Seminar

Pancreatic cancer

Lancet 2025; 405:1182-202 Amsterdam UMC,location University ofAmsterdam, Department of Surgery (TFStoop MD, AA Javed MD,
Prof M G Besselink MD PhD) and Department of Medical Oncology (Prof WWimink MD PhD), Amsterdam, Netherlands; CancerCenterAmsterdam, Amsterdam,Netherlands (TF Stoop, AA Javed, Prof w wilmink,
Prof MGBesselink);Divisionof
Surgical Oncology,Department of Surgery,New York
UniversityMedicalCenter,w York, NY,USA(AAJaved); Department of Hepatobiliary
and PancreaticSurgery,Cancer InstituteHospital,Japanse Foundation forCancer
Researchriakky (A Oba MD PhD); Department
of Hepatobiliary and Pancreatic Surgery,GraduateSchoolof Medicine, Tokyo Medical and
DentalUniversity,Tokyo,Jaan (A Oba); Division of Surgical Oncology,Deparmentf
Surgery,University ofColorado Anschutz Medical Campus, Aurora, CO,USA (A Oba); Department of Surgery, ErasmusMCCancerInstitute, Rotterdam,Netherlands (Prof B G Koerkamp MD PhD); Department of International Medicinel, Ulm University Hospital, Ulm, Germany (ProfT Seufferlein MD PhD) Correspondence to: Prof Marc G Besselink, Amsterdam UMC,location University of Amsterdam, Department of Surgery, Amsterdam 1081HV, Netherlands m.g.besslink@ amsterdamUMC.nl

Thomastpmaavetshasrotrmhmalilina

Pancreatic canceris frequentlyalethal disease with anaggressivetumourbiolgy often presenting with non-specifc symptoms.Median survivalis approximately 4monthswith a5-year survival of 13% .Surveillanceisrecommended in individuals with familial pancreatic cancer, specific mutations, and high-risk intraductal papillary mucinous neoplasm,as theyareathighrisk ofdeveloping pancreaticcancer.Chemotherapycombinedwithsurgical resection remains the cornerstone oftreatment.However, only asmallsubset of patients are candidates for surgery.Multiagent chemotherapy has improved survival in the pallative setting for patients with metastatic disease, as (neo) adjuvant andinduction therapy have in patients withborderline resectable and locallyadvanced pancreatic.Given that panreaticcanesprdictedtmtheondladincausfcanc-relatddaty3elthra are urgently needed.

Introduction

Pancreatic ductal adenocarcinoma (hereafter: pancreatic cancer)is alethal disease for most patients with a reported median overall survival of 4 months across all stages of disease.2 This poor survival is driven by aggressive tumourbiology and the condition's asymptomatic nature, often resulting in late clinical presentation. As a consequence,just more than half of patients with pancreatic cancer present with metastatic disease at diagnosis. Early systemic spread and the insufficient effect of systemic therapies make systemic disease control challenging,even in patients presenting with radiologically localised disease. Despite the dismal prognosis and small improvements in survival for individuals with pancreatic cancer, the 5-year overall survival has increased over the last 30 years from 4% to 13% This change is mostly due to improved oncological therapies, surgical techniques, and centralisation of care.56

Among all cancers, pancreatic cancer ranks 12th in incidence and 6th in cumulative mortality.? Pancreatic cancer is predicted to become the second leading cause of cancer-related deaths in the USA by 2030.8 The global lifetime risk of developing pancreatic cancer is 0.89% (95% CI 0·88-0.89),ranging from 0.15% (0·13-0·18) in middle Africa to 2.06% (2.04-0.08) in western Europe. The global lifetime risk of death from pancreatic cancer is 0.85% (0·85-0.85)." The age-standardised incidence of pancreatic cancer has gradually increased from 6·3 to 6·6 per 100 000 between 2010 and 2019, driven by countries with a middle or low sociodemographic index. The incidence of pancreatic cancer is increasing among young adults with a global age-standardised incidence of 0.2% among adolescents and young adults aged 15-39 years,12 influenced by the growing prevalence of obesity.3

Epidemiology

Approximately 95% of these tumours arise from precancerous lesions called pancreatic intraepithelial neoplasias."5 Other precursorlesions are pancreatic cysts, including intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms. In about half of patients with pancreatic cancer and a concomitant IPMN, the invasive tumour is not derived from IPMN.15.16 In the general population, pancreatic cysts are estimated to occur in 16% 95% CI 13-18) of individuals, and IPMN isthemostcommonandhasthehighest risk of malignant transformation."IPMNs with low-risk features has a cumulative incidence of malignant transformation of 8% (4-12) at 10 years, although the risk can be up to 25% (15-36) for patients with high-risk features.1s

Pancreatic cancer is the most common solid tumour of the pancreas, comprising more than 95% of all pancreatic neoplasms.4 This type of cancer originates from normal glandular epithelium that changes into precursor lesions and ultimately invasive cancer.

Multiple molecularalterations areobservedin pancreatic cancer,whichinvolve activation ofoncogenes,inactivation of tumour suppressor genes, and alterations in DNA damage repair genes and homologous repair deficiency genes." Tumorigenesis is entirely somatic in 91% of patients, whereas germline mutations are found in 9% of individuals.2 The most common somatic mutations are KRAS (-88%) ，TP53 (61-74%) ，CDKN2A (16-44%) ,and SMAD4 (20-22%) 2The major genetic event in the development of pancreatic ductal adenocarcinoma is the somatic KRAS oncogene mutation, which is observed in more than 90% of patients with low-grade pancreatic intraepithelial neoplasia. The KRAS mutation remains active during the progression from epithelial cell to invasive cancer, contributing to the processes of proliferation,survival, migration,and invasion. By its effect onthetumour stroma andmicroenvironment,the KRAS protein plays an important role in the process of metastatic spread and chemotherapy resistance.22

Pathogenesis

Transcriptomic analyses have identified several unique subtypes of pancreatic cancer,for which the categorisation intobasal-like and classical subtypes seems to be the most relevant with regard to prognosis and chemotherapy response.2 Basal-like tumours are enriched for epithelialto-mesenchymal transition, cell cycle progression, and TGF *{^{p}} signalling, and are associated with worse prognosis.2Epithelial-mesenchymal transition has been implicated in reprogramming of cancer cells. The

Searchstrategyandselectioncriteria

Aliterature searchwasdoneduringApril19-22,2024,n PubMed, Embase, and Cochrane Library, with the aim to identifythe most recent English literature with the highest leve of evidence published since Jan1,2010.Systematic search strategiesweredesignedincollaborationwith a clinical librarian,focusingnpathogenesis,riskfactors,creening surveillance,magingpathologybiliarystenting,treatmentf localised and metastatic pancreatic cancer, and alternative ablativetherapies.orallseparatesearchstrategies,search terms were:“pancreaticneoplasms","pancreatic cancer", "pancreatictumour","pancreatic ductal adenocarcinoma", "pancreaticadenocarcinoma",“pancreas cancer','pancreas neoplasm","pancreas carcinoma","pancreas adenocarcinoma", and“pancreas tumour".Forthe sectiononpathogenesis,the basicsearchstrategywas extended withthefollowing terms: “"molecular","genomics","proteomics","multiomics", "subtyping","PDACtumormicroenvironment”,“pancreatic cancerepigenome",and"tumour associated macrophage".For thesection Riskfactors,thebasicsearchstrategywas extended with the following terms:"smoking",“pancreatitis","diabetes mellitus","Peutz-Jeghers Syndrome","new-onset diabetes", "obesity”,“familial pancreaticcancer，"hereditary pancreatitis" “"familial melanoma",“lynch syndrome”,"intraductal papillary mucinous neoplasms","mucinous cystic neoplasms","high-risk individuals","alcohol",and"lifestyle".In additionto this latter searchstrategyonriskfactors,thesearchstrategyforscreening and surveillance,was extended with the following terms:"early detection","early diagnosis", and“screening"Forthe sectionor imaging,thebasicsearchstrategywas extendedwiththe following terms:"magnetic resonance imaging" "endosonography","positron emission tomography", "multidetector computed tomography","diagnostic imaging"

"computed tomography","endoscopicultrasonography", "PDAC CT","accuracy”,"staging",“malignancy","texture analysis","resectability assessment", and"differentiation".For thesection onpathology,thebasicsearchstrategywas extended withthe following terms:"aspiration","biopsy",

"tissue acquisition","pancreatic", and "biliary stricture" To identify evidence about endoscopic retrograde cholangiopancreatography,thefollowing termswereused: "endoscopicretrogradecholangiopancreatography","post endoscopic retrograde cholangiopancreatography","ERCP" "postoperative complications","complication rate”, "pancreatitis","accuracy”,"pancreas malignancy”,and"risk". The following terms were used to identify evidence about biliary drainage:“stent”,"biliary stricture”,"biliaryobstruction", "pancreatic neoplasm","malignancy","pancreatic","cancer", "carcinoma",and"mass"Forthesection on treatmentof metastatic pancreaticcancer,thebasicsearchstrategywas extended with the following terms:"drug therapy", "antineoplasticcombined chemotherapy","antineoplastic agent”","cancer chemotherapy”,"chemotherapy”,"metastatic", "metastasis","“metastases","advanced",and"survival".Forthe sectionontreatmentoflocalisedpancreaticcancer,thebasic search strategy was extended with the following terms: "neoadjuvant therapy","induction chemotherapy", “preoperativechemotherapy”,"chemoradiotherapy”, "preoperative chemoradiotherapy","adjuvantchemotherapy" "adjuvantchemoradiotherapy","antineoplasticcombined chemotherapy protocols","resectable","borderline", "irresectable","irresectability",“unresectable","unresectability” “borderlineresectable","locally advanced","resected"，and "resection".Forthe section localablative therapy,the basic searchstrategy was extended withthefollowing terms: "ablation techniques","electrochemotherapy","ablation", "ablative”,"induction chemotherapy”,"resectable”,“borderline” "irresectable","irresectability","unresectable","unresectability" "borderline resectable”,“locally advanced",“localized", "advanced stages", and "resection".From the identifed literaturereferencelistsandcitationrecordswerescreenedfor otherrelevant literature that waspublished beforeJan1,2010, or published afterthe literature searchfromApril 23,2024, until Dec 9, 2024.

transition allows these cells to escape into the circulation and facilitates immune evasion,and metastasis.26

Pancreatic cancer is characterised by desmoplastic stroma,mainly consisting of an extracellular matrix, vasculature,andcancer-associatedfibroblasts.The desmoplastic stroma causes elevated intratumoural interstitial pressure,hampering chemotherapy delivery. Pancreatic cancer cells extend along vessels, nerves, and collagen structures.28 This extending of cancer cells explains the high rates of perineural (~62%) and lymphovascular (-54%) invasion, which are associated with worse overall survival.29

Riskfactors

The rising age-adjusted incidence of pancreatic cancer suggests an increasing prevalence of risk factors,°in addition to an ageing global population.31 Various modifiable lifestyle and heritable risk factors for pancreatic cancer are known (table 1).

Cigarettesmokingistheleadingmodifiablerisk factor of pancreatic cancer with a relative risk (RR) of 1.8( 95% CI 1.7-1.9%) compared with individuals who have never smoked.34 The age-standardised proportion of all pancreatic cancer deaths attributable to smoking is 21% 95% CI 19-24% , followed by high fasting plasma glucose (9% 95% CI 2-19% and high BMI 6% 95% CI 3-11%) 31 Smoking cessation mitigates the risk, as illustrated by the smaller risk difference among former versus never smokers (RR 1.2, 95% CI 1.1-1.2)—longer smoking cessation time further reduces the risk. Heavy alcohol consumption is associated with an increased risk for pancreatic

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cancer.36 The increased risk might attenuate after 10 years of abstinence.51

Diabetes is considered to be another risk factor for pancreatic cancer (RR 1·5, 95% CI 1.4-1·6).37 However, diabetes can also be a prodrome of pancreatic cancer (ie, type3cor pancreatogenicdiabetes).s²Thefact that diabetes canbeboth a risk factor and aprodome of pancreatic cancer is illustrated by a possibly stronger association of new-onset diabetes (ie, \scriptstyle<=3-4 years)with pancreatic cancer compared with long-standing diabetes (ie, >3-4 years).Elevated HbAlc inindividuals with new-onset diabetesis associated with anincreased risk of pancreatic cancer.5" Even in individuals with normal glucose concentrations，increased fasting glucose concentrations are associated with an increasedrisk of pancreatic cancer." Metabolic syndrome is associated with an increased risk for pancreatic cancer (RR 1·3, 95% CI 1*2-1*5%) 38 in which the risk increases with the individual having more constituent factors.56.5 Recovering from metabolic syndrome is associated with a reduction of this increased risk.58

Pancreatitis is established as a strong risk factor for pancreatic cancer, including chronic pancreatitis (standardised incidence ratio [SIR] 22·6, 95% CI 14.4-35.4),with an increasing cumulative incidence during its disease course. Contrastingly, in patients with acute pancreatitis,the risk of pancreatic cancer is the highest within the first 2 months from symptom onset, as the condition might be a first symptom of pancreatic cancer (HR 172·8, 95% CI 54.9-544.7).32 The risk gradually decreases over time until the risk disappears 10 years after diagnosis.32.59

Heritability is suspected in about 21perthousand of patients with pancreatic cancer, although the actual rate is uncertain.o61 Familial pancreatic cancer (ie, ^{>1} firstdegree relative) is a strong risk factor for pancreatic cancer (SIR 4.9, 95% CI 4.0-5.9).6 The risk of developing pancreatic cancer is even higher in the case of more affected first-degree family members \scriptstyle(>=3 firstdegree relatives SIR 10.8, 95% CI 4.7-10·1) compared with having one (SIR 3·46, 95% CI 2·52-4.76) or two (SIR 5.44, 95% CI, 4.07-7.26) first-degree relatives.63 Furthermore,the risk of developing pancreatic cancer is higher in individuals having a family history of youngonset (ie, <50 years of age) pancreatic cancer. However, germline mutations are found in only about 10% 95% CI 8-12%) of individuals with familial pancreatic cancer.64 Individuals with a germline mutation have a higher risk of developing pancreatic cancer compared with individuals with a positive family history alone.63.64 Various mutations and genetic syndromes are associated with pancreatic cancer (table 1).

