gln was associated with shorter PFS, while the lack of association with overall survival/PFS in gemcitabine monotherapy-treated patients suggested its role only for platinum-based regimens., Conclusion: Polymorphisms of DNA-repair genes appear to be candidate biomarkers of primary resistance to gemcitabine/cisplatin-based polychemotherapeutic regimens. The relatively small sample size, coupled with the retrospective and exploratory design of the present study, imply that these results should be considered as hypothesis generators, and should be further evaluated in larger and adequately designed retrospective/prospective studies.

Background: At the time of upfront treatment failure, over half of the patients with advanced pancreatic cancer are candidates for further treatment., Methods: Patients with metastatic gemcitabine-resistant pancreatic cancer were treated with mitomycin 8 mg/m(2) on day 1, ifosfamide 2,500 mg/m(2) and mesna 3,000 mg/m(2) on days 1-3 every 28 days until progressive disease. A positive responder was defined as a patient who was progression free at 6 months from trial enrollment. According to the Fleming design, a sample size of 34 patients was estimated assuming p0 = 0.05 and p1 = 0.20., Results: Between May 2006 and December 2007, 21 patients (median age 56 years; median Karnofsky performance score 80) were enrolled. One patient died before receiving any treatment. Eighteen patients interrupted chemotherapy due to progressive disease (n = 15), toxicity (n = 2) or refusal (n = 1). Grade >2 toxicity consisted of neutropenia in 80% of patients, thrombocytopenia and fatigue in 20% and anemia in 10%. Only 1 patient was progression free at 6 months (5%). One patient had a partial response (5%) and 2 patients had stable disease (10%). Median survival was 3.7 months., Conclusion: Based on the poor outcome observed and on the high level of grade 3-4 toxicity, the trial was prematurely stopped and the mitomycin and ifosfamide regimen was considered insufficiently active in gemcitabine-pretreated advanced pancreatic cancer., (Copyright © 2011 S. Karger AG, Basel.)

Background: More than half of patients with pancreatic adenocarcinoma (PA) are candidates for further treatment when they experience upfront treatment failure., Patients and Methods: Patients with gemcitabine-resistant PA, age <76 years and Karnofski performance status (KPS) >50 were treated with a XELIRI or FOLFIRI regimen until progressive disease or a maximum of six months. As this was an observational study, no statistical design was performed., Results: Between July 2007 and December 2009, 34 patients (median age 60 years; median KPS 90) were treated with XELIRI (26) or FOLFIRI (8) regimen. Grade >2 toxicity consisted of neutropenia in 9% of patients, anemia and fatigue in 3% and hand-foot syndrome in 12%. Median progression-free survival was two months (range 1-4). Maximum response was stable disease in four patients (12%). Median survival was 4.2 (range 1-15) months., Conclusion: Fluoropyrimidine and irinotecan combination does not seem to have any role in the treatment of gemcitabine-resistant PA.