Randomized data suggest improved survival with adjuvant chemotherapy for biliary tract cancers; however, subset analyses of intrahepatic cholangiocarcinoma (IHC) show limited survival benefit. This study evaluated the impact of adjuvant chemotherapy on recurrence patterns and overall survival (OS) in patients with resected IHC.

Patients who underwent curative-intent resection for IHC were identified within a bi-institutional dataset and the National Cancer Database (NCDB). Patients were stratified by receipt of adjuvant chemotherapy. Site of first recurrence was categorized as liver only, regional, distant, or multifocal. Survival outcomes within each dataset were compared using Kaplan-Meier methods.

In the bi-institutional dataset, 347 patients underwent resection for IHC, and 149 (43%) patients received adjuvant cytotoxic chemotherapy. Recurrence was observed in 222 (64.0%) patients. OS was similar between groups (adjuvant vs. observation: 42 vs. 49 months; p = 0.13), and did not differ in patients who received capecitabine specifically (p = 0.09) or in a risk-adjusted multivariable analysis. Recurrence-free survival was worse in those who received adjuvant chemotherapy (p = 0.04), although the liver was the most common site of recurrence in both groups (0.63). A similar analysis of 1159 resected IHCs from the NCDB also demonstrated no association between adjuvant chemotherapy and OS (49 vs. 57 months; p = 0.1).

Adjuvant chemotherapy may not be associated with improved OS in IHC and did not have an impact on hepatic recurrence in this retrospective analysis. Future investigation to identify more effective adjuvant systemic regimens and/or explore the potential role of adjuvant liver-directed therapies to reduce hepatic recurrence that may improve OS for IHC is warranted.

The role of recurrence-free survival (RFS) as a validated surrogate endpoint for overall survival (OS) among patients undergoing upfront surgery for intrahepatic cholangiocarcinoma (ICC) has not been defined. We sought to evaluate the correlation between RFS and OS after surgical resection for ICC. We hypothesized that RFS was a reliable surrogate endpoint for OS among patients with ICC.

Patients who underwent upfront curative-intent surgery for ICC between 2000 and 2023 were identified from an international, multi-institutional database. The correlation between RFS and OS was assessed using rank correlation. Landmark analysis evaluated concordance between survival at 5 years and recurrence status at 6, 12, 24, 36, 48, and 54 months postoperatively.

Among 1541 patients who underwent curative-intent hepatic resection, the median RFS and OS were 22.6 months and 41.5 months, respectively. A moderately strong correlation between RFS and OS was identified (ρ = 0.79, 95% CI 0.76 to 0.82). In the landmark analysis, the concordance between 5-year OS after surgery and recurrence status at different time points (6, 12, 24, 36, 48, and 54 months) was 60.7%, 72.0%, 81.4%, 83.1%, 83.0%, and 82.5%, respectively. Restricted cubic spline analysis indicated that the prediction of OS based on RFS increased with time and plateaued 3 years after surgery.

Among patients undergoing curative-intent resection of ICC, there was a moderately strong correlation between RFS and OS. Three-year RFS may be a reliable surrogate endpoint to predict 5-year OS and should be considered in future trial design.

A limited number of randomized controlled trials (RCTs) investigated adjuvant chemotherapy in biliary tract cancers (BTCs). Recurrences and deaths are common in the first 2 years and survival remains poor despite adjuvant treatment.

Phase-III RCTs were included comparing adjuvant chemotherapy and observation in resected BTCs. The primary endpoints were recurrence-free (RFS) and overall survival (OS). Proportional hazard results were used for trial-based analyses. Patient data was curated from published Kaplan-Meier curves to analyze short-term (2-year) hazards. The Parmar and generic inverse variance methods were used.