Screening and surveillance

Screeningfor pancreaticcancerin asymptomatic adults is not recommended given the low incidence and the absence of accurate screening modalities.6 New-onset diabetes is being discussed as a possible indication for screening for pancreatic cancer. Given the low standardised incidence ratio (1·5, 95% CI 1.4-1·6) of pancreatic cancer among individuals with new-onset diabetes together with low capacity of prediction models and the absence of evidence on the survival benefit, screening is currently not recommended.67.68

Genetic testing is recommended in individuals at high risk, including people with Li-Fraumeni or Lynch syndrome,familial pancreatic cancer, or relatives with a known pathogenic mutation (table 1).o7 The 2024 National Comprehensive Cancer Network (NCCN) guideline emphasizes that patient counselling is crucial when surveillance is considered, considering the potential drawbacks (eg, uncertainty about the benefits, false-positive findings, and costs).43

Surveillance aims to detect high-grade precursors or pancreatic cancer at an early stage, generally started after an age of 50 years or 10 years earlier than the age of diagnosis in the youngest affected relative." The recommended screening modalities are endoscopic ultrasonography (EUS)and MRI with magnetic resonance cholangiopancreatography (MRCP)once per year. The diagnostic accuracy of EUS and MRI in detecting high-grade dysplasia or early-stage pancreatic adenocarcinoma seems tobe similar.7However,the value of MRI/MRCP in addition to EUS is debated.2 Accurate liquid biomarkers are not available.72

In individuals at high risk of pancreatic cancer, the number of patients needed to screen (NNS) to detect a high-risk lesion with EUS or MRI is 135( 95% CI88-303), although this number is lower in people with a pancreatic cancer susceptibility mutation, particularly in individuals with hereditary pancreatitis (NNS{=}130) ，Peutz-Jeghers syndrome (NNS{=}71) ，and CDK2NA germline mutation (NNS{=}51) 73Guidelines recommend surveillance for individuals with radiology-based IPMN diagnosis in the absence of an absolute indication for surgery, including radiological (eg, main pancreatic duct size, enhancing mural node size, and cystic growth) and clinical (eg, acute pancreatitis, diabetes de novo) features.7475 Individuals at high risk with screening-detected pancreatic cancer are more likely to have early-stage disease at diagnosis compared with the general population of patients diagnosed with pancreatic cancer. This difference possibly leads to a prolonged overall survival in patients diagnosed with pancreatic cancer revealed via screening. Annual imaging does not preclude failure of surveillance.7 Almost half of new lesions appear at a median of 11 months from last EUS or MRI/MRCP.78

Figure1:Symptoms of pancreaticcancer Most commonsymptomsandsignsof pancreaticcancerat diagnosis.8\*Thesesymptoms aremoreoftenseen inpatientswithpancreaticcancerlocatedinthepancreaticbodyortailcomparedwithpancreaticheadtumours. Thesesymptomsaremoreoftenseeninpatients withpancreaticancerlocatedinthepancreaticheadcompared with pancreatic body or tail tumours.

Diagnosis

Clinical symptoms

Pancreatic cancer typicallycauses non-specific symptoms,resulting in a diagnostic delay.Figure 1 shows the incidence of clinical symptoms and signs.79-81 The only high-risk feature with a positive predictive value of more than 1% is painless jaundice: 13% (95%CI8-27%) at an age of at least 40 years and 22% (14-52%) at an age of at least 60 years.80.82 Painless jaundice occurs among 71% of patients with a pancreatic head tumour."Given thelowincidenceof jaundice in the early phase of the disease course and the nonspecific symptoms, it is challenging for primary care physicians to decide on appropriate timing for further investigations.Pancreaticcancershould be considered indifferentialdiagnosiswarrantingfurther investigation in people with concomitant conditions including a positive family history of pancreatic cancer, new onset diabetes, or acute or recurrent pancreatitis (figure 2).32.85

Diagnostics

Imaging

The imaging modality of choice in individuals with suspicionofpancreaticcancerisacontrast-enhanced three-phase (ie, pancreatic, arterial, and portal venous phase）computed tomography (\mathbf{CT}),^{69,70} which has a diagnostic accuracy of 89% 95% CI 85-93).8 Pancreatic cancer in the head often causes dilatation of both the common bile duct and main pancreatic duct (ie,double duct sign).8 Differentiating between pancreatic cancer and other periampullary carcinomas can be challenging, as illustrated by the 13-32% preoperative misdiagnosis risk among resected pancreatic head adenocarcinomas.8889 Pancreatic adenocarcinoma typically appears as a hypodense lesion on CT, in contrast with hyperdense pancreatic neuroendocrine tumours.However, about 5-17% of lesions are isoattenuating on CT, particularly smaller lesions." In the absence of a visible mass, other key findings raising suspicion for pancreatic cancer include pancreatic duct dilatation with an abrupt cutoff and glandular atrophy.9" \mathbf{MRI}^{69,70} or EUS^{92} can be performed in individuals with a suspected isoattenuated mass or patients with a contraindication for contrast-enhanced CT. MRI aids in characterising liver lesions that are indeterminate on CT and detecting liver metastases that are not visible on CT, given the difference in sensitivity of

83% 95% CI 74-88) for MRI versus 45% (21-71) for CT.^{93} Positron emission tomography (PET) can be considered to exclude distant metastases in patients with inconclusive CT or MRI or in individuals at high risk of metastatic disease (eg, highly elevated serum carbohydrate antigen 19-9 [CA19-9], regional lymphadenopathy, and large primary tumour).6970.94

Pathology

In patients with suspected metastatic pancreatic cancer, pathology from possible metastasis should be obtained..\* In case of a localised pancreatic mass (ie, no metastases seen on imaging),pathology is needed when imaging cannot differentiate between benign or malignant disease, orin patients forwhom chemotherapy is considered as first-line treatment.697 EUS with fine needle biopsy is preferred over fine needle aspiration,9.70 considering the higher diagnostic accuracy of fine needle biopsy compared with fine needle aspiration 185% 95% CI 83-87% Vs 80% 95% CI 78-83%) .95

Genetic testing for inherited mutationsis recommendedby the2024 NCCNguidelinefor all patientsdiagnosedwithpancreaticcancer.When tumour-directed treatment is considered in patients with locally advanced and metastatic disease,molecular profiling is recommended to investigate the presence of actionablesomaticmutationswiththerapeutic consequences.697o These include entities such as BRCA1, BRCA2, DNA mismatch repair deficiency (eg, MLH1, MSH2, MSH6), and KRAS wild type (eg, fusion genes such as NRG and NTRK),despite their low incidences.21

Laboratory

Serum CA19-9 (and carcinoembryonic antigen), liver enzymes, and bilirubin concentrations are measured in patients with (suspected)pancreatic cancer. The biomarker serum CA19-9 is routinely used in patients with the suspicion of pancreatic cancer.9 However, serum CA19-9 is inaccurate for establishing a diagnosis of pancreatic cancer,eitherin screening or to differentiate from other pathologies,because elevated serum CA19-9 can be caused by other benign and malignant pathologies (eg, biliary obstruction,pancreatitis).% Moreover, about one-third of patients with pancreatic cancer have nonelevated serum CA19-9 (ie, <=37\ U/mL ,including 8% of patients who are non-secretors of CA19-9 (ie, {<}2\ U/mL) .97 Liquid biomarkers with a higher diagnostic accuracy than serum CA19-9 are not available. Despite its limitations for diagnostic purposes, serum CA19-9 is valuable in patients with proven pancreatic cancer as an indicator for micrometastatic disease,risk assessment for occult metastases, and treatment response evaluation.8.99

Staging laparoscopy

Staging laparoscopy can be donebeforeinitial treatment with chemotherapy or before surgery to detect occult metastases and thus avoid unnecessary local therapy including surgery.0 Staging laparoscopy's yield to detect occult metastaseshasdecreasedfromabout 20% in 1988-2006^{101} to 15% in 2009-21^{102-104} most likely due to improved cross-sectional imaging. Staging laparoscopy should especially be considered in patients with high-risk features97 (eg, indeterminate extra-pancreatic lesions, strongly elevated serum CA19-9, large tumours, pancreatic body or tail cancer, borderline and locally advanced cancer, and ascites).103.104

Figure3:Anatomicalstaging of pancreaticcancer Resectability criteriaaccording tothe NationalComprehensive CancerNetwork(NCCN)guideline(version 2.2024)^{78} CA=coeliac axis.\*Solid tumour contact with vaa arteryandthepresenceanddegreeftourcontactholdentedifpresentaitmayaffecturgicallannng

Staging

Approximately 57% of patients with pancreatic cancer present with metastatic disease at the time of diagnosis,105 with cancer predominantlylocated in theliver (75-80%) ， peritoneum (13-30%) ,lung (15-18%) ,and extra-regional lymph nodes (12%) 10 In the absence of metastases, the primary tumour is anatomicallystagedasresectable (RPC), borderline resectable (BRPC),or locally advanced (LAPC), depending on the presence and extent of involvement of peripancreatic major vasculature including the superior mesenteric artery, coeliac axis, hepatic artery branches，and portomesenteric venous axis." The resectability criteria according to the NCCN guideline are most commonly used.Besides this mainly technical classification, the Tumour, Node, and Metastasis classification of the American Joint Committee on Cancer is used for prognostication,both based on imaging-based staging and after resection based on the histopathology."7 For adequate assessment of vascular involvement, pancreas protocol contrastenhanced three-phase CT is essential.69.7 Moreover, the use of a standardised reporting template is important9.70 because of high inter-observer variability.1o8 Imaging for staging should be done within 4 weeks before initiation of treatment andbefore biliary drainage.9

Clinical staging can be further improved by considering not only the anatomical extent of the tumour, but also taking the tumour biology and patients' condition (A-B-C nomenclature) into account.1-12 When serum CA19-9 concentrations are notelevated, serum carcinoembryonic antigen and CA-125 can be used.u3.14 In patients with cholestasis,serum CA19-9 should be measured after normalisation of bilirubin and close to the initiation of tumour-directed treatment for adequate staging and response evaluation after chemotherapy.

A nationwide observational cohort study including 688 patients with anatomically RPC treated with upfront surgery underlined the clinical relevance of including biology-based resectability criteria.Biology-based borderline resectable disease (ie, serum CA19-9 {>=}500~\U/mL) wasassociatedwithimpairedoverall survival."s This finding was confirmed by a bi-national observational cohort study"'including1835patients with localised pancreatic cancer who started with a (modified) combination of 5-fuorouracilwith leucovorin, irinotecan, and oxaliplatin (ie, [m]FOLFIRINOX) as firstline treatment. This study identified anatomical (ie, BRPC and LAPC), biological (ie,serum CA19-9 \ge500\ ~U/mL) ，and conditional (ie,WHO performance status \scriptstyle>=1 factors at diagnosis as poor prognostic factors for overall survival, giving a range in 5-year overall survival from 5% in presence of the worst A-B-C prognosticators versus 5-year overall survival of 47% in presence of the most favourable A-B-C conditions. This finding underscores the relevance of systematically assessing anatomical,biological,and conditional factors for optimisationof treatmentdecisionsandpatient outcomes.Figure 3 presents the anatomical staging of pancreatic cancer.

Treatment

Treatment decision making is primarily driven by the stage of disease at diagnosis.Figure 2 shows the clinical workflow for patients with pancreatic cancer.

Metastaticpancreaticcancer

Palliative chemotherapy is the standard of care in patients with metastatic pancreatic cancer, with (m) FOLFIRINOX and gemcitabine-nab-paclitaxel as preferred regimens.69.70 Table 2 shows key randomised controlled phase 3 trials on palliative chemotherapy regimens. Both (m) FOLFIRINOX andgemcitabine-nab-paclitaxelaresuperiorto gemcitabine alone. Median and 1-year overall survival in the FOLFIRINOX group was 11 months ( 95% CI 9-13)

and 48% ,respectively, and 9 months (8-10) and 35% in the gemcitabine-nab-paclitaxel group, compared with a median and 1-year overall survival of about 7months and 21-22% after gemcitabine alone.u.un Therefore, gemcitabine is only reserved for patients with a poor performance status.nu.m A growing body of evidence suggests that some pancreatic cancer subtypes respond better to FOLFIRINOX, whereas others respond better to gemcitabine-basedchemotherapy.24122-124 However, randomised trials confirming the clinical effect of these findings are not available.

