Next Article in Journal
The Future of Liver-Targeted Protein Synthesis Inhibition: Current Treatments, Emerging Strategies, and Next-Generation Therapeutics
Previous Article in Journal
Primary Biliary Cholangitis—The Changing Biomarker Paradigms for Staging Fibrosis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Livers
Volume 6
Issue 2
10.3390/livers6020024
livers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy

by
Kizuki Yuza
1,2,
Miho Akabane
1 and
Timothy M. Pawlik
1,*
1
Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 670, Columbus, OH 43210, USA
2
Department of Gastroenterological Surgery, Yokohama City University, Yokohama 236-0004, Japan
*
Author to whom correspondence should be addressed.
Livers 2026, 6(2), 24; https://doi.org/10.3390/livers6020024
Submission received: 15 January 2026 / Revised: 13 February 2026 / Accepted: 24 March 2026 / Published: 27 March 2026
(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)
Browse Figure
Versions Notes

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is an uncommon but increasingly recognized primary liver malignancy with a poor prognosis. Although surgical resection offers the only realistic opportunity for cure, recurrence is common and the optimal integration of surgery with systemic and liver-directed therapies continues to evolve. Summary: This review summarizes contemporary evidence on the diagnosis and multidisciplinary management of ICC with particular emphasis on surgical, systemic, locoregional, and transplant-based strategies. Cross-sectional imaging plays a central role in staging and assessing resectability including evaluation of vascular invasion and the future liver remnant. Upfront resection is appropriate for selected patients with resectable disease and preserved liver function, with margin-negative resection and lymphadenectomy remaining key oncologic goals. Systemic therapy continues to evolve with cytotoxic chemotherapy forming the backbone of treatment for advanced disease and immunotherapy and targeted agents demonstrating promise in biomarker-defined subgroups. Locoregional modalities such as hepatic arterial infusion therapy and radioembolization may provide disease control in liver-dominant ICC and are increasingly used within a multidisciplinary framework. Liver transplantation remains investigational but may offer favorable outcomes in highly selected early-stage disease.

1. Introduction

Cholangiocarcinoma comprises a heterogeneous group of biliary tract cancers with distinct biological and clinical characteristics according to anatomic location. Intrahepatic cholangiocarcinoma (ICC) represents a biologically unique entity, and its incidence has been increasing worldwide [1]. Despite growing awareness and improvements in diagnostic technology, most patients present with advanced disease and recurrence after treatment is common with poor long-term survival [2]. Surgical resection currently offers the only realistic opportunity for cure, yet it is often technically demanding and associated with variable oncologic outcomes [3,4,5]. Systemic treatment options for ICC remain limited, although recent developments in chemotherapy, immunotherapy, and molecularly targeted therapies have expanded available strategies [6]. However, the optimal integration of these modalities—particularly in relation to surgery—continues to evolve.
In this review, we summarize contemporary evidence on the management of ICC, with an emphasis on surgical therapy, systemic treatment, locoregional strategies, and the emerging role of liver transplantation. Increasing recognition that ICC is a biology-driven disease underscores the need for multidisciplinary, personalized treatment strategies that integrate surgery with systemic and liver-directed therapies.

2. Epidemiology and Risk Factors

The incidence of ICC varies widely by geographic region, reflecting differences in underlying risk factors and population exposure patterns. Over the last 10–20 years, registry data from Europe and North America have demonstrated a clear increase in ICC incidence and mortality, in contrast to relatively stable or declining rates for extrahepatic cholangiocarcinoma [7,8]. This trend has been attributed to improved classification and detection, as well as the increasing prevalence of chronic liver disease and metabolic risk factors such as metabolic dysfunction–associated steatotic liver disease (MASLD; previously non-alcoholic fatty liver disease, NAFLD), diabetes, and alcohol-related liver disease [7,8]. The highest incidence of ICC remains in East and Southeast Asia, where liver fluke infestation (Opisthorchis viverrini and Clonorchis sinensis), chronic biliary inflammation, and hepatolithiasis are more common [7].
A broad range of hepatobiliary and systemic conditions are associated with ICC, including chronic viral hepatitis B and C, cirrhosis, MASLD, diabetes, alcohol-related liver disease, and autoimmune cholangiopathies such as primary sclerosing cholangitis [7,8]. Other data further demonstrate a strong association of ICC with choledochal cysts, choledocholithiasis, and cirrhosis, with cirrhosis conferring a particularly high relative risk for ICC compared with extrahepatic cholangiocarcinoma [9]. These heterogeneous etiologic backgrounds contribute to variability in tumor biology, liver reserve, and treatment tolerance, all of which directly influence surgical candidacy and outcomes [10]. Notably, however, a substantial proportion of ICC cases occur in the absence of identifiable risk factors, underscoring the challenges of early detection and prevention [9].