1308 patients in 4 trials (BILCAP, ASCOT, BCAT, PRODIGE-12) were included. Capecitabine (BILCAP) and S-1 (ASCOT) were grouped as 5-FU-based, gemcitabine (BCAT) and gemcitabine-oxaliplatin (PRODIGE-12) were grouped as gemcitabine-based chemotherapy. Adjuvant 5FU-based chemotherapy improved RFS [HR: 0.80 (95 % CI:0.68-0.95), p = 0.012] and OS [HR: 0.78 (95 % CI:0.65-0.94), p = 0.009]. However, gemcitabine-based chemotherapy did not provide benefit in RFS [HR: 0.90 (95 % CI:0.70-1.15), p = 0.428] and OS [HR: 1.03 (95 % CI:0.78-1.36), p = 0.794]. The benefit of 5-FU-based chemotherapy was more apparent in the short-term (2-year hazards) (RFS: [HR: 0.67 (95 %CI:57-0.79), p < 0.001] and OS: [HR: 0.61 (95 % CI:59-0.64), p < 0.001]). However, gemcitabine-based chemotherapy did not provide RFS benefit in the short term either [HR: 0.80 (95 % CI:0.64-0.1.01), p = 0.067] and seemed to be even detrimental for OS [HR: 1.22 (95 % CI:1.14-1.31), p < 0.001] in the first 2 years.

This study confirms using 5FU-based monotherapy in the adjuvant treatment of resected BTCs. The more prominent benefit in the first 2 years emphasizes that more effective adjuvant treatments with sustained long-term benefits are needed. Two-year proportional hazards OS and RFS are proposed here as an additional secondary end-point to consider in future clinical trials. in this setting. Registration ID (PROSPERO): CRD42024614444.

The only treatment with curative potential for distal cholangiocarcinoma (dCCA) is radical surgery which can be complemented with adjuvant chemotherapy. The aim of the present study was to perform an independent external validation of a prognostic model for 3-year overall survival based on routine clinicopathological variables for patients treated with pancreatoduodenectomy for dCCA.

All patients with a histopathological confirmed dCCA that underwent pancreatoduodenectomy in Sweden from 2009 through 2019 were identified in the Swedish National Registry for Pancreatic and Periampullary Cancer. Model performance was estimated using the C-index and calibration plots.

In total 220 patients were included in the study. The median survival was 33 months (IQR 26-40) and 3-year survival rate 47% (95% CI 40-53%). The prognostic model had a C-index of 0.69 (95% CI 0.62-0.72). Calibration plots revealed overestimated risk of death across risk groups in the full cohort. Calibration was good in the subgroup of patients that did not receive adjuvant treatment.

The prognostic model showed reasonable discriminative ability but some miscalibration likely since the effect of adjuvant treatment is not included in the model. Given that the model was developed in cohorts treated prior to the current adjuvant standard of care the model can be used to estimate baseline risk prior to risk/benefit decision for adjuvant treatment as well as stratification for clinical trials but with a risk to underestimate 3-year overall survival for patients that receive adjuvant treatment.

Intrahepatic cholangiocarcinoma is an aggressive malignancy with rising incidence and poor outcomes. This review examines recent advancements in locoregional therapies for unresectable intrahepatic cholangiocarcinoma, focusing on external beam radiotherapy, transarterial radioembolization (TARE), hepatic artery infusion pump (HAIP) chemotherapy, and liver transplantation. Stereotactic body radiation therapy and proton beam therapy have shown promise in achieving local control and improving survival. TARE, with personalized dosimetry, has demonstrated encouraging results in select patient populations. HAIP chemotherapy, primarily studied using floxuridine, has yielded impressive survival outcomes in phase II trials. Liver transplantation, once contraindicated, is now being reconsidered for carefully selected patients with localized disease. While these locoregional approaches show potential, randomized controlled trials comparing them to standard systemic therapy are lacking. Patient selection remains crucial, with factors such as liver function, tumor burden, and molecular profile influencing treatment decisions. Ongoing research aims to optimize treatment sequencing, explore combination strategies with systemic therapies, and refine phenotype identification and patient selection criteria. As the landscape of intrahepatic cholangiocarcinoma management evolves, a multidisciplinary approach is essential to tailor treatment strategies and improve outcomes for patients with this challenging disease.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy. Here we performed a comprehensive proteogenomic analysis of 198 samples from Chinese AMPAC patients and duodenum patients. Genomic data illustrate that 4q loss causes fatty acid accumulation and cell proliferation. Proteomic analysis has revealed three distinct clusters (C-FAM, C-AD, C-CC), among which the most aggressive cluster, C-AD, is associated with the poorest prognosis and is characterized by focal adhesion. Immune clustering identifies three immune clusters and reveals that immune cluster M1 (macrophage infiltration cluster) and M3 (DC cell infiltration cluster), which exhibit a higher immune score compared to cluster M2 (CD4+ T-cell infiltration cluster), are associated with a poor prognosis due to the potential secretion of IL-6 by tumor cells and its consequential influence. This study provides a comprehensive proteogenomic analysis for seeking for better understanding and potential treatment of AMPAC.