The international NAPOLI-3 trial showed longer overall survival after NALIRIFOX (ie, 5-fuorouracil with leucovorin, liposomal irinotecan, and oxaliplatin) with a median overall survival of 11 months 95% CI 10-12) and 1-year overall survival of 46% (41-51),compared with a median overall survival of 9 months (8-11) and 1-year overall survival of 40% (35-44) after gemcitabine-nabpaclitaxel.ns However, randomised trials comparing (m) FOLFIRINOX with either gemcitabine-nab-paclitaxel or NALIRIFOX are lacking.A reconstructed individual patient data and network meta-analysis including only randomised trials found no significant difference in overall survival between(m)FOLFIRINOX and respectively gemcitabine-nab-paclitaxel and NALIRIFOX.125

In case of non-progressive disease after 6 months of palliative chemotherapy, treatment can be halted or maintenance therapy can be considered.?In patients with a germline BRCA mutation, maintenance therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib afterplatinum-based chemotherapyis recommended.69. This treatment isassociated with prolonged progression-free survival, but without improvement in overall survival,u9.126 In case of disease progression during first-line treatment with (m) FOLFIRINOX, second-line gemcitabine-based chemotherapy should be considered (or vice versa), although randomised trials are scarce and heterogeneous.27 Two randomised trials128.129 showed a survival benefit of second-line chemotherapy. The CONKO-003 trial showedthatoxaliplatinand5-fuorouracilwith leucovorinwassuperiorto5-fluorouracil withleucovorin alone in patients diagnosed with advanced pancreatic cancer with disease progression during first-line gemcitabine: median overall survival of 6 months 95% CI 47) versus 3 months (3-4).2s The NAPOLI-1 trial showed thatliposomalirinotecan with 5-fuorouracil andleucovorinwassuperiorto5-fuorouraciland leucovorin:median overall survival of 6 months (5-9) versus 4 months (3-5).2 The PRODIGE UNICANCER randomised trial,however, showed no difference in overall survival between second-line gemcitabinepaclitaxel compared with gemcitabine alone after first-line (m)FOLFIRINOX with a median overall survival of 6 months (5-7) in both arms.121

Toxicity of multi-agent chemotherapy causing serious adverseeventsis commonwith rates of 60-76% with (m)FOLFIRINOX, 50-86% withgemcitabine-nabpaclitaxel, and 87% with NALIRIFOX.1718,129-134 Most common are haematological events (eg, neutropenia, leukopenia, and thrombocytopenia), fatigue, peripheral neuropathy, diarrhoea, nausea, and vomiting.7.ns.129-134 Chemotherapy-related toxicitycan frequentlybe managed with dose reduction, which does not seem to affect the effcacy of FOLFIRINOX, although level-1 evidence is not available.133 Despite its toxicity, (multiagent)chemotherapy is associated with prolonged or even improved quality of life due to reduction of disease-related symptoms,34.13 particularly in patients witha lowerperformance status and quality of life at baseline.36 Outside clinical trials, patients with metastatic pancreatic cancer have a median overall survival of 2 months and a 1-year overall survival rate of

8% because thevast majority of patients never receive chemotherapy because of frailty, rapid disease progression, or some degree of fatalism.

In a small subset of patients with some tumour profiles, specific regimens could be considered, such as (m)FOLFIRINOX or gemcitabine-cisplatin for patients with a BRCA or PALB2 germline mutation,24.137 or adding pembrolizumab to first-line chemotherapy in the presence of microsatellite instable or mismatch-repair deficienttumours.1First-line treatmentwith targeted therapy of tropomyosin receptor kinase inhibitors larotrectinib or entrectinib is recommended in patients with a KRAS wild type with NTRK gene fusion.139.140 The availability of personlised treatments for small subsets of patients underlines the importance of genetic testing and molecular profiling in patients with pancreatic cancer in daily clinical practice and for clinical trials.69.70

Localisedpancreaticcancer Multimodaltreatment

The cornerstone of the treatment forlocalised pancreatic cancer is surgical resection combined with chemotherapy.4 The timing of chemotherapy and the chances for surgery depend on the tumour resectability.

In patients with RPC,upfront surgery followed by 6 months of adjuvant chemotherapy is the standard of care,96 as randomised trials have not shown superior overallsurvival with the use of neoadjuvant chemotherapy.1 Randomised trials on neoadjuvant therapy versus upfront surgery were designed based on purely tumour anatomy-based resectability criteria.In light of the shift towards an A-B-C approach, the 2024 NCCN guideline also provides the option to treat RPC with neoadjuvant therapy, including for patients with high-risk A-B-C disease features (eg, large primary tumour, regional lymphadenopathy, markedly elevated serum CA19-9, and excessive weight loss),7 which at least might reduce the risk of futile surgery.43 In patients with RPC, the rate of resection after neoadjuvant therapy is 77% 95% CI71-83).1" After upfront surgery, the preferred adjuvant regimens are (m)FOLFIRINOX, gemcitabinecapecitabine, and in Asia the S-1 regimen.14s-w Although the 2024 NCCN guideline proposes to consider to use adjuvant chemoradiation, the benefit on overall survival shown by randomised controlled trials is conficting.148.149 Table 3 presents randomised phase 3 trials on adjuvant chemotherapy.After pancreatic cancer surgery, about 33% of patients do not receive adjuvant chemotherapy, mainly due to impaired functional recovery caused by surgical complications.s This ommission might have less or no effect in patients who already received preoperative chemotherapy,15+ but clearly worsens survival in individuals undergoing upfront surgery.15s

In patients withBRPC,thestandardofcareis neoadjuvant chemotherapy (with or without radiotherapy)followed by surgery and eventually adjuvant chemotherapy to complete 6 months chemotherapy.67 Randomised controlled trials showed superior overall survival with neoadjuvant therapy compared with upfront surgery followed by adjuvant therapy." However, evidence is inconclusive about the optimal neoadjuvant chemotherapy regimen, optimal number of cycles, and benefit of subsequent adjuvant chemotherapy. See appendix (p 1) for randomised phase 3 trials on neoadjuvant therapy versus upfront surgery in patients with (B)RPC. The resection rate after neoadjuvant therapy for patients with BRPC is 61% 95% CI 55-66).14

Patients with LAPC are primarily treatedwith systemic chemotherapyfor46months.Themost commonregimensare (m)FOLFIRINOX and gemcitabine-nab-paclitaxel.69.7o However, randomised controlled phase 3 trials on different chemotherapy regimens such as neoadjuvant or induction therapy for patients with localised pancreatic cancer are still not available.Three phase 2 randomised controlled trials157-159 showed similar overall survival between neoadjuvant or induction (m) FOLFIRINOXandgemcitabine-nabpaclitaxel for localised pancreatic cancer. The preliminary published results from the PREOPANC-2 phase 3 trial found that neoadjuvant FOLFIRINOX did not improve overall survival compared with gemcitabine-based chemoradiotherapy in patients with (B)RPC.160 In the subset of patients with LAPC who are candidates for surgical resection after induction chemotherapy, evidence is inconclusive,particularly about the optimal number of cycles and the benefit of subsequent adjuvant chemotherapy."About 22% 95% CI 17-29) of patients initially diagnosed with LAPC undergo resection after induction chemotherapy. The resection rates of BRPC and LAPC after systemic chemotherapy are lower on the population level, due to referral bias.161.162

Current guidelines allow for the possibility to administer additional (chemo)radiotherapy after neoadjuvant or induction chemotherapy,7 including stereotactic body radiotherapy (SBRT), which allows for precise and therefore higher dosing compared with conventional external beam radiation.163 Radiotherapy is associated with increased rates of a microscopically radical (ie, RO) resection and pathological complete response.164165 Randomised trials, however, have not shown a survival benefit of adding preoperative radiotherapy (appendix p 2). Moreover, the ALLIANCE A021501 phase 2 randomised controlled trial showed longer 18-month overall survival after neoadjuvant mFOLFIRINOX alone comparedwithmFOLFIRINOX combined with hypofractionated radiotherapy in patients with BRPC: 67% 95% CI 56-79) versus 47% (36-63).166

Response evaluation after chemotherapy is challenging duetotheinabilitytodifferentiatebetweenkeytumour tissue and fibrosis on CT, illustrated by the sensitivity and specificity of CT to predict on RO resection of 78% 95% CI 68-86) and 60% (44-74), respectively.167 Excluding disease progression by metastatic disease is the main radiological parameter assessed at restaging." The poor ability of CT to differentiate between tumour tissue and fibrosis underlines the importance of an A-B-C approach at restaging.Serum CA19-9 concentration needs tobe stable at least after neoadjuvant therapy for patients with (B) RPC, whereas a substantial decrease after induction chemotherapyis required in patients with LAPC according to the 2024 NCCN guideline. Diverging targets for a sufficient serum CA19-9response are described,either based on the relative response and absolute concentrations at restaging.168.169 Fluorodeoxyglucose positron emission tomography before and after chemotherapy can be used to assess biological disease response,particularly in patients with non-elevated serum CA19-9concentrations at diagnosis.ro.n Considering the complexity,it is crucial that staging, restaging, and subsequent treatment decision making are done by a multidisciplinary tumour board.

Surgery

Surgery combined with systemic chemotherapy provides by far the best chance to achieve long-term overall survival.However, after surgical resection 5-year overall survival is still only 17% 172 This is due to high rates of locoregional and distant recurrence; 48% at 12 months and 86% at 5 years postoperatively.73.174 Predicting early recurrence is difficult as the presence of unfavourable parameters does not preclude long-term overall survival.29175 High-level evidence about the oncological benefit of active surveillance strategies after surgical resection is not available.176

The most common resection is a pancreatoduodenectomy,"” followed by left pancreatectomy (ie, distal pancreatectomy)7s and total pancreatectomy.79 Pancreatoduodenectomy is associated with a 90-day major morbidity rate of 26% and a mortality of 5% 180A lower failure to rescue rate is seen in high-volume centres with experienced multidisciplinary teams and round-theclock interventional radiology and interventional endoscopy services.7 Pancreatic cancer surgery might require portomesenteric venous, arterial,， and multivisceral resectionsi82-84 to obtain a radical resection.85,186 Therefore, centralisation of pancreatic cancer surgery is highly advocated,6.18 as higher hospital volumes are associated with lower surgical mortality.88 Pancreatic surgery is associated with risks of endocrine and exocrine insufficiency of, respectively, 22% and 43% after pancreatoduodenectomy,189.190 23% and 12% after left pancreatectomy,78.179 and 100% after total pancreatectomy.9 Open surgery via laparotomy is standard of care,9 but minimally invasive surgery (ie, either laparoscopic or robot-assisted) is increasingly used in patients without vascular involvement, as minimally invasive surgery might enhance functional recovery.? The feasibility and safety of laparoscopic pancreatic surgery compared with an open approach, specifically for patients with pancreatic cancer, has been shown for pancreatoduodenectomy and left pancreatectomy, whereas level-1-evidence for robotic pancreatic surgery is awaited.192.193

Local ablative therapy

Local therapies have been and are being studied in patients with studies in patients with LAPC after induction chemotherapyinwhom extensivevascularinvolvement, poor tumour biology, or insufficient performance status preclude surgical resection. International guidelines propose to consider palliative (chemo)radiotherapy to achieve local disease control.9o Ablative radiotherapy including SBRT has shown promising locoregional control and survival, but level-1 evidence is awaited.194 Randomised controlled trials195.1% found no survival benefit for irreversible electroporation and radiofrequency ablation in patients with LAPC.