3. Workup and Diagnostic Evaluation

ICC is often detected incidentally or presents with nonspecific symptoms. Laboratory studies, including carbohydrate antigen 19-9 (CA19-9), may aid evaluation but lack diagnostic specificity [4]. Cross-sectional imaging is central to staging, assessing tumor burden, vascular involvement, multifocality, nodal disease, and extrahepatic spread. Treatment planning is typically undertaken in a multidisciplinary tumor board, which stratifies patients into resectable, technically high-risk resectable (often termed “borderline”), or unresectable disease according to expected oncologic clearance, technical feasibility of R0 resection, and functional liver reserve [5,11]. The criteria and clinical implications of resectable, borderline-resectable, and unresectable disease are discussed in detail in Section 5.1.
Tissue diagnosis is generally recommended before nonsurgical or systemic therapy, as biopsy can confirm the diagnosis of ICC distinguishing it from hepatocellular carcinoma or combined hepatocellular–cholangiocarcinoma, and enables molecular profiling [4]. In clearly resectable disease, however, biopsy may be omitted because histologic confirmation will be obtained from the resection specimen and biopsy carries a small risk of bleeding or tumor seeding [4].
Although the American Joint Committee on Cancer (AJCC) staging system provides prognostic information, treatment decisions rely on integrating disease extent, vascular involvement, liver reserve, and performance status within a multidisciplinary framework [5,12].

4. Imaging Modalities

Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are the primary imaging modalities to evaluate ICC, providing essential information on tumor location, size, morphology, and the relationship to intrahepatic vascular and biliary structures. Multiphasic cross-sectional imaging allows assessment of multifocal disease, satellite lesions, and extrahepatic spread, all of which directly influence clinical staging and treatment selection [13]. MRI with cholangiographic sequences is particularly useful to delineate biliary anatomy and evaluate centrally located tumors [13].
Imaging findings also guide assessment of resectability. CT-based volumetry is used to estimate the future liver remnant (FLR) in patients being considered for major hepatectomy with an anticipated small FLR, informing the need for portal vein embolization [13]. Evaluation of vascular invasion, proximity to the hepatic hilum, nodal involvement, and the presence of multifocal or extrahepatic disease is critical to determine whether curative-intent R0 resection is feasible [13].
Fluorodeoxyglucose positron emission tomography (FDG-PET) is not routinely required but may be useful in selected patients to identify occult nodal or distant metastatic disease and refine staging [13]. Overall, high-quality cross-sectional imaging forms the cornerstone of pretreatment evaluation and provides the key determinants for selecting surgical, locoregional, or systemic therapy.