Despite a rising incidence, biliary tract cancers (BTCs) are still considered a rare tumor entity. The disease's subtle clinical presentation and lack of effective early detection strategies often lead to a diagnosis at an advanced or unresectable stage, where curative options are limited.

This review provides an overview of current systemic therapies and emerging novel approaches for BTC. For decades, the combination of gemcitabine with cisplatin (GemCis) has been the standard of care for palliative treatment. However, since 2020, the diagnostic and therapeutic landscape for BTC has evolved considerably, not only in the first-line setting but also beyond, driven by the development of clinical trials exploring immunotherapy and molecularly targeted agents. Due to the high frequency of targetable genetic alterations in BTC patients, there is a growing emphasis on obtaining tissue or liquid biopsy samples to identify markers like microsatellite instability and other actionable oncogenic driver genes.

Early initiation of systemic therapies in combination with multimodal approaches is essential for maximizing survival outcomes in patients with BTC.

Ampullary carcinoma (AC) is a rare and severe gastrointestinal cancer with a disease recurrence rate of around 40% after curative-intent surgery and for which the main prognostic factors and adjuvant treatment decision remain a matter of debate.

The FFCD-AC cohort is a French nationwide prospective cohort, which included patients with non-metastatic resected AC. The primary objective of this study was to describe prognostic factors associated with disease-free survival (DFS) and overall survival (OS) after pancreaticoduodenectomy (PD) so as to propose a user-friendly score to better estimate the risk of recurrence. The secondary objective was to study the benefit of adjuvant therapy in terms of DFS and OS.

Three hundred and seventy patients with resected AC were included. Median follow-up was 40.6 months. Median age was 68.5 years (32.0-87.0 years), 53.8% of patients were male and 56.1%/37.4%/6.5% had an Eastern Cooperative Oncology Group performance status 0/1/2, respectively. Pathological subtype was intestinal/pancreatobiliary/mixed-undetermined in 29.5%/40.5%/30.0% of patients, respectively. Adjuvant chemotherapy was carried out in 61% of patients. In multivariable analysis, stage III tumor [hazard ratio (HR) 2.86, (95% confidence interval {95% CI}: 1.89-4.17), P < 0.0001], high tumor grade [HR 2.51, (95% CI: 1.42-4.43), P = 0.002] and non-intestinal subtype [HR 1.58, (95% CI: 1.00-2.49), P = 0.052] were associated with shorter DFS. A score based on these three parameters divided patients into low (n = 83), intermediate (n = 133) and high risk (n = 96) with median DFS not reached (NR)/73.1/15.2 months and a median OS NR/86.1/38.2 months, respectively. After propensity score matching, adjuvant chemotherapy was associated with longer DFS [HR 0.57, (95% CI: 0.45-0.72), P < 0.0001] in the cohort.

Our integrated score based on three easy-to-collect items-lymph node invasion, tumor grade and non-intestinal subtypes-seems highly prognostic in resected AC and needs to be confirmed in an external validation dataset to help adjuvant treatment decision making.

The efficacy of adjuvant treatment (AT) in ampullary cancer (AmC) remains controversial. This systematic review and meta-analysis aimed to evaluate the role of AT for AmC.

A comprehensive systematic search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science databases. Studies comparing overall survival (OS) and recurrence-free survival (RFS) of patients who underwent AT or not following AmC resection were included.

A total of 3971 patients in 21 studies were analyzed. Overall pooled data showed no significant difference in effect on the OS by AT [hazard ratio (HR) = 0.998, 95% confidence interval (CI): 0.768-1.297]. No significant difference in recurrence between the AT and non-AT (nAT) groups was noted (HR = 1.158, 95% CI: 0.764-1.755). In subgroup analysis, patients who received AT showed favorable outcomes in the OS compared with those who received nAT in nodal-positive AmC (HR = 0.627, 95% CI: 0.451-0.870). Neither AT consisted of adjuvant chemotherapy with radiotherapy (HR = 0.804, 95% CI: 0.563-1.149) nor AT with adjuvant chemotherapy (HR = 0.883, 95% CI: 0.642-1.214) showed any significant effect on the OS.