Supportive care

Supportive care comprises multiple domains including management of pain,nutrition and rehabilitation, management of biliary and duodenal obstruction, and quality of life and psychosocial support.197

Attentiontosymptomsisimportantconsideringtheir modifiability and effect on quality of life.9 Abdominal or back pain is reported in up to 62% of patients before diagnosis.9 This pain can be multifactorial including perineural invasion,ingrowth in surrounding visceral structures,andmetastases,requiringamultidisciplinary evaluation.2oo In case pharmacological therapy is insuffcient to control tumour-related pain, interventionssuchascoeliacplexusneurolysisand radiation should be considered. Coeliac plexus neurolysis is mainly indicated in patients with a short life expectancy considering this therapy's temporal effect of about 1-3 months.2 Palliative SBRT possibly reduces pain and improves quality of life for a longer time period.194

Screening for malnutrition should be standardised as approximately 63% of patients with pancreatic cancer have cachexia at diagnosis.20 Prehabilitation including physical training and dietary consultation is important to prepare patients for tumour-targeted treatment.2o3 The APACap GERCOR randomised trial2o in patients with advanced pancreaticcancer showed thepositive effect of adapted physical activity training on global health status, functioning, and symptoms without effect on chemotherapy treatment and survival. A contributing factor to the development of weight loss and cachexia is pancreatic exocrine insufficiency. Exocrine insufficiency occurs in about 72% 95% CI 55-86) of patients with advanced pancreatic cancer2o5 and requires pancreatic enzyme replacement therapy, according to the 2024 European guideline.20 However, a standardised approach regarding malnutrition screening, dietary consultation, and pancreatic enzyme replacement therapy is often missing in the daily clinical practice.207.2s Considering the high incidence of exocrine insufficiency in patients with pancreatic cancer (particularly when located in the pancreatic head), the diagnosis of exocrine insufficiency can be made on symptoms (eg, diarrhoea, steatorrhea, bloating, abdominal cramps, and fatulence) and nutritional status alone.2°Malnutrition can also be caused by a gastric outlet or duodenal obstruction, which can be managed with a surgical or endoscopic gastrojejunostomy after securing biliary drainage, as a gastrojejunostomy is typically superior to a duodenal stent.70.207

In patients with cholestasis,biliary drainage is advised in individuals being scheduled for neoadjuvant or induction therapy, having delay of upfront surgery with more than 2 weeks, having symptoms of cholangitis or fever, or having severe symptomatic jaundice.69.70 Biliary drainage is preferably performed via endoscopic retrograde cholangiopancreatography (ERCP）with placement of a self-expandable metal stent, considering its longer patency compared with plastic stents.21.21

Diabetes is common with a prevalence of approximately 30% in the general population of individuals with pancreatic cancer.Diabetes should be recognised and appropriately managed in thisgroup ofpatients.2o In addition, new-onset diabetes might occur after pancreatic surgery.890.19 Management of diabetes after total pancreatectomy is particularly challenging with a negative effect on quality of life. However, the long-term quality of life outcomes after total pancreatectomy are similar compared with patients undergoing partial pancreatectomy.22

Psychological support is relevant considering thehigh prevalence of depression( 31% 95% CI 20-42) and anxiety 20% ;9-32) of patients with pancreatic cancer.2 In the 6 months before and after diagnosis, the rates of depression are even higher (up to 70% before and 80% after diagnosis).2 Theinvolvement of informal caregivers (eg, relatives) should not be forgotten as anxiety and depression among patients' relatives during the disease course occurs in about 33% and 12-32% respectively.215

Futuredirections

Further improvements in the care of patients with pancreatic cancer are urgently needed.

First, tumour markers of improved accuracy are needed for early disease detection, assessment of treatment response，patient selection, and prognostication. Circulating tumour DNA has shown promising results, being associated with survival at time of diagnosis and after treatment.216

Second,pancreatic cancerin thehead often requires biliary drainage through ERCP. However, ERCP results in acute pancreatitis in about 10% 95% CI 9-11%) and cholangitis in about 3% (1-6%) of patients,27 which might worsen the patient's condition and delay neoadjuvant therapy or upfront surgery.28 An EUSguided transduodenal biliary drainage, as alternative to ERCP, can avoid acute pancreatitis. A meta-analysis includingfiverandomisedtrialsshowedthatEUSguided biliary drainage was associated with a lower stent dysfunction, similar technical success rate, and no pancreatitis,219 but this approach has not yet been included in international guidelines.697 Furthermore, the EUS-guided gastroenterostomy is being studied to manage gastric outlet and duodenal obstruction as alternative to surgical gastroenterostomy.20

Third, results are awaited from randomised trials investigating the value of neoadjuvant therapy for patients with RPC and the optimal neoadjuvant and induction therapy for patients with BRPC and LAPC. These trials assess various strategies including total neoadjuvant therapy, the optimal number of cycles of chemotherapy, different multi-agent chemotherapy regimens,and the added value of radiotherapy.Moreover,randomised trials are needed to investigate the value of second-line neoadjuvant and induction chemotherapy in patients with biochemical or radiological locoregional disease progression.2 Even though about one-fifth of patients diagnosed with LAPC are resected after (m)FOLFIRINOX or gemcitabine-nab-paclitaxel, with 5-year overall survival rates up to 20-25%,^{222} the survival benefit of subsequent surgery remains unclear.223

Fourth, pancreatic resections are increasingly performed minimally invasively.24 However, evidence about robot-assisted surgery specifically in patients with pancreatic cancer is awaited,and the indications and selection criteria for minimally invasive pancreatic surgery remain a topic of debate.225

AC=eiteae radiotherxla Paceasstciifrw rteaxllddl R diseaserecurrence.

Fifth, a subset of patients present with synchronous oligometastatic disease,mostly defined ashaving three or fewer metastatic lesions in the liver, lung, or both.226 Highly selected patients might benefit after extensive chemotherapy from locoregional treatment, such as radiation, resection, or ablation of the metastatic lesions,2 eventually combined with resection of the primary tumour, with a reported median overall survival of 16 months ( 95% CI 12-23).226 Ongoing randomised trials have to clarify the added value of local therapy in this setting."TheEXTENDrandomisedphase2 trial showed a benefit of metastasis-directed therapy with systemic chemotherapy compared with systemic chemotherapy alone in patients with oligometastatic pancreatic cancer:median progression-free survival was 10 months (5-14) versus 3 months (2-5, \scriptstyle\mathtt{p=0}*030) 228

Sixth, targeted therapy for pancreatic cancer remains a major challenge.Table 4 presents clinical phase3 trials on targeted therapy for pancreatic cancer. Clinicals trials should determine the added value of routine genetic and transcriptomic tumour profiling (eg, basal-like vs classic subtype, SMAD4A,BRCA1, BRCA2, and GATA6)to determine sensitivity to specific chemotherapy regimens, given the growing evidence suggesting a difference in chemosensitivity between tumour subtypes.2412-124.236.237 Since about 88% of pancreatic adenocarcinomas have a KRAS mutation, KRAS inhibitors hold a high potential for treatment in patients with this mutation.23 Although directKRASinhibitionin pancreaticcancerhashistorically been challenging, in the last few years advances in KRASdirected therapies offer hope for improved outcomes with the use of K R A S^{G12D} and RAS-GTP239240 Additionally, approximately 12% of tumours are K R A S^{wr} with numerous targetable alterations including gene fusions and amplifications and a higher rate of microsatellite instability, which opens up various treatment possibilities.2124 These developments illustrate the importance of genetic and molecular tumour profiling for clinical trials in patients diagnosed with pancreatic cancer.

Seventh, pancreatic cancer is a so-called immunologically cold tumour. Wherefore, previous immunotherapy trials did not show prolonged survival,2.243 except for the less than 1% of patients who had a DNA mismatch deficient tumour,2 for which immunotherapy with checkpoint inhibition leads to promising survival.3824245 However, there are first signs that this dogma might be broken in the near future, with novel generation immunotherapies in combination with chemotherapy and radiotherapy.246.247 Furthermore, mRNA-based individualised neoantigen-specific and dendritic cell-based immunotherapy in the adjuvant setting is promising.248.49

Conclusions

Pancreatic cancer is a highlylethal disease due to its aggressive tumour biology that frequently presents with non-specific symptoms and has a high rate of metastatic disease at diagnosis. A multidisciplinary approach is mandatory to adequately stage and treat patients with pancreatic cancer with tumour-targeted therapy and concomitant supportive care. Chemotherapy combined with surgicalresection is the cornerstone of treatment, but only a small set of patients are candidates for surgery. Given the complexity of pancreatic cancer care, patients shouldbe managed at expert centres.The introduction of multi-agent chemotherapy, either as palliative chemotherapyfor metastatic disease or as (neo)adjuvant or induction therapy in patients with localised pancreatic cancer, has improved the survival of patients with pancreatic cancer. Given the prospect that pancreatic cancer will become the second leading cause of cancer-related deaths by 2030,there is an urgent need for novel tumour-targeted therapies with promising results from new generation immunotherapies and KRAS-directed therapies.

Contributors

TFS,AAJ, and AO were responsible for the conception, design, execution of the literature reviews, interpretation of data, and drafted the manuscript. BGK, TS, JWW, and MGB were responsible for the conception and design,interpretation of data, drafting of the manuscript, and revising the manuscript critically for important intellectual content.

Declaration of interests

AO has received a grant from Bayer Yakuhin to conduct an observational study assessing the clinical impact of gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. All other authors declared no competing interests.

Acknowledgments

We thank Faridi S Jamaludin for her assistance in designing the literature search strategy.We also thank Ingmar F Rompen and Mahsoem Ali for their assistance with interpreting the literature.