5. Surgical Management

5.1. Principles of Resectability and Preoperative Assessment

Building upon pretreatment imaging assessment, curative-intent resection for ICC depends on appropriate patient selection, careful operative planning, and complete tumor removal while preserving adequate liver function [4]. Determination of resectability is increasingly framed within a three-tier classification to guide multidisciplinary decision-making: resectable, borderline-resectable (high-risk resectable), and unresectable disease [11]. While less strictly codified than in pancreatic cancer, the ‘borderline’ designation in ICC integrates technical feasibility with biological risk to identify patients who may benefit from neoadjuvant strategies [11].
Resectable disease is defined as disease amenable to complete (R0) resection with acceptable morbidity. This clinical situation typically encompasses solitary tumors without major vascular involvement, suspicious regional nodes, or distant metastases, in patients with an adequate FLR [4,5,11]. Borderline-resectable (high-risk) disease includes tumors with technical or oncologic challenges, such as contact with major hepatic veins or the portal bifurcation, multifocality (e.g., 2–3 nodules), or suspected regional lymphadenopathy [11]. Borderline-resectable disease also encompasses patients with marginal FLR or high biological risk, even when complete resection appears technically feasible, often characterized by markedly elevated CA19-9 levels [11]. In these cases, neoadjuvant systemic therapy is increasingly utilized to assess tumor biology and facilitate downsizing, often in combination with portal vein embolization to induce hypertrophy of the FLR, followed by reassessment for surgical conversion [11,14,15]. Unresectable disease encompasses tumors with extensive vascular involvement (e.g., encasement of the main portal vein or all three hepatic veins), extrahepatic metastases, or multifocal spread not amenable to R0 resection, as well as patients with prohibitive comorbidities or inadequate liver function [16].
Current guidelines from the National Comprehensive Cancer Network (NCCN) and the European Association for the Study of the Liver (EASL) recommend upfront resection for patients with anatomically resectable, solitary tumors, and preserved performance status [4,5]. A critical component of preoperative planning is the assessment of the FLR; in general, a volume of at least 30% is recommended in patients without cirrhosis, and 40% in individuals with underlying liver disease or significant chemotherapy-induced steatohepatitis [17,18,19].
While volumetric assessment of the FLR remains central to preoperative planning, liver volume alone does not fully reflect functional hepatic reserve, particularly in patients with underlying chronic liver disease, cholestasis, or prior systemic therapy [20]. As such, integration of functional assessment with volumetry is increasingly emphasized to more accurately estimate postoperative liver failure risk [20]. Several modalities are used in clinical practice to assess functional liver reserve. Indocyanine green (ICG) clearance testing is widely employed in Asia and selected Western centers to provide a global estimate of hepatic functional capacity, while nuclear medicine techniques such as technetium-99m–labeled hepatobiliary scintigraphy allow for regional assessment of functional FLR, which may be particularly informative when hypertrophy is induced preoperatively [17,20,21]. Functional impairment related to cholestasis or chemotherapy-associated liver injury should also be considered when interpreting volumetric thresholds [22,23].
When predicted FLR volume or function is inadequate, portal vein embolization remains the most established strategy to induce hypertrophy [24]. Emerging approaches such as liver venous deprivation and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may achieve more rapid hypertrophy in highly selected patients; however, their role in ICC remains evolving and should be reserved for specialized centers with careful patient selection [25,26,27].
Anatomic versus non-anatomic resection in ICC remains debated, unlike hepatocellular carcinoma in which anatomic resection is generally preferred. A recent meta-analysis of 1801 patients reported anatomic resection was associated with superior overall survival (HR 0.71, 95% CI 0.57–0.88 in the entire cohort; HR 0.70, 95% CI 0.59–0.83 after propensity score matching) and disease-free survival (HR 0.75, 95% CI 0.62–0.91 and HR 0.68, 95% CI 0.58–0.79, respectively) compared with non-anatomic resection, particularly for tumors >5 cm without increased perioperative risks [28]. However, benefits are inconsistent across early-stage disease or tumors ≤5 cm, suggesting that anatomic resection may not confer a universal benefit [28,29]. In clinical practice, anatomic resection is often favored for large or multi-segmental tumors to optimize clearance along portal territories, whereas non-anatomic resection may be appropriate for small, peripheral lesions when liver preservation is a priority [4,7].
Ultimately, achieving an R0 resection remains the primary objective, as R1 resection has been consistently associated with high recurrence and worse survival [7,30]. Data suggest that wider resection margins are associated with incremental improvements in both overall and disease-free survival. In particular, margins ≥10 mm have been demonstrated to be superior to margins <10 mm (overall survival: HR 1.54, 95% CI 1.34–1.77; disease-free survival: HR 1.51, 95% CI 1.14–2.00) [30]. The clinical benefit of margin width appears to plateau beyond approximately 10 mm; adverse tumor biology, such as vascular invasion, multifocality, and nodal metastasis remain the dominant determinant of prognosis [3,12,30,31,32,33,34]. As such, margin width alone cannot overcome aggressive disease. In clinical practice, a margin of ≥5–10 mm is generally targeted when feasible, provided that pursuit of a wider margin does not compromise the future remnant or vascular inflow [7].