The effect of AT in AmC on survival and recurrence did not show a significant benefit. Furthermore, effectiveness according to AT strategies did not show enhancement in survival. AT had an advantage in survival compared with nAT strategy in nodal-positive AmC. In cases of AmC with positive lymph nodal involvement, AT may be warranted regardless of detailed strategies.

Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use.

To test external validity of the prognostic value of the hidden genome classifier of AA.

This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020.

The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin.

Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models.

Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability.

The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

Lymph node (LN) metastasis is an important prognostic factor in the ampulla of Vater (AoV) adenocarcinoma. Various LN parameters have been proposed, but their prognostic efficacy has not been compared in the same population. We aimed to evaluate the prognostic values of LN parameters in AoV adenocarcinoma patients who underwent surgical resection and adjuvant treatment based on the long-term follow-up data.

A total of 86 patients with surgically resected AoV adenocarcinoma followed by adjuvant treatment were analyzed. We evaluated the prognostic values of various LN parameters such as pathologic N stage, number of metastatic regional LN (LNN), LN ratio (LNR), and log odds of positive LNs (LODDS). Each LN parameter was separately analyzed using Cox regression models with the same confounders.

The median follow-up period was 69.4 months, and the median overall survival (OS) was 114 months. The median number of dissected LNs is 15, with an interquartile range of 8 to 25. In the univariable analyses, all LN parameters showed significant prognostic efficacy for OS, disease-free survival (DFS), and distant metastasis-free survival (DMFS). In the multivariable Cox regression analyses, LNN ≥ 2 was a statistically significant prognostic factor for OS (hazard ratio (HR) 2.10, 95% confidence interval (CI), 1.11-3.97; p = 0.022), DFS (HR 2.51, 95% CI 1.28-4.93; p = 0.007), and DMFS (HR 2.74, 95% CI 1.39-5.41; p = 0.004). LNR showed significant prognostic performance for DFS (HR 2.35, 95% CI 1.23-4.50; p = 0.010), and DMFS (HR 2.26, 95% CI 1.17-4.35; p = 0.015). N stage showed significant prognostic performance in DFS (HR 1.55 for pN1; p = 0.243 and HR 4.31 for pN2; p = 0.003), DMFS (HR 1.46 for pN1; p = 0.323 and 4.59 for pN2; p = 0.002). LODDS and the presence of LN metastasis, did not demonstrate significant prognostic value across survival outcomes.

LN parameters showed good long-term predictive performance in AoV adenocarcinoma patients treated with curative resection and adjuvant treatments. Among LN parameters, LNN ≥ 2 showed better prognostic value than others. Further large-scale studies are needed to validate the clinical usefulness of various LN parameters.

Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC.

This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT).

The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed.

The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.

The best adjuvant chemotherapy for resected biliary tract cancer (BTC) is under debate, with capecitabine supported by weak evidence. Aim of this network meta-analysis is to estimate the efficacy of different phase II/III regimens, comparing monotherapies (gemcitabine or fluoropyrimidines) head-to-head, against observation and combination regimens.

A comprehensive literature search was conducted on PubMed and EMBASE for phase II/III randomized clinical trials (RCTs) available as of December 2023, reporting hazard ratios (HRs) of overall survival (OS) and event-free survival (EFS). A frequentist framework employing a random-effects model was applied; treatment rankings were outlined according to P-score, based on direct and indirect evidence. Exploratory subgroup analyses for OS were also performed (primary site, resected margin status and nodal involvement).

Six RCTs (1979 total patients) were identified. Fluoropyrimidine monotherapy showed significantly better OS (HR .84 [.72-.97]) and EFS (HR .79 [.69-.91]) than observation, as any monotherapy did (HR .84 [.74-.96]; HR .79 [.70-.89]). In the head-to-head comparison for OS, only S1 confirmed to be superior to observation alone (HR .69 [.49-.98]) while fluoropyrimidines achieved the best P score (.81), similarly to any monotherapy (0.92). Combinations failed to prove superior to monotherapies with respect both to OS and EFS. Subgroup analyses were inconclusive due to results' inconsistency and limited sample size.