References

1 Siegel RL, Giaquinto AN,Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024; 74: 12-49.
2 Mackay TM, Latenstein AEJ,Augustinus S,et al, and the Dutch Pancreatic Cancer Group. Implementation of best practices in pancreatic cancer carein theNetherlands:a stepped-wedge randomized clinical trial. JAMA Surg 2024; 159: 42937.
3 Connor AA,Gallinger S.Pancreatic cancer evolution and heterogeneity:integrating omics and clinical data.Nat Rev Cancer 2022; 22: 13142.
4 Latenstein AEJ,van der Geest LGM, Bonsing BA,et al, and the Dutch Pancreatic Cancer Group.Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma. Eur J Cancer 2020;125: 83-93.
5 LatensteinAEJ,MackayTM,van derGeest LGM,etal,and th Dutch Pancreatic Cancer Group.Effect of centralization and regionalization of pancreatic surgery on resection rates and survival. Br J Surg 2021; 108: 82633.
6 Kotecha K, Tree K,Ziaziaris WA, et al. Centralization of pancreaticoduodenectomy: a systematic review and spline regression analysis to recommend minimum volume for a specialist pancreas service. Ann Surg 2024; 279: 953-60.
7 Bray F, Laversanne M, Sung H,et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer JClin 2024; 74: 22963.
8 Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open 2021; 4: e214708.
9 WangS,hengR,Li J,etal.Global,regional,and national lifetime risks of developing and dying from gastrointestinal cancers in 185 countries: a population-based systematic analysis of GLOBOCAN.Lancet Gastroenterol Hepatol 2024; 9: 229-37.
10 Kocarnik JM,ComptonK,DeanFE,etal,and the Global Burdenf Disease09CanerCollaboratonancernidencemrtalit yearsiaidiiltdibilit life yearsfor29cancergroups from2010to2019:asystematic analysisforthe globalburden of disease study2019.JAMA Oncol 2022; 8: 42044.
11 Sung H,ieLRnrgPmlmrgingcacr among young adults inthe USA:analysis of a population-based cancer registry.Lancet Public Health 2019;4:e137-47.
12 Hughes T,HarperA,GuptaS,etal.The current and future global burden of cancer among adolescents and young adults: a population-based study.Lancet Oncol 2024;25: 1614-24.
13SungH,SiegelLTorreLA,etal.Global patternsinexcessbody weight and the associated cancer burden.CA CancerJClin 2019; 69: 88-112.
14 Luo G,Fan Z,Gong Y,et al. Characteristics and outcomes of pancreatic cancer by histological subtypes.Pancreas 2019; 48: 817-22.
15 Muraki T, Jang KT, Reid MD, et al. Pancreatic ductal adenocarcinomas associated with intraductal papillarymucinous neoplasms (IPMNs) versus pseudo-IPMNs:relative frequency, clinicopathologiccharacteristics anddiferential diagnosis. Mod Pathol 2022; 35: 96-105.
16FelstMMaiDalIPMi invasive cancers:neighbours but not always relatives.Gut 2018; 67: 165262.
17 VilelaA,QuingalahuaE,VargasA,tal.Global prevalencef pancreaticcystic lesions in thegeneral population on magnetic resonanceimaging:a systematic reviewandmeta-analysis. Clin Gastroenterol Hepatol 2024; 22:1798-1809.e6.
18 Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of unresected intraductal papillary mucinous neoplasms of the pancreas to cancer: a systematic reviewandmeta-analysis. Clin Gastroenterol Hepatol 2017; 15: 1509-1520.e4.
19 Cancer Genome Atlas Research Network.Integrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell 2017; 32: 185-203.e13.
20Astiazaran-Symonds E,Goldstein AM.A systematic review of the prevalence ofgermline pathogenicvariantsin patientswith pancreatic cancer.JGastroenterol 2021;56:713-21.
21 de Bruijn I,Kundra R,Mastrogiacomo B,et al,and theAACR ProjectENIEPCCoreTeamACRProjectGENIEConsortium. Analysis and visualization of longitudinal genomic and clinical data from the AACRProject GENIE Biopharma Collaborative in cBioPortal. Cancer Res 2023; 83: 3861-67.
22 Buscail L,Bournet B,Cordelier P.Role of oncogenic KRAS in the diagnosis,prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020; 17:153-68.
23KandaM,Mathaei H,WuJ,etalPresencef somaticmutations most early-stagepancreaticintraepithelialneoplasia.Gastroenterology 2012; 142: 730733.e9.
24RashidNU,PengXL,JiC,tal.Purityndendent subtyingf tumorsPurT)lnicallyrobustsinle-samllassiferformr subtyping in pancreatic cancer.Clin Cancer Res 2020;26:82-92.
25 Aung KL,Fischer SE,Denroche RE,et al. Genomics-driven precisionmedicineforadvanced pancreaticcancer:earlyresults from the COMPASS trial. Clin Cancer Res 2018; 24:1344-54.
26 Manoukian P,Kuhnen LC, van Laarhoven HWM,Bijlsma MF. Associatonfpigeneticlandscapewithtrgeneityanplatity in pancreatic cancer. Crit Rev Oncol Hematol 2025; 206:104573.
27 Hosein AN, Brekken RA, Maitra A.Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev GastroenterolHepatol 2020;17:487-505.
28 KiemenAL,Braxton AM,Grahn MP,et al.CODA:quantitative3D reconstruction oflarge tissues at cellularresolution.NatMethods 2022; 19: 1490-99.
29 Javed AA,Mahmud O,Fatimi AS,et al, and the PANC-PALS Consortium.Predictorsforlong-term survivalafterresection of pancreatic ductal adenocarcinoma:a systematic review and metaanalysis. Ann Surg Oncol 2024; 31: 4673-87.
30KleinAP.Pancreatic cancer epidemiology:understanding therole oflifestyle and inherited riskfactors.Nat Rev Gastroenterol Hepatol 2021:18: 493502
31 Pourshams A,Sepanlou SG,Ikuta KS,et al, and the GBD 2017 PancreaticCancerCollaborators.heglobalregionalandatinal burdenof pancreaticcanceranditsattributableriskfactorsin 195countriesandterritories19902017:systematicanalysisforthe Global Burden of Disease Study 2017.Lancet Gastroenterol Hepatol 2019; 4: 93447.
32Sadr-Azodi,OskarssonV,Discacciati,talPancreatic canc following acute pancreatitis:a population-based matched cohort study. Am J Gastroenterol 2018; 113: 1711-19.
33Gandhi S,delaFuent J,Murad MH,MajumderS.Chronic pancreatitis is a risk factor for pancreatic cancer, and incidence increases with durationof disease:asystematicreviewandmetaanalysis.Clin Transl Gastroenterol 2022;13:e00463.
34 LugoA,PeveriG,osetti,tal.trongxcessriskof panreat cancerforlowfrequencyand durationof cigarette smoking: acomprehensivereviwandmeta-analysisEurJCancer2018； 104: 117-26.
35 GenkingerM,pigelmanD,AndersonKE,etal.Alcoholintake and pancreatic cancer risk:a pooled analysis of fourteen cohort studies.Cancer Epidemiol Biomarkers Prev 2009;18:765-76.
36 Anderson MA,Zolotarevsky E, Cooper KL,et al. Alcohol and tobaccolower the ageof presentation insporadic pancreatic cancer ina dose-dependent manner:amulticenter study. Am J Gastroenterol 2012;107: 1730-39.
37 PangKartsonakiC,GuYt al.iabetes,plasma glucoseand incidence of pancreaticcancer:a prospective studyof0.5million Chinese adultsand a meta-analysis of 22cohort studies. Int J Cancer 2017; 140: 1781-88.
38Zhong L,Liu J,Liu S,Tan G.Correlation between pancreatic cancer and metabolic syndrome: A systematic review and meta-analysis. Front Endocrinol 2023; 14: 1116582.
39 Kyrgiou M,Kalliala IMarkozannes G,et al.Adiposity and cancer at major anatomical sites:umbrella review of the literature.BMJ 2017; 356: j477.
40 Porter,ahruD,au,taliskfpancreaticancer long-termprospectivefollow-upof familialpancreaticcancer kindreds.J Natl Cancer Inst 2022;114: 1681-88.
41 GogginsM,verbeekKA,randR,tal,and theIntrnatinl Cancer of the Pancreas Screening (CAPS) consortium. Management of patientswithincreased riskforfamilial pancreatic cancer:updated recommendationsfrom the International Cancer of thePancreas Screening(CAPS) Consortium. Gut 2020; 69: 7-17.
42 LiS,Silvestri,eslG,tal.Canerrisksassociatedwi BRCA1and BRCA2 pathogenic variants.J Clin Oncol 2022; 40: 152941.
43 Daly MB,PalT,lHilli Z,et al.CCN clinical practice guidelines n oncology (NCCN Guidelines)-genetic/familial high-risk assessment: breast, ovarian, and pancreaticversion 32024.2024.https://www. nccn.org/guidelines/guidelines-detail?category=2&id=1503 (accessed Aug 31, 2024).
44 YangX,LesliG,oroszuk,tal.Cancer risksassociatedwith germlinePALB2 pathogenic variants:aninternational study of 524 families.J Clin Oncol 2020;38: 67485.
45 Hsu FC,RobertsNJ,ChildsE,etal.Riskof pancreatic cancer among individuals with pathogenic variants in the ATM gene. JAMA Oncol 2021; 7: 166468.
46 Kastrins,Mukhraybliskfanretica in families with Lynch syndrome. JAMA 2009; 302: 1790-95.
47 Hu C,HartN,ollyC,tal.ssociationbetweeninhrit germlinemutationsincancer predisposition genes and risk of pancreatic cancer. JAMA 2018;319: 2401-09.
48 KlatteCF,oekestijnB,WasserMNJM,talPancreatic can surveillancein carriers ofagermline CDKN2A pathogenic variant: yield and outcomes ofa 20-year prospective follow-up.JClin Oncol 2022; 40: 3267-77.
49 van LierMG,WagnerA,MathusVliegenEM,t al.Highcancr risk in Peutz-Jeghers syndrome:a systematic reviewand surveillancerecommendations.AmJGastroenterol 2010; 105: 125864, author reply 1265.
50 Park JH,Hong JY,Shen JJ, Han K,Park YS,Park JO.Smoking cessation and pancreatic cancerriskinindividualswith prediabetes and diabetes:a nationwide cohort study.JNatl Compr Canc Netw
51 Lucenteforte E, La Vecchia C,Silverman D,et al.Alcohol consumption and pancreatic cancer: a pooled analysis in the International PancreaticCancer Case-Control Consortium (PanC4). Ann Oncol 2012; 23: 374-82.
52 HartPAellinD,ndesenKtalnd thConsortium theStudyofChronicPancreatitisDiabetes,and PancreaticCaner (CPDPC).Type 3c(pancreatogenic) diabetes mellitus secondary to chronic pancreatitisand pancreatic cancer. Lancet Gastroenterol Hepatol 2016; 1: 226-37.
53 Lee HSChaeW,ungMJ,tal.Diffrencef riskof paneat cancer in new-onset diabetes and long-standing diabetes: a population-based cohort study.JClinEndocrinolMetab 2023;
108: 1338-47.
54 Lu Y,GarciaRodriguezA,Magerud Lt al.ew-nset ty diabetes,levatedHc,ant-diabeticmedicationsandriskf pancreatic cancer Br JCancer 2015; 113: 1607-14.
55 Koo DH,Han KD,ParkCY.The incremental risk of pancreatic canceraccordingtofastingglucoselevelsnationwidepopulationbased cohort study.J Clin Endocrinol Metab 2019;104:4594-99.
56 MiyashitaHitumotTFukudaHtal.Mtabolicyrom linkedtotheincidence of pancreaticcancer.EClinicalMedicine2023:
67: 102353.
57 Park SK, Oh CM, Kim MH, Ha E, Choi YS,Ryoo JH.Metabolic syndrome,metaboliccomponents,andtheirrelationtotheriskf pancreatic cancer. Cancer 2020;126:1979-86.
58 Park JH,Han K,Hong JY,et al. Changes in metabolic syndrome statusare associated withalteredrisk of pancreatic cancer: a nationwide cohort study.Gastroenterology2022;162:509-20.7.
59Park BK,Seo JH,Son KJ,Choi JK.Risk of pancreatic cancer aftr acute pancreatitis: a population-based matched cohort study. Pancreatology 2023;23: 449-55.
60 Lichtenstein P,Holm NV,Verkasalo PK,et al.Environmental and heritable factorsinthe causation of cancer-analysesofcohortsof twins from Sweden,Denmark, and Finland.N Engl J Med 2000;
343: 7885.
61 ChenFChisMccalyifitbilt geneticarchitecture of pancreaticcancer:aPanC4study. Cancer Epidemiol Biomarkers Prev 2019;28:1238-45.
62RobertsNJ,NorrisALPetersenGM,et al.Wholegenome sequencing definesthegeneticheterogeneityof familial pancreatic cancer. Cancer Discov 2016; 6:166-75.
63 Abe T,lackfordLTamuraK,tal.Deleterious germlie mutationsareariskfactorforeoplastic progressionamonghih risk individualsundergoing pancreatic surveillance.JClin Oncol
2019; 37: 1070-80.
64 OverbeekKA,Levink IJM,Kopmann BDM,et al, and theDutch Familial PancreaticCancerSurveillanceStudy Group.Long-term yieldof pancreatic cancer surveillance inhigh-riskindividuals.Gut
2022; 71: 115260.
65 Owens DK,Davidson KW,KristAH,et al, and the US Preventive ServicesTaskForce.Screening for pancreatic cancer:US preventive servicestaskforcereaffirmationrecommendation statement.JAMA
2019; 322: 43844.
66 SchwartzRM,MatrisianM,hraderEE,FengZ,ChariS,t JA.Potential cost-effectiveness of risk-based pancreatic cancer screening in patientswith new-onset diabetes. JNatl Compr Canc Netw 2021;20: 451-59.
67 ShenB,LiShengCS,et alAssociationbetween ageat diab onset ordiabetesdurationand subsequent risk ofpancreaticcancer results from a longitudinal cohortandmendelianrandomization study. Lancet Reg Health West Pac 2022; 30:100596.
68CliftAK,Tan PS,Patone M,et al.Predicting the risk of pancreatic cancerinadults with new-onset diabetes:development andinternal externalvalidation ofaclinical risk prediction model.BrJCancer
2024; 130: 1969-78.