5.2. Lymphadenectomy

Regional lymphadenectomy is important for accurate staging in ICC and is recommended when resection is performed. Retrieval of at least six lymph nodes from hepatoduodenal ligament is advised to ensure adequate staging and guide decisions regarding adjuvant therapy, including capecitabine [4]. However, this nodal benchmark is achieved in only ~50% of patients [2,4,7,35,36]. A recent meta-analysis including 5787 patients reported that lymphadenectomy was associated with superior overall survival even among clinically node-negative patients, particularly when R0 resection was achieved [37]. These findings suggest that lymphadenectomy has potential therapeutic value in addition to improving staging accuracy [36,37,38,39]. Standardized nodal dissection increases detection of occult nodal metastasis, which is observed in approximately 20–40% of patients, and may also facilitate enrollment in clinical trials [40]. Given the relatively low procedure-related morbidity, routine lymphadenectomy is reasonable when resection is undertaken, although debate regarding its magnitude of therapeutic benefit continues [7,37].

5.3. Multifocal Disease

The role of surgery for multifocal ICC remains controversial. Multiple lesions, whether satellite or non-satellite, are associated with worse outcomes following resection compared with solitary tumors (HR 1.89, 95% CI 1.67–2.13) [41]. Median overall survival in this population typically ranges from 15 to 25 months compared with approximately 43 months in patients with solitary tumors [42,43,44]. Nevertheless, selected patients, particularly individuals without nodal or extrahepatic disease, may still derive meaningful benefit from resection, and survival generally exceeds that of patients with metastatic disease [41]. Given current evidence, risk stratification by tumor number, distribution, and nodal status supports resection rather than precluding it entirely [41]. Multidisciplinary discussion is essential given high recurrence risk and preoperative systemic therapy should be strongly considered; further prospective data are needed.

6. Systemic Therapies

Systemic therapy plays a central role in the management of patients with unresectable or metastatic ICC. Key contemporary regimens and pivotal trial outcomes related to cytotoxic chemotherapy, targeted therapy, and immunotherapy are summarized in Table 1.