Our work confirmed that adjuvant chemotherapy grants OS and EFS benefit for resected BTC patients. Fluoropyrimidines appeared the most effective option, confirming capecitabine as the preferred choice for the Western population.

The role of adjuvant therapy in resected periampullary adenocarcinomas is equivocal due to contrasting data and limited prospective trials.

The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP), included data from 8 institutions across India. Of the 1679 pancreatic resections, 736 patients with T3/T4 and/or Node positive adenocarcinomas (considered as high risk for recurrence) were included for analysis. Three (adjuvant): one (observation) matching, using T3/T4 T staging, nodal positivity and ampullary subtype was performed by using the nearest neighbour matching method.

Of 736 patients eligible for inclusion, 621 patients were matched of which 458 patients received adjuvant therapy (AT) (predominantly gemcitabine-based) and 163 patients were observed (O). With a median follow-up of 42 months, there was a statistical difference in overall survival in favour of patients receiving AT as compared to those on observation [68.7 months vs. 61.1 months, Hazard ratio: 0.73 (95% CI: 0.54-0.97); p = 0.03]. Besides AT, presence of nodal involvement (median OS: 65.4 months vs not reached; p = 0.04) predicted for inferior OS.

The results of the match-pair analysis suggest that adjuvant therapy improves overall survival in periampullary adenocarcinomas at high risk of recurrence with a greater benefit in T3/T4, node-positive and ampullary subtypes.

Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior.

This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC.

Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P  =  0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size.

Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.

Management of ampullary tumors (AT) is challenging because of a low level of scientific evidence. This document is a summary of the French intergroup guidelines regarding the management of AT, either adenoma (AA) or carcinoma (AC), published in July 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org).

A collaborative work was conducted under the auspices of French medical, endoscopic, oncological and surgical societies involved in the management of AT. Recommendations are based on recent literature review and expert opinions and graded in three categories (A, B, C), according to quality of evidence.

Accurate diagnosis of AT requires at least duodenoscopy and EUS. All patients should be discussed in multidisciplinary tumor board before treatment. Surveillance may only be proposed for small AA in familial adenomatous polyposis. For AA, endoscopic papillectomy is the preferred option only if R0 resection can be achieved. When not possible, surgical papillectomy should be considered. For AC beyond pT1a N0, pancreaticoduodenectomy is the procedure of choice. Adjuvant monochemotherapy (gemcitabine, 5FU) may be proposed. For aggressive tumors (pT3/T4, pN+, R1, poorly differentiated AC, pancreatobiliary differentiation) with high risk of recurrence, 6 months polychemotherapy (CAPOX/FOLFOX for the intestinal subtype and mFOLFIRINOX for the pancreatobiliary or the mixed subtype) may be a valid alternative. Clinical and radiological follow up is recommended for 5 years.

These guidelines help to homogenize and highlight unmet needs in the management of AA and AC. Each individual case should be discussed by a multidisciplinary team.

The published data had contradictory information on the role of adjuvant therapy on resected periampullary carcinomas (PACA). The study was performed to evaluate the survival benefit of adjuvant treatment.

This was a propensity score matched case-control study from a prospectively maintained database from 2004-2019. The study included patients with nonpancreatic PACA who underwent curative resection. The patients (cases) who received adjuvant chemotherapy were compared with patients (controls) who were observed alone after surgery.

Of 510 patients with PACA, 230 patients (cases = 107, controls = 123) formed the unmatched study cohort. After propensity score matching, 140 patients (cases = 70, controls = 70) formed the matched study cohort. The median overall survival (OS) was similar in cases than controls in the unmatched population but doubled non-significantly in cases after matching (unmatched population, 54 months vs. 54 months, p-value = 0.624; matched population, 71 months vs. 36 months, p-value = 0.087). However, the median recurrence-free survival (RFS) was non significantly higher in the control group (unmatched population, 59 months vs. 38 months, p-value = 0.195; matched population, 53 months vs. 40 months, p-value = 0.797). In cox regression analysis, age < 60 years, advanced T stage, and presence of perineural invasion were independent factors for worse RFS, while tumor recurrence was an independent factor for poor OS.

Patients with nonpancreatic PACA may have an OS benefit from adjuvant chemotherapy, and this needs to be validated with large prospective randomized studies.