69 ConroyT,iffe,Vigraintaland thMGuidlin Committee.Pancreatic cancer:ESMO clinical practice guideline for diagnosis,treatment and follow-up.Ann Oncol 2023；
34: 987-1002.
70 Tempero MA,Malafa MP,enson AB,et al.Pancreati adenocarcinoma,version2.2024,NCCN clinical practice guidelinesin oncology.2024.https://www.nccn.org/guidelines/ guidelines-detailcategory=1&id=14552024 (accessed May 27,2024).
71 KogekarN,DiazKE,Weinberg AD,LucasALSurveillance of high risk individualsforpancreaticcancer with EUS andMRI:ametaanalysis.Pancreatology 2020; 20:1739-46.
72 Boyd LNC, Ali M, Leeflang MMG,et al. Diagnostic accuracy and addedvalueofblood-basedproteinbiomarkersforpancreatic cancer:ameta-analysisofaggregateandindividual participant data. EClinicalMedicine 2022;55:101747.
73 Corral JE,MarethKF,Rigert-Johnson DL,Das A,WallaceB. Diagnostic yield from screening asymptomatic individuals at high risk for pancreatic cancer: ameta-analysis ofcohort studies. Clin Gastroenterol Hepatol 2019;17:41-53.
74 Ohtsuka T,Fernandez-Del Castillo C,Furukawa T,et al. International evidence-basedKyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2024; 24: 255-70.
75 European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines onpancreaticcystic neoplasms. Gut 2018; 67: 789-804.
76 BlackfordAL,CantoM,DboukM,tal.ancreaticcaner surveillance and survival of high-risk individuals. JAMA Oncol 2024; 10: 1087-96.
7 Chhodsasta cancerdetectedduringhigh-riskindividualsurveillance:asystematic review and meta-analysis.Gastroenterology 2022;162: 786-98.
78 OverbeekKA,GogginsMG,Douk M,et al,and theInternational Cancer of the Pancreas Screening Consortium.Timeline of development of pancreatic cancerand implications forsuccessful early detectioninhigh-risk individuals.Gastroenterology2022; 162: 77285.e4.
79 WalterFM,MillsK,MendonaC,tal.ymptoms and patin factorsassociatedwithdiagnosticintervalsforpancreaticcancer (SYMPTOM pancreatic study):a prospective cohort study. Lancet Gastroenterol Hepatol 2016;1: 298-306.
80 Schmidt-Hansen M,Berendse S,Hamilton W.Symptoms of pancreaticcancerin primary care:a systematicreview.Pancreas 2016; 45: 81418.
81 Watanabanishalt msan locations as prognostic factors of pancreatic cancer.Pancreas 2004; 28: 16065.
82 StapleyS,Peters TJ,Neal RD,Rose PW,WalterFM,HamiltonW. Theriskof pancreaticcancerinsymptomatic patientsnprimary care:alargecase-control studyusingelectronic records.BrJCancer 2012; 106: 194044.
83 van Erning FN, Mackay TM, van der Geest LGM, et al, and the Dutch Pancreatic Cancer Group.Association of the location of pancreatic ductal adenocarcinoma (head,body,tail) with tumor stage,treatment, andsurvival: apopulation-based anal. Acta Oncol 2018; 57: 1655-62.
84 Tan PS,Garriga C,Clift A,et alTemporality ofbody mass nx, blood tests,comorbidities andmedicationuseasearlymarkersfor pancreatic ductal adenocarcinoma (PDAC):a nested case-control study. Gut 2023; 72: 51221.
85 Park SM, Kim KB, Han JH, et al. Incidence and risk of pancreatic cancerinpatients with acuteorchronicpancreatitis:apopulationbased cohort study. Sci Rep 2023; 13: 18930.
86 Toft J,HaddenWJ,Laurence M,et al.Imaging modalities in the diagnosis of pancreatic adenocarcinoma:a systematicreview and meta-analysisfsensitivityspecifcityanddiagnosticaccuray. EurJRadiol 2017; 92:17-23.
^{87} Ten BergeC,ukerM,runoMJtal.rea double duct sir endoscopic biopsies reliable predictors of malignancy in periampullary lesions? Dig Surg 2015; 32: 306-11.
88 van RoesselS,oerEC,DaamenLA,etal,and theDuthPancreati Cancer Group.Preoperativemisdiagnosisof pancreatic and periampullary cancerinpatientsundergoingpancreatoduodenectomy: amulticentreretrospectivecohort study.EurJSurgOncol2021; 47: 252532.
89 ByrlingJ,GhaziS,AnderssonB.Tumour origin,diagnostic accuracyand histopathologicalevaluation in patients with periampullary cancer:nationwide cohort study.BJS Open 2023; 7: zradi04.
90 Zins M,Matos C, Casnotto C.Pancreaticdenocarcinma stan intheeraofpreperativechemtherapandradiationthera Radiology 2018; 287: 374-90.
91 AhmedMChvedtal.einlaini: commonly missed early signs of pancreatic cancer on CT. Abdom Radiol (NY) 2024; 49: 3599614.
92 Krishna SG,Rao BB,Ugbarugba E,et al. Diagnostic performance of endoscopicultrasound for detection of pancreaticmalignancyfollowing anindeterminatemultidetector CT scan:a systemic review andmeta-analysis.Surg Endosc 2017; 31: 455867.
93 Alabousi M,McInnes MD,Salameh JP,et al.MRI vs CTfor the detection of liver metastases in patients with pancreatic carcinoma: a comparative diagnostic test accuracy systematicreview andmetaanalysis.J Magn Reson Imaging 2021;53:38-48.
94 Carlson DM,Abdelrahman AM,Adjei Antwi SK,et al.Baseline characteristics and use of pretherapeutic 18 F-FluorodeoxyglucosePETfor pancreatic cancer.JAm CollSurg 2024; 239: 917.
95 van Riet PA,ErlerNS,Bruno MJ,Cahen DL.Comparison of fne needle aspirationand fine-needle biopsy devicesforendoscopic ultrasoundguidedsamplingofsolidlesonsystemireviwand meta-analysis.Endoscopy 2021;53:411-23.
96 Pereira SP, Oldfield L,Ney A,et al. Early detection of pancreatic cancer.Lancet Gastroenterol Hepatol 2020;5:698-710.
97 BergquistuiAhubertal.arbyraant 19-9elevationinanatomicallyresectable,earlystagepancreatic cancer is independently associated with decreased overall survival and an indication for neoadjuvant therapy: a national cancer database study. J Am CollSurg 2016; 223:52-65.
98 Raza SS,Khan H,HajibandehS,t al.Can preoperative carbohydrate antigen19-9 predict metastatic pancreatic cancer?Results ofa systematic review and meta-analysis. HPB 2024; 26: 630-38.
99 Stoop TF,Theijse RT,Seelen LWF,et al,and the International Collaborative Group on Locally Advanced Pancreatic Cancer. Preoperativechemotherapy,radiotherapyandsurgical decisionmaking in patients with borderline resectable and locally advanced pancreatic cancer.Nat Rev Gastroenterol Hepatol 2024; 21: 10124.
100 SellNM,Fong ZV,Del Castillo CF,et al.Staging laparoscopy not only savespaientsannisionumayalpthmlivelnger. Ann Surg Oncol 2018; 25: 1009-16.
101 Ta R, O'Connor DB, Sulistijo A, Chung B, Conlon KC.The role of staging laparoscopyinresectable and borderlineresectable pancreatic cancer:a systematic review and meta-analysis.Dig Surg 2019; 36: 251-60.
102 van Dongen JC,Versteijne E,Bonsing BA,et al,and the Dutch PancreaticCancerroupheyieldfstaingaparosopyfor resectableandborderlineresectable pancreaticcancerinthe PREOPANCrandomizedcontrolled trial.EurJSurgOncol2023； 49: 811-17.
103GumusotiHnkus,lvaRuiztalYdof stain laparoscopyfor pancreatic cancer in the modern era:analysisof more than1000 consecutive patients.JAm Coll Surg 2023; 237: 49-57.
104 Fong ZV,Alvino DML,Fernandez-Del Castillo C,et al. Reappraisal of staginglaparoscopyforpatients with pancreatic adenocarcinoma. a contemporary analysis of 1001 patients.Ann Surg Oncol 2017; 24: 320311.
105HuangL,JansenL,Balavarca,etal.esectionof pancreaticcane inEuropeandA:anintationallargescalestuyhighlghing large variations. Gut 2019; 68: 130-39.
106 Mackay TM,van Erning FN, van der Geest LGM,et al, and the Dutch Pancreatic Cancer Group. Association between primary origin (head, body and tail) of metastasised pancreatic ductal adenocarcinoma and oncologic outcome:a population-based analysis.Eur J Cancer 2019;106: 99-105.
107 Chun YS,PawlikTM,Vauthey JN.8th Edition of the AJCC cancer staging manual:pancreas and hepatobiliary cancers.AnnSurgOncol 2018; 25(4): 84547.
108JooI,Lee JM,LeeES,et al.PreoperativeCTclassificationof the resectabilityof pancreatic cancer:interobserveragreement. Radiology 2019; 293: 343-49.
109 Katz MHG, Pisters PWT, Evans DB,et al. Borderline resectable pancreatic cancer:theimportance of thisemergingstageofdisease. IAm CollSurg 2008: 206: 833-46. discussion 846-48.
110 Oba A,Croce C,Hosokawa P,et al.Prognosis based definition of resectabilityin pancreatic cancer: a road map to newguidelines. Ann Surg 2022; 275: 175-81.
111Dekker EN,vanDam JL,JanssenQP,etal, and therans-Atlant Pancreatic Surgery (TAPS) Consortium.Improved Clinical staging systemforlocalizedpancreaticcancerusingtheABCfactors: a TAPS Consortium study.J Clin Oncol 2024; 42: 1357-67.
112 Oba A, Del Chiaro M, Satoi S, et al. New criteria of resectability for pancreaticcancer:a position paperbytheJapanese Society of Hepato-Biliary-PancreaticSurgery(ISHPS) JHepatobiliary Pancreat Sci 2022;29:725-31.
113Doppenberg D,StoopTF,vanDierenS,etal, and theTrans-Atlanti Pancreatic Surgery (TAPS) Consortium.Serum CEA as prognostic markerforoverall survivalinpatientswithlocalizedpancreatic adenocarcinoma and non-elevated CA19-9 levels treated with FOLFIRINOX as initial treatment: a TAPS consortium study. Ann Surg Oncol 2024; 31: 1919-32.
114 Diab HMH,Smith HG,Jensen KK,Jorgensen LN.The current role ofblood-basedbiomarkerinsurgicaldecisionmainginpatients with localised pancreatic cancer:a systematicreview.EurJCancer 2021; 154: 7381.
115SchoutenTJ,vanGoorIWJM,Dorland GA,tal,and theDuth PancreaticCancer Group.The value of biologicaland conditional factorsforstagingofpatientswithresectablepancreaticcancer undergoing upfront resection: a nationwide analysis. Ann Surg Oncol 2024; 31: 4956-65.
116ConroyT,DesseigneF,chouM,etaland theGroupeTumeurs DigestivesofUnicancer andthePRODIGEIntergroup. FOLFIRINOXversusgemcitabineformetastatic pancreaticcancer. N Engl J Med 2011; 364: 1817-25.
117 Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-703.
118ess,tal.dxallatnl acid,and fuorouracil versus folinic acid and fuorouracil alone for gemcitabine-refractory pancreaticcancer:outcomesfromthe CONKO-003 trial.J Clin Oncol 2014; 32: 2423-29.
119 GolanT,Hammel P,ReniM,etal.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med 2019; 381: 31727.
120 Wang-GillamA,LiCP,Bodoky G,etal, and the NAPOLI-1Study Group.Nanoliposomal irinotecan with fuorouracil and folinic acid inmetastaticpancreaticcancerafterpreviousgemcitabine-based therapy(NAPOLI-1):aglobal,randomised,open-label,hasetrial. Lancet 2016; 387:545-57.
121DeLaFouchardiereC,MalkaD,CropetC,tal.Gemcitabine and paclitaxelversusemcitabinealoneaferfuorouraciloxalilatin and irinotecan in metastatic pancreatic adenocarcinoma: a randomized phaseIIIPRODIGE65-UCGI36-GEMPAX UNICANCER study.J Clin Oncol 2024;42: 1055-66.
122KunzmannV,Siveke JT,Alguil H,et al,and the German Pancreatic Cancer Working Group(AIO-PAK)and NEOLAPinvestigators. Nab-paclitaxel plusgemcitabineversus nab-paclitaxel plus gemcitabinefollowedbyFOLFIRINOXinduction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre,randomised,phase 2 trial.Lancet Gastroenterol Hepatol 2021; 6: 128-38.
123 Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plusgemcitabine.NEnglJMed 2013; 369: 1691-703.
124 Ecker BL, Tao AJ, Janssen QP, et al. Genomic biomarkers associated with response to induction chemotherapy in patients withlocalized pancreatic ductal adenocarcinoma. Clin Cancer Res 2023; 29:1368-74.
125 Nicolle R,Bachet JB,Harle A,et al.Prediction of adjuvant gemcitabine sensitivity in resectable pancreatic adenocarcinoma using the GemPred RNA signature:an ancillary study of the PRODIGE-24/CCTG PA6 clinical trial.J Clin Oncol 2024; 42: 106776.
126 RebelattoTF,Falavigna M,PozzariM,et al.Should platinum-based chemotherapybepreferredforgermlineBReastCAncergenes (BRCA)1and 2-mutated pancreatic ductal adenocarcinoma(PDAC) patients?A systematic review and meta-analysis. Cancer Treat Rev 2019; 80: 101895.
127WaAMlDllTlI nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI3): a randomised,open-label,phase3trial.Lancet 2023;402:12781.
128 NichettiF,Rota S,Ambrosini P, et al.NALIRIFOX,FOLFIRINOX, and gemcitabine with nab-paclitaxel as first-line chemotherapy for metastatic pancreaticcancer:asystematic reviewandmeta-analysis. JAMA Netw Open 2024; 7: e2350756.
129 KindlerHL,Hammel P,ReniM,etal. verall survival results frm thePOLOtrial:a phaseIIstudyofactivemaintenance olaparib versus placebofor germline BRCA-mutatedmetastatic pancreatic cancer.JClin Oncol 2022;40:3929-39.
130 TemperoMA,PelzerU,O'ReillyEM,t al, and theAPACT Investigators.Adjuvant nab-paclitaxel ^+ gemcitabine in resected pancreatic ductal adenocarcinoma:resultsfrom arandomized, open-label, phase IIItrial.JClin Oncol 2023; 41: 2007-19.