6.1. Cytotoxic Chemotherapy

For patients with unresectable, locally advanced, or metastatic biliary tract cancer, including ICC, gemcitabine plus cisplatin remains the standard first-line systemic cytotoxic therapy [4]. The ABC-02 trial established gemcitabine plus cisplatin as the standard first-line regimen for advanced biliary tract cancer, demonstrating superior overall survival (11.7 vs. 8.1 months) and progression-free survival (8.0 vs. 5.0 months) compared with gemcitabine alone without a substantial increase in toxicity [45]. Despite being introduced more than a decade ago, gemcitabine–cisplatin continues to serve as the backbone of cytotoxic systemic treatment for advanced ICC [4,46].
Recent efforts have investigated intensifying gemcitabine–cisplatin by adding nab-paclitaxel [56,57]. Early-phase studies, including multi-institutional phase II trials, reported high disease-control rates and encouraging survival with this triplet regimen compared with historical outcomes [56]. However, preliminary results from a randomized phase III trial did not demonstrate a clear overall survival advantage in an unselected biliary tract cancer population [49]. These findings underscore the ongoing challenge of improving outcomes with cytotoxic therapy alone [49].
Given the high risk of early recurrence following resection, the role of perioperative systemic therapy has been examined in patients with resectable or locally advanced, technically resectable ICC [57,58,59,60,61]. Retrospective studies suggest that neoadjuvant chemotherapy can facilitate biologic selection by revealing aggressive disease unlikely to benefit from surgery, and may enable downstaging in selected patients [57,58,59,60]. Prospective evidence remains limited, although phase II data indicate that neoadjuvant gemcitabine-based regimens are generally feasible and do not appear to adversely affect perioperative outcomes [57].
In the adjuvant setting, capecitabine remains the internationally accepted standard of care based on the BILCAP trial, which demonstrated improved overall survival compared with observation [50]. In Asia, the randomized phase III JCOG1202 (ASCOT) trial further demonstrated a statistically significant overall survival benefit with adjuvant S-1, an oral fluoropyrimidine combining tegafur with modulators of 5-fluorouracil metabolism, compared with observation following curative resection of biliary tract cancers including ICC (3-year OS 77.1% vs. 67.6%; HR 0.69, p = 0.008) [51]. Other gemcitabine-based adjuvant regimens in biliary tract cancers have not consistently demonstrated benefit, and current guidelines therefore recommend adjuvant capecitabine following curative-intent resection [4,5,62,63].
For patients with progression after first-line gemcitabine–cisplatin–based therapy, second-line cytotoxic chemotherapy remains an important option for individuals with preserved performance status. The phase III ABC-06 trial established modified leucovorin (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX) as a reference second-line regimen, demonstrating a modest but statistically significant improvement in overall survival compared with active symptom control alone (6.2 vs. 5.3 months) [52]. Beyond oxaliplatin-based therapy, irinotecan-based regimens have shown clinical activity, although results have been inconsistent across studies and regions [64,65]. Liposomal irinotecan combined with 5-fluorouracil/leucovorin may be considered in selected patients, particularly those with residual platinum-related neuropathy; however, its role remains less well defined compared with FOLFOX [5,66]. Overall, objective response rates to second-line cytotoxic therapy are low and survival gains remain limited, underscoring the importance of comprehensive molecular profiling to prioritize targeted or immunotherapy-based strategies when available [52,65,67].

6.2. Targeted Therapies

Given the increasing therapeutic relevance of molecularly defined subsets in ICC, a structured approach to molecular profiling is essential in contemporary practice. Comprehensive next-generation sequencing is recommended for patients with unresectable or advanced disease at diagnosis, as well as at recurrence, to identify actionable genomic alterations that may inform treatment selection beyond cytotoxic chemotherapy [16]. In addition to fibroblast growth factor receptor 2 (FGFR2) fusions and isocitrate dehydrogenase 1 (IDH1) mutations, clinically relevant alterations include BRAF V600E mutations, human epidermal growth factor receptor 2 (HER2) amplification or overexpression, neurotrophic tyrosine receptor kinase (NTRK) fusions, and biomarkers of immune sensitivity such as microsatellite instability–high (MSI-H), mismatch repair deficiency, and high tumor mutational burden [16,55,68,69,70,71,72,73].
When adequate tumor tissue is available, tissue-based comprehensive genomic profiling remains the preferred approach [72]. However, in patients with limited or inaccessible tissue, repeat biopsy or liquid biopsy (circulating tumor DNA–based assays) may be considered to facilitate timely molecular characterization [74]. Integration of molecular profiling into routine management enables a biology-driven treatment strategy and provides the foundation for targeted and immunotherapy-based approaches in selected patients [16,68,72]. Within this framework, advances in molecular profiling have identified clinically actionable genomic alterations in a subset of patients with ICC, most notably FGFR2 fusions and IDH1 mutations [69]. These alterations are more common in ICC than in extrahepatic cholangiocarcinoma, reinforcing the biological distinction between these entities [6,75].
FGFR2 fusions occur in approximately 10–15% of ICC cases and have emerged as a major therapeutic target [76]. Selective FGFR inhibitors, such as pemigatinib and futibatinib, have demonstrated clinically meaningful objective response rates and disease control in single-arm phase 2 trials in previously treated patients, leading to regulatory approval in this setting [53,54]. Ongoing phase III trials, such as FIGHT-302 evaluating first-line pemigatinib versus gemcitabine–cisplatin in FGFR2-rearranged cholangiocarcinoma, are assessing these agents as initial therapy in molecularly selected populations [77].
IDH1 mutations are present in approximately 15–20% of ICC cases [75]. Ivosidenib, an oral IDH1 inhibitor, has demonstrated a progression-free survival benefit compared with placebo in previously treated patients and is now an approved second-line option for IDH1-mutant disease [55]. While responses are generally modest, these agents represent an important step toward personalized treatment strategies in ICC.