The adjuvant S-1 trial affirmed adjuvant chemotherapy for biliary tract cancer but excluded pT1N0 distal cholangiocarcinoma (DCC) according to the seventh edition of the American Joint Committee on Cancer (AJCC) classification. The introduction of tumor depth of invasion (DOI) for T-classification in the eighth edition complicates identifying DCC patients less likely to benefit from adjuvant chemotherapy.

Our cohort consisted of 185 patients with DCC who underwent pancreaticoduodenectomy between 2002 and 2019. We compared clinicopathological factors and survival outcomes between pT1N0 patients in the seventh edition and those in the eighth edition. New DOI cutoffs for subdividing pT1N0 (8th edition) patients were evaluated to identify patients less likely to benefit from adjuvant chemotherapy.

Transitioning to the eighth edition increased in pT1N0 cases from eight to 46. The 5-year cumulative recurrence rates of them were 14.3% for the seventh edition and 28.3% for the eighth edition. We proposed a DOI cutoff of <2 mm, at which the 5-year cumulative recurrence rate was 11.5%.

The eighth AJCC classification revealed that a significant proportion of pT1N0 DCC patients were at risk for recurrence. A DOI cutoff of <2 mm may be considered to potentially improve patient selection for adjuvant chemotherapy.

There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer.

Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching.

Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004).

Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Periampullary adenocarcinomas typically exhibit either intestinal or pancreatobiliary (PB) differentiation, and the type of differentiation may be prognostically more important than the anatomic site of origin. This study aimed to evaluate prognostic significance of histological type of periampullary carcinomas.

Microscopic slides from 110 consecutive pancreatoduodenectomies performed between 2010 and 2020 were reviewed and classified as intestinal or PB type. Clinicopathological factors were compared between PB-(n=93) and intestinal-type (n=17) differentiation.

The intestinal type included significantly more patients with well-differentiated histology (35.3% vs. 11.8%, p=0.001) and fewer patients with perineural invasion (41.2% vs. 76.4%, p=0.029), advanced T stage (> T3; 41.2% vs.74.2%, p=0.007), and systemic recurrence (71.4% vs. 92.9%, p=0.005) than PB type. The 5-year-overall survival rate of intestinal-type was significantly higher than that of PB-type (58.8% vs. 20.4%, p=0.003). When pancreatic cancer was separately analyzed, the intestinal type showed the best 5-year-overall survival rate, with no significant difference between the PB types excluding PDAC and PDAC (39.4% vs. 19.2%, p=0.148). In multivariate analysis, curative resection (hazard ratio, 0.417; 95% CI, 0.219-0.792, p=0.008) was the only significant prognostic factor.

Although intestinal histologic phenotype was not an independent prognostic factor on multivariate analysis, it showed pathologic features associated with better survival, while the PB type showed more aggressive tumor biology and consequently worse survival. Further studies are needed to demonstrate the prognostic significance of histologic phenotype.

Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10-20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.

Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB.

Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS).

The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively).

Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with poor prognosis and rising incidence globally. Multimodal therapy that includes surgical resection and chemotherapy with or without radiation offers the best chance for optimal outcomes. The development of established criteria for anatomic staging of local primary tumors into potentially resectable (PR), borderline resectable (BR), and locally advanced (LA) has greatly clarified the optimal treatment strategies. While upfront surgical resection was traditionally the recommended approach for localized PDAC, increasingly neoadjuvant therapy (NT) is recommended prior to surgery. Whereas NT can lead to downstaging that facilitates surgical resection for BR/LA cancers, NT also enhances patient selection for surgery, improves margin-negative resection rates, and increases the odds of completing multimodality therapy for all patients with PDAC. Herein, we review the rationale for NT for localized PDAC and summarize existing and ongoing literature.

To assess the correlation between recurrence-free survival (RFS) and overall survival (OS) in the hepatobiliary-pancreatic (HBP) surgical setting to validate RFS as a surrogate endpoint.

Reliable surrogate endpoints for OS are still limited in the field of HBP surgery.

We analyzed patients who underwent curative resection for HBP disease [986 patients with pancreatic ductal adenocarcinoma (PDAC), 1168 with biliary tract cancer (BTC), 1043 with hepatocellular carcinoma, and 1071 with colorectal liver metastasis] from September 2002 to June 2022. We also conducted meta-analyses of randomized controlled trials of neoadjuvant or adjuvant therapy to validate the surrogacy in PDAC and BTC.