131ConroyT,Hamml ,HbaMalandtCanadianCa Trials Group and the Unicancer-GI-PRODIGE Group. FOLFIRINOXorgemcitabineasadjuvant therapyfor pancreatic cancer. N Engl J Med 2018; 379: 2395-406.
132 Suker M,Beumer BR,Sadot E,et al.FOLFIRINOXfor locally advanced pancreaticcancer:asystematicreviewand patient-level meta-analysis. Lancet Oncol 2016; 17: 801-10.
133JungK,ChoiS,SongH,etal.Real-world dose reductionf standard and modifiedFOLFIRINOXinmetastatic pancreatic cancerasytematreviw,evidenemappingndmtaanly Ther Adv Med Oncol 2023; 15: 17588359231175441.
134 KristensenA,Vagnildhaug OM,Gronberg BH,Kaasa S,Laird , SolheimTS.Does chemotherapy improve health-related quality of life in advanced pancreatic cancer?A systematicreview. Crit Rev Oncol Hematol 2016; 99: 286-98.
135HagiwarahashikusakaT,tal.Healthrelatedqualityl ina randomised phaseIlI studyofgemcitabine plusSi,S1alone and gemcitabine aloneforlocallyadvanced ormetastaticpancreatic cancer: GEST study. ESMO Open 2017; 2: e000151.
136Laquente,MacarullaT,uges,tal.Qualityfliffpatint withmetastatic pancreaticadenocarcinoma initiatingfirst-line chemotherapy in routine practice.BMC Palliat Care 2020; 19:103.
137OReillyEM,ee W,aupskiM,et al.Randomized,multicenter, phaseII trial of gemcitabine and cisplatinwith or without veliparib in patients with pancreasadenocarcinoma andagermline BRCA/ PALB2mutation.JClin Oncol 2020;38:1378-88.
138 MarabelleA,Le DT, Ascierto PA,et al.Efficacy of pembrolizumab in patientswithnoncolorectalhighmicrosatelliteinstability/ mismatchrepair-deficient cancer:resultsfromthephaseI KEYNOTE-158 study.J Clin Oncol 2020; 38:1-10.
139 DemriGDBrau F,rloA,talUdatd intra analysisof theefficacyand safetyofentrectinibinpatientswith NTRKfusion-positive solid tumors.Clin Cancer Res 2022; 28: 1302-12.
140 HongDS,DuBoisSG,Kummar S,et al.arotrectinib in patients withTRKfusion-positive solid tumours:a pooled analysis of three phase 1/2 clinical trials.Lancet Oncol 2020; 21:531-40.
141LiaoWC,Chien KL,Lin YL,et al.Adjuvant treatments forresected pancreatic adenocarcinoma:a systematic review and network metaanalysis. Lancet Oncol 2013;14: 1095-103.
142AlidD,MarCruhazaG,aauat versus upfront surgeryinresectable pancreaticcancer: reconstructed patient-level meta-analysis of randomized clinical trials. BJS Open 2024; 8: zrae087.
143 CripaS,MalleoG,MazzaferroV,et al.Futility ofup-front resectionforanatomicallyresectable pancreaticcancer.JAMA Surg 2024; 159: 1139-47.
144BrownZJ,HehV,Labiner HE,et al.Surgical resection rates aftr neoadjuvant therapyfor localized pancreaticductal adenocarcinoma: meta-analysis. Br J Surg 2022;110: 3442.
145 ConroyT,CastanF,LopezA,etal,and the anadian CancerTrials Group and the Unicancer-GI-PRODIGE Group.Five-year outcomes of FOLFIRINOXvsgemcitabine as adjuvant therapyforpancreatic cancer: a randomized clinical trial. JAMA Oncol 2022; 8: 1571-78.
146 Uesaka K,Boku N,Fukutomi A, et al, and the JASPAC 01 Study Group.Adjuvant chemotherapy of S-1 versus gemcitabine for resectedpanreatcanceasen-lbandomied inferiority trial (JASPAC 01). Lancet 2016; 388: 248-57.
147Palmer DH,Jackson R,Springfeld C,et al.Pancreatic adenocarcinoma:long-term outcomes of adjuvant therapyin the ESPAC4 phase III trial.JClin Oncol 2024; JCO2401118.
148NeoptolemosJ,StockenDD,FrissH,taland thEuropean Study Group for Pancreatic Cancer.A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200-10.
149 Abrams RA, Winter KA, Goodman KA, et al. NRG Oncology/RTOG 0848:results after adjuvant chemotherapy +1- chemoradiation for patients withresected periampullary pancreatic adenocarcinoma (PA).J Clin Oncol 2024;42: 42.
150 Hecht JR, Lonardi S, Bendell J, et al. Randomized phase III study ol FOLFOX alone or with pegilodecakin as second-line therapy in patients withmetastatic pancreaticcancerthat progressed after gemcitabine (SEQUOIA).J Clin Oncol 2021;39:1108-18.
151etahhausadata with gemcitabine and long-termoutcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013; 310: 147381.
152 Neoptolemos JP,Palmer DH,Ghaneh P,et al, and the European Study Groupfor Pancreatic Cancer.Comparison of adjuvant gemcitabine and capecitabine with gemcitabinemonotherapyin patients withresected pancreatic cancer(ESPAC-4):a multicentre, open-label,randomised, phase 3 trial. Lancet 2017; 389: 101124.
153 Mackay TM, Smits FJ,Roos D,et al, and the Dutch Pancreatic Cancer Group.The risk of not receiving adjuvant chemotherapy afterresection of pancreatic ductal adenocarcinoma:a nationwide analysis.HPB (Oxford) 2020; 22: 233-40.
154 ShimizuT,MaedaS,LinkJ,etal.Clinical and pathologicalfactors associatedwithsurvivalinpatientswith pancreaticcancerwho receiveadjuvant therapyafterneoadjuvant therapy:aretrospective multi-institutional analysis.Surgery 2024;175: 137785.
155 Henry AC, van Dongen JC, van Goor IWJM, et al. Impact of complications after resection of pancreatic cancer on disease recurrence and survival, and mediation effect of adjuvant chemotherapy:nationwide,observational cohort study.BJS Open 2023; 7: zrac174.
156 van Dam JL, Janssen QP,Besselink MG,et al, and the Dutch PancreatiCancerroupeauantthrayrufrnturey forresectable and borderlineresectable pancreaticcancer:ametaanalysis of randomised controlled trials.EurJ Cancer 2022; 160: 14049.
157 Sohal DPS,Duong M,Ahmad SA,et al.Effcacy of perioperative chemotherapyforresectable pancreatic adenocarcinoma:a phase2 randomized clinical trial. JAMA Oncol 2021; 7: 421-27.
158Yamaguchi J,Yokoyama Y,Fuji T,et al.Results ofa phase II study on theuse of neoadjuvant chemotherapy (FOLFIRINOX or GEM/ nab-PTX) for borderline-resectable pancreatic cancer (NUPAT-01). Ann Surg 2022; 275: 1043-49.
159 Ozaka M, Nakachi K, Kobayashi S, et al, and the Hepatobiliary and Pancreatic Oncology Group of Japan Clinical OncologyGroup (JCOG).A randomised phase II study ofmodified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407). Eur J Cancer 2023;181:135-44.
160 Groot Koerkamp B,JanssenQP,van Dam JL,et al, and the J.de vos-Geelen.LBA83Neoadjuvant chemotherapy withFOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2): a multicenter randomized controlled trial. Ann Oncol 2023;34: S1323.
161Farnes I,KleiveD,VerbekeCS,etal.Resection rates and intention to-treat outcomes inborderline andlocally advanced pancreatic cancer:real-worlddatafromapopulation-based,prospectivecohort study (NORPACT-2). BJS Open 2023; 7: zrad137.
162 Walma MS,Brada J,Patuleia SIS,et al, and the Dutch Pancreati Cancer Group.Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer: a multicenter prospective cohort.EurJSurg Oncol 2021; 47: 699-707.
163Tchelebi LT,Lehrer EJ,TrifleiDM,et al.Conventionallyfractionated radiation therapyversusstereotacticbodyradiationtherapyforlocally advanced pancreatic cancer(CRiSP):aninternational systematic review and meta-analysis. Cancer 2020; 126: 2120-31.
164 Janssen QP,van Dam JL,Kivits IG,et al.Added value f radiotherapyfollowingneoadjuvantFOLFIRINOXforresectable and borderlineresectable pancreatic cancer:asystematicreview and meta-Analysis.Ann Surg Oncol 2021;28:8297-308.
165StoopTFbaWuHAtalPatlogicalmletre patientswithresectedpancreaticadenocarcinomaaferpreoperative chemotherapy. JAMA Netw Open 2024; 7: e2417625.
166KatMHGhiQMyerslfcacyfrratv mFOLFIRINOX vsmFOLFIRINOX plus hypofractionated radiotherapyforborderlineresectableadenocarcinoma of the pancreas:the A021501 phase 2 randomized clinical trial. JAMA Oncol 2022; 8: 1263-70.
167Yang HK,ark MS,Choi M,et al.Systematic review and mta analysis of diagnostic performance of CTimaging for assessing resectability of pancreatic ductal adenocarcinoma after neoadjuvant therapy:importance of CT criteria.Abdom Radiol 2021; 46: 5201-17.
168SeelenLWF,DoppenbergD,StoopTF,et al, and theDutch Pancreatic Cancer Group.Minimum and optimal CA19-9 response after two months induction chemotherapy in patients with locally advanced pancreatic cancer: a nationwide multicenter study. Ann Surg 2024; 279: 832-41.
169TsaiS,GeorgeB,WitmannD,et al.Importance ofnormalization ofCA19-9levelsfollowing neoadjuvanttherapyinpatientswith localized pancreatic cancer.Ann Surg 2020;27i:740-47.
170 de JongTLKoopmanD,van derWorpCAJ,etal.Added valuf digital FDG-PET/CTin disease staging and restaging inpatients withresectableorborderlineresectablepancreaticcancerSurgOncol 2023; 47: 101909.
171 Abdelrahman AM, Goenka AH, Alva-Ruiz R, et al. FDG-PET predicts neoadjuvant therapy response and survival inborderline resectable/locallyadvanced pancreaticadenocarcinoma. J Natl Compr Canc Netw 2022; 20: 1023-32.e3.
172 Bengtsson A,Andersson R,Ansari D.The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data. Sci Rep 2020; 10:16425.
173 Daamen LA,Dorland G,Brada LJH,etal, and the Dutch Pancreatic CancerGroup.Preoperative predictorsforearly and veryearly diseaserecurrencein patientsundergoingresectionof pancreatic ductal adenocarcinoma. HPB 2022;24: 535-46.
174 van Goor IWJM,SchoutenTJ,Verburg DN,et al,and theDuth PancreaticCancer Group.Predicting long-termdisease-freesurvival afterresection of pancreatic ductaladenocarcinoma:anationwide cohort study. Ann Surg 2024; 279: 132-37.
175 Leonhardt CS, Gustorff C, Klaiber U, et al. Prognostic factors for earlyrecurrenceafterresectionof pancreaticcancer:asystematic review and meta-analysis. Gastroenterology 2024; 167: 977-92.
176 Halle-Smith JM,Hall L, Damen LA, et al. Clinical benefit of surveillance after resection of pancreatic ductal adenocarcinoma: a systematic review and meta-analysis.EurJSurg Oncol 2021; 47: 224855.
177 Sanchez-Velazquez P,Muller X,Malleo G,et al.Benchmarks in pancreatic surgery:a novel toolfor unbiased outcome comparisons. Ann Surg 2019; 270: 211-18.
178DurinT,MarcheseU,Sauvanet,et al.Defningbenchmark outcomes for distal pancreatectomy:results of a french multicentric study. Ann Surg 2023;278: 103-09.
179LoMMnlCaoriza types of total pancreatectomy. JAMA Surg 2022; 157: 120-28.
180PancreasGroup.org Collaborative.Pancreatic surgery outcomes: multicentre prospective snapshot study in 67countries.BrJSurg 2024; 111.
181 Ratnayake B,Pendharkar SA,Connor S,et al.Patient volume and clinicaloutcomeafterpancreaticcancerresection:acontemporary systematicreviewandmeta-analysis.Surgery2022;172:27383.
182 Zwart ES, Yilmaz BS, Halimi A, et al. Venous resection for pancreaticcancer,asafandfeasibleoption?systematicreviw and meta-analysis.Pancreatology 2022;22: 803-09.
183 RebeloA,Bdeyri I,HecklerM,etal.Systematic review and mta analysis of contemporary pancreas surgery with arterial resection. Langenbecks Arch Surg 2020; 405: 903-19.
184 PetruccianiN,Debs T,Nigri G,et al.Pancreatectomy combined withmultivisceralresectionfor pancreaticmalignancies:isit iustifed? Results of a svstematic review. HPB 2018: 20: 3-10.
185DemirIE,JagrC,chlitrM,tal.ROversusreectin mattersafter pancreaticoduodenectomy,andless afterdistalr total pancreatectomy for pancreatic cancer.Ann S u r g2018 268: 1058-68.
186 Leonhardt CS,HankT,Pils D,etal.Prognostic impact of resection marginstatusonsurvivalafterneoadjuvant treatmentforpancreatic cancer:systematicreview and meta-analysis.IntJSurg 2024; 110: 453-63.
187 Boggi U,Kaufmann E,apoli N,etal, and the REDISCOVER MultidisciplinaryAdvisory Board.REDISCOVERinternational guidelines ontheperioperative care of surgical patientswith borderline-resectable and locallyadvanced pancreatic cancer. Ann Surg 2024; 280: 5665.
188 Scholten LMungropTH,Hajtink SALtal. New-onset diabt after pancreatoduodenectomy: A systematic review and metaanalysis. Surgery 2018; 164: 6-16.
189 Moore JV,TomS,Scoggins CR,Philips P,Egger ME,Martin RCG 2nd.Exocrine pancreatic insuffciency afterpancreatectomyfor malignancy:systematic review and optimal management recommendations.J Gastrointest Surg 2021; 25:2317-27.
190YuuHanL.abtmelltus afs pancreatectomy: a systematicreview and meta-analysis. JLaparoendosc Adv Surg Tech A 2020;30:1215-22.
191 Scholten L,StoopTF,Del Chiaro M,etal, and the Dutch PancreaticCancer Group.Systematic reviewof functional outcome and quality of life aftertotalpancreatectomy.BrJSurg 2019; 106: 173546.
192 Korrel M, Jones LR, van Hilst J,et al, and the European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS).Minimally invasiveversusopendistalpancreatectomyforresectablepancreatic cancer(DIPLOMA):aninternational randomised non-inferiority trial. Lancet Reg Health Eur 2023; 31: 100673.
193 Uijterwijk BA,Wei K,Kasai M,et al. Minimally invasive versus open pancreatoduodenectomy for pancreatic ductal adenocarcinoma:Individual patient data meta-analysisof randomized trials. Eur JSurg Oncol 2023; 49:1351-61.
194 Shouman MA,Fuchs F,Walter F,et al.Stereotactic body radiotherapy for pancreatic cancer-A systematic review of prospective data.Clin Transl Radiat Oncol 2024;45:100738.
195TmmerFEF,GeboersB,RuarusAH,etalRI-guided stereotacti ablativebodyradiotherapyversusCT-guided percutaneous irreversibleelectroporationforlocally advanced pancreatic cancer (CROSSFIR)singlecentrepen-labelrandomisedpha trial.Lancet Gastroenterol Hepatol 2024; 9: 448-59.
196 Seelen LWF, Brada LJH, Walma MS, et al. Radiofrequency ablation and chemotherapyversuschemotherapy aloneforlocallyadvanced pancreatic cancer (the PELICAN trial):aninternational randomized controlled trial. HPB 2024; 26: S36-37.
197 Law B, Windsor J, Connor S, Koea J, Srinivasa S.Best supportive care in advanced pancreas cancer a systematicreview to definea patient-care bundle.ANZJ Surg 2024;94:1254-59.
198 Mavros MN, Davis LE, Hallet J, et al. Symptom burden of nonresected pancreatic adenocarcinoma:an analysis of 10753 patientreported outcome assessments.Pancreas 2020; 49: 1083-89.
199 MeayTDigbeuDEBaillarenG,talPrdiagi painin patientswith pancreatic cancer signalstheneedfor aggressive symptom management. Oncologist 2023;28:e1185-97.
200DrewesMCampbellCMCyhanGOtalPainpancreat ductal adenocarcinoma: a multidisciplinary, International guideline for optimized management.Pancreatology 2018;18:446-57.
201 OkitaM,OtaniK,MatsuiS.fcacyfendoscopicultrasoud guidedceliacplexusneurolysisforabdominal paininpatients with unresectable pancreatic cancer:network meta-analysis of randomized controlled trials.J Clin Gastroenterol 2023; 57: 1054-62.
202 Permuth JB,Park MA, Chen DT,et al. Leveraging real-world data to redictcaercahxistaequalitflanduviva racially and ethnically diverse multi-institutional cohort of treatment-naive patients with pancreatic ductal adenocarcinoma. Front Oncol 2024; 14: 1362244.
203 Ngo-Huang AT, Parker NH, Xiao L, et al. Effects of a pragmatic home-basedexercise programconcurrentwithneoadjuvanttherapy on physicalfunction of patientswith pancreatic cancer: thePancFit randomized clinical trial. Ann Surg 2023: 278: 2230.
204 NeuzilltC,ouchTournigand,tal.ffectofadapt physicalactivityin patients withadvanced pancreaticcancer:the APACaP GERCOR randomized trial.J Natl Compr Canc Netw 2023; 21: 1234-42.e17.
205 Iglesia D,Avci B,Kiriukova M,et al.Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: a systematicreview and meta-analysis.United European Gastroenterol J2020;8:1115-25.
206Dominguz-MunozJE,VujasinovicM,delaIglesiaD,t al,and th EuropeanPEIMultidisciplinary Group.European guidelinesfor the diagnosis and treatment of pancreatic exocrine insuffciency:UEG,EPC,EDS,ESPEN,ESPGHAN,ESDO,and ESPCGevidence-based recommendations. United European GastroenterolJ2025;13:125-72.
207 Russell TB,Murphy P, Tanase A, Sen G, Aroori S.Results from a UK-wide survey: the nutritional assessment andmanagement of pancreatic resection patients is highlyvariable.EurJClin Nutr 2022; 76: 103840.
208 Latenstein AEJ,Dijksterhuis WPM,MackayTM,t al, and the Dutch PancreaticCancer Group.Cachexia,dietetic consultation, and survival in patients with pancreatic and periampullary cancer: a multicenter cohort study.Cancer Med 2020; 9: 9385-95.
209 Teoh AYB,LakhtakiaS,Tarantino I,et al.Endoscopic ultrasonography-guidedgastroenterostomy versusuncovered duodenalmetalstenting forunresectablemalignantgastricoutlet obstruction(DRA-GOO): a multicentre randomised controlled trial. Lancet Gastroenterol Hepatol 2024;9:124-32.
210 Watanabe J,MikiA,Sasanuma H,Kotani K,SataN.Metals plasti stentsforpreoperativebiliarydrainageinpatientswith periampullary cancer:anupdated systematic reviewandmetaanalysis.JHepatobiliary Pancreat Sci2023;30:6-20.
211AlmadiMA,Barkun A,MartelM.Plastics.Self-expandable metal stentsforpalliationinmalignantbiliaryobstruction:aseriesof meta-analyses.Am J Gastroenterol 2017;112:260-73.
212 Stoop TF,ergquist E,Theijse RT,et al, and the Collaborators. Systematic review andmeta-analysis of therole of total pancreatectomy as an alternative to pancreatoduodenectomy in patients at highriskfor postoperative pancreaticfistula:isita justifiable indication? Ann Surg 2023; 278: e702-11.
213 Zamani M,Alizadeh-Tabari S.Anxiety and depression prevalence in digestive cancers:a systematic reviewand meta-analysis. BMJ Support Palliat Care 2023;13:e235-43.
214 SeoudT,yedA,CarltonN,etal.Depressionbfore and af diagnosisofpancreaticcancerresultsfromanational,population based study. Pancreas 2020; 49: 111722.
215Chong E,CroweMentorKPandanaboyanahar Systematicreviwofcaregiverburdenunmeteedsandquality-of life among informal caregivers of patientswith pancreatic cancer. Support Care Cancer 2022;31:74.
216 Guven DC, Sahin TK, Yildirim HC, Aktepe OH, Dizdar O, Yalcin S. Asystematicreviewandmeta-analysis of the associationbetween circulating tumor DNA (ctDNA)and prognosis in pancreatic cancer. Crit Rev Oncol Hematol 2021; 168:103528.
217AkshintalaKanthasamyKhullarFA,tal.nidenceeeity andmortality of post-ERCPpancreatitis:anupdatedsystematic reviewandmeta-analysis of 145randomized controlled trials. Gastrointest Endosc 2023; 98: 1-6.e12.
218LaboriKJratlie,AnderssonB,etaland theNordicancreati Cancer Trial-1 study group.Neoadjuvant FOLFIRINOXversus upfront surgeryforresectablepancreatichead cancer (NORPACT1）:amulticentre,randomised,hase2ral. Lancet Gastroenterol Hepatol 2024; 9: 205-17.
219 Barbosa EC, Santo PADE, Baraldo S, Nau AL, Meine GC. EUSversus ERCP-guided biliary drainage formalignant biliary obstruction:a systematic reviewand meta-analysis of randomized controlled trials. Gastrointest Endosc 2024; 100: 395-405.e8.
220 Bronswijk M,Vanella G,van Malenstein H,et al.Laparoscopic versus EUS-guided gastroenterostomy forgastric outlet obstruction:an international multicenter propensity scorematched comparison (with video).Gastrointest Endosc 2021; 94: 526-36.e2.
221Dekker EN,Narayan RR,Ahmami MA,etal.Chemotherapy switch for localized pancreatic cancer: a systematic review and metaanalysis. Br J Surg 2024; 111: znae244.
222 Eshmuminov D,Aminjonov B, Palm RF,et al. FOLFIRINOX or gemcitabine-basedchemotherapyforborderlineresectableandlocally advanced pancreatic cancer a multi-institutional,patient-level, metaanalysis and systematic review. Ann Surg Oncol 2023; 30: 4417-28.
223 Theijse RT,StoopTF,JanssenQP,etal.Impactofanon-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX:Trans-AtlanticPancreatic Surgery (TAPS) Consortium study. Br J Surg 2024; 111: znae033.
224vanRamshorst TME,vanHilst JBannoneE,etal,and the02 first Internationallyvalidated EuropeanGuidelinesMeetingon MinimallyInvasivePancreaticSurgeryandtheIHPBAIovation and Research Committees.International survey on opinions and use of robot-assistedand laparoscopicminimallyinvasive pancreatic surgery:5-year follow up. HPB 2024; 26: 63-72.
225 Abu Hilal M, van Ramshorst TME, Boggi U, et al, and the CollaboratorsThebresciainternationallyvalidatedEuropean guidelines on minimally invasive pancreatic surgery (EGUMIPS). Ann Surg 2024; 279: 45-57.
226 Leonhardt CS,Stamm T, Hank T, Prager G,Strobel O.Defining oligometastatic pancreaticcancer:a systematic review and critical synthesis of consensus.ESMO Open 2023;8: 102067.
227 TimmerFEF,Geboers B,NieuwenhuizenS,et al.locoregional treatment of metastatic pancreatic cancerutilizing resection, ablation and embolization:a systematic review.Cancers 2021;
13: 1608.
228LudmirEB,SherryAD,Fellman BM,et al.Addition ofmetastasis directed therapytosystemictherapyforoligometastatic pancreatic ductal adenocarcinoma(EXTEND):amulticenter,randomized phase II trial.J Clin Oncol 2024; 42:3795-805.
229VanCutsemEmperoMA,SialD,taland theHAL01 Investigators.RandomizedphaseIlltrialofpegvorhyaluronidase alfawithnab-paclitaxel plusgemcitabineforpatientswith hyaluronan-highmetastatic pancreatic adenocarcinoma. JClin Oncol 2020;38:3185-94.
230HechtonardiBendell,tal.RandomizedhaseIII studf FOLFOXaloerwitheildecakinasecond-intherapyn patientswithmetastatic pancreaticcancerthat progressed after gemcitabine (SEQUOIA).JClin Oncol 2021;39:1108-18.
231 Hammel P,Huguet F,van Laethem JL,etal, and the LAP07Trial Group.Effect of chemoradiotherapy vs chemotherapy on survival in patients withlocallyadvanced pancreaticcancer controlledafter
4months ofgemcitabine with or without erlotinib:theLAP07 randomized clinical trial. JAMA 2016; 315: 184453.
232 Sinn M, Bahra M, Liersch T, et al. CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinibversus gemcitabine alone in patients after RO resection of pancreatic cancer: a multicenter randomized phase IItrial.J Clin Oncol 2017;
35: 333037.
233TemperoM,hDYTabernero J,etal.Ibrutinib incombination withnab-paclitaxelandgemcitabineforfirst-line treatmentof patientswith metastatic pancreaticadenocarcinoma:phaseII RESOLVE study. Ann Oncol 2021; 32: 6008234
234 HewittDB,Nissen N, Hatoum H,et al.A phase3randomized clinical trial of chemotherapy with or without algenpantucel-1 (hyperacute-pancreas)immunotherapy insubjectswith borderline resectable orlocallyadvanced unresectable pancreatic cancer. Ann Surg 2022; 275: 4553.
235 Philip PA, Sahai V, Bahary N, et al. Devimistat (CPI-613) with modified fluorouarciloxaliplatin,rinotecan,andleucovorin() VersusFFXforpatientswithmetastaticadenocarcinoma of the pancreas:the phase III AVENGER 500 study.JClin Oncol 2024;
42: 3692701.
236 Lansbergen MF, Dings MPG,Manoukian P, et al. Transcriptomebased classificationto predict FOLFIRINOXresponseinareal-world metastatic pancreatic cancer cohort. Transl Res 2024; 273: 13747.
237BoilvCaryuralrgaft precisionmedicineinadvanced pancreatic cancer.Gastroenterology
2024; 167: 961-76.e13.
238 Hu ZI, O'Reilly EM.Therapeutic developments in pancreatic cancer.Nat Rev Gastroenterol Hepatol 2024;21:7-24.
239 Mahadevan KK,McAndrewsKM,LeBleu VS,etal.KRA inhibitionreprogramsthemicroenvironment of earlyandadvanced pancreatic cancer to promote FAS-mediated killing by CD8T cells. Caucov Call2022:41:1606620
240 Wasko UN,Jiang J, Dalton TC, et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature 2024; 629: 927-36.
241 Ben-Ammar I, Rousseau A, Nicolle R, et al. Precision medicine for KRAS wild-type pancreatic adenocarcinomas. Eur J Cancer 2024; 197: 113497.
242 Renouf DJ, Loree JM, Knox JJ, et al. The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma.Nat Commun 2022;13:5020.
243 Singhi AD,George B,Greenbowe JR,et al.Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targetedwith existing drugs or used as biomarkers. Gastroenterology 2019; 156: 2242-53.e4.
244 TaiebJ,SayahL,HeinrichK,et al.Effcacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient advanced pancreatic adenocarcinoma: an AGEO European Cohort. Eur J Cancer 2023;188: 90-97.
245 Coston T,Desai A,Babiker H,et al. Effcacy of immune checkpoint inhibition andcytotoxic chemotherapyinmismatchrepair-deficient and microsatelliteinstability-high pancreatic cancer:Mayo Clinic experience.JCO Precis Oncol 2023;7:e2200706.
246 Van Laethem JL, Borbath I, Prenen H,et al. Combining CD40 agonist mitazalimabwith mFOLFIRINOX in previouslyuntreated metastatic pancreatic ductal adenocarcinoma(OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study.Lancet Oncol 2024; 25: 85364.
247ZhuX,CaoY,LiuW,etal.Stereotacticbody radiotherapy plus pembrolizumab and trametinib versusstereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancerafersurgicalresection:anopen-labelrandomised, controlled, phase 2 trial. Lancet Oncol 2022; 23: e10515.
248 Rojas LA, Sethna Z,Soares KC,et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 2023; 618: 14450.
249 van't Land FR, Willemsen M, Bezemer K, et al. Dendritic cell-based immunotherapy in patients with resected pancreatic cancer. J Clin Oncol 2024; 42: 3083-93.

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