Correlation coefficients between RFS and OS were low for hepatocellular carcinoma ( p = 0.67) and colorectal liver metastasis ( p = 0.53) but strong for PDAC ( p = 0.80) and BTC ( p = 0.75). In a landmark analysis, the concordance rates between survival or death at 5 years postoperatively and the presence or absence of recurrence at each time point (1, 2, 3, and 4 years) were 50%, 70%, 74%, and 77% for PDAC and 54%, 67%, 73%, and 78% for BTC, respectively, both increasing and reaching a plateau at 3 years. In a meta-analysis, the correlation coefficients for the RFS hazard ratio and OS hazard ratio in PDAC and BTC were p = 0.88 ( P < 0.001) and p = 0.87 ( P < 0.001), respectively.

Three-year RFS can be a reliable surrogate endpoint for OS in clinical trials of neoadjuvant or adjuvant therapy for PDAC and BTC.

Surgical resection is considered an effective cure for biliary tract cancer (BTC); however, the prognosis is unsatisfactory despite improved surgical techniques and perioperative management. The recurrence rate remains high even after curative resection. The efficacy of adjuvant chemotherapy in pancreatic and gastric cancers has been previously reported, and the feasibility of adjuvant therapy with S-1 has recently been reported in patients with resected BTC. We aimed to retrospectively investigate the effects of adjuvant chemotherapy with S-1 on resected advanced BTC.

We included data from 438 BTC patients who underwent resection between 2001 and 2020. After excluding patients with pTis-pT1 (n = 112) and other exclusion criteria, 266 patients were included in the analysis.

After propensity score matching, 48 patients received S-1 adjuvant chemotherapy (S-1 group), and 48 patients received non-S1 adjuvant chemotherapy or underwent surgery alone (Non-S-1 group). The patients in the S-1 group had significantly better overall survival (OS) than those in the non-S-1 group (MST 51 vs 37 months, hazard ratio [HR]:.54, 95% confidence interval [CI]:.30-.98, P = .04). The S-1 group had a significantly better recurrence-free survival (RFS) than the non-S-1 group (94 vs 21 months, HR: .57, 95% CI: .33-.97, P = .03). Subgroup analyses for OS and RFS exhibited the benefits of S-1 in patients aged <75 years and in patients with primary sites of extrahepatic and perineural invasion and curability of R0.

S-1 adjuvant therapy is promising for improving the postoperative survival of patients with resected advanced BTC, positive nerve invasion, and R0 resection.

Biliary tract cancers continue to increase in incidence and have a high mortality rate. Most of the patients present with advanced-stage disease. The discovery of targetable genomic alterations addressing IDH, FGFR, HER2, BRAFV600 E, and others has led to the identification and validation of novel therapies in biliary cancer. Recent advances demonstrating an improved outcome with the addition of immune checkpoint inhibitors to chemotherapy have established a new first-line care standard. In case of contraindications to the use of checkpoint inhibitors and the absence of targetable alterations, chemotherapy remains to be the standard of care.

Pancreatic adenocarcinoma characterized by a mere 10% 5-year survival rate, poses a formidable challenge due to its specific anatomical location, making tumor tissue acquisition difficult. This limitation underscores the critical need for novel biomarkers to stratify this patient population. Accordingly, this study aimed to construct a prognosis prediction model centered on S100 family members. Leveraging six S100 genes and their corresponding coefficients, an S100 score was calculated to predict survival outcomes. The present study provided comprehensive internal and external validation along with power evaluation results, substantiating the efficacy of the proposed model. Additionally, the study explored the S100-driven potential mechanisms underlying malignant progression. By comparing immune cell infiltration proportions in distinct patient groups with varying prognoses, the research identified differences driven by S100 expression. Furthermore, the analysis explored significant ligand-receptor pairs between malignant cells and immune cells influenced by S100 genes, uncovering crucial insights. Notably, the study identified a novel biomarker capable of predicting the sensitivity of neoadjuvant chemotherapy, offering promising avenues for further research and clinical application.

Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021.

Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop.

In November 2021, the finalized draft was presented for public scrutiny during a formal hearing.

The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.