6.3. Immunotherapy

Immune checkpoint inhibition has recently been incorporated into the treatment of advanced biliary tract cancers [78]. The TOPAZ-1 trial demonstrated a statistically significant improvement in survival with the addition of durvalumab to gemcitabine and cisplatin (12.9 vs. 11.3 months), establishing chemo-immunotherapy as a new first-line standard of care [5,47]. Improvements in survival have also been reported with pembrolizumab in combination with chemotherapy (12.7 vs. 11.5 months), although direct head-to-head comparisons between regimens are lacking [48].
Despite these advances, the absolute survival gains remain modest [47,48], and the role of immunotherapy in earlier disease stages—including the neoadjuvant and adjuvant settings—has yet to be defined. Ongoing studies are evaluating combination strategies aimed at improving response rates and the durability of clinical benefit [77].

7. Locoregional Therapies

Hepatic arterial infusion pump (HAIP) therapy is a liver-directed treatment that delivers chemotherapy directly into the hepatic artery, allowing high intrahepatic drug concentrations while minimizing systemic exposure. This approach exploits the predominantly arterial blood supply of liver tumors and has been most extensively studied in metastatic colorectal cancer [79,80]. More recently, HAIP has been investigated in selected patients with ICC, particularly individuals with liver-dominant or multifocal disease [81]. The rationale for HAIP in ICC is supported by the observation that a substantial proportion of patients with advanced disease have liver-confined tumor burden and ultimately have survival limited by progressive intrahepatic disease despite modern systemic therapy [82]. As such, liver-directed strategies may provide additional benefit when used alongside systemic treatment.
Several early-phase studies have evaluated HAIP in combination with systemic chemotherapy for unresectable ICC. Across multiple single-center phase II trials, objective response rates of approximately 50% and 3-year overall survival approaching 30–40% have been reported, outcomes that compare favorably with historical systemic therapy alone [82,83,84]. More recently, similar results have been reproduced in European cohorts, supporting the broader applicability of this approach beyond isolated expert centers [81]. However, available data are largely derived from non-randomized studies in highly selected patients treated at high-volume institutions [81,82,83,84]. A multinational randomized controlled trial comparing HAIP plus systemic chemotherapy with systemic therapy alone for unresectable, liver-confined ICC is ongoing (ClinicalTrials.gov Identifier: NCT01862315) and will be important to define the role of HAIP in contemporary treatment algorithms [85].
At present, HAIP should be considered for carefully selected patients with liver-dominant ICC and delivered in experienced, high-volume centers, ideally as part of a multimodality strategy incorporating systemic therapy [86]. While early outcomes are promising, further prospective, multicenter studies are needed to clarify patient selection, refine integration with immunotherapy-based regimens, and determine long-term oncologic benefit.
Other liver-directed treatments, including transarterial chemoembolization, radioembolization with yttrium-90, and stereotactic body radiotherapy, have been used in selected patients with unresectable ICC [7]. These modalities may provide local tumor control and, in some cases, disease stabilization; however, robust comparative data demonstrating a clear survival advantage over systemic therapy remain limited. As such, their role is generally considered adjunctive and should be individualized within a multidisciplinary treatment framework.

8. Liver Transplantation in ICC

Liver transplantation (LT) has historically been contraindicated for ICC because of high recurrence rates and poor survival [87,88]. Although outcomes have improved for perihilar cholangiocarcinoma under highly structured neoadjuvant protocols, the role of LT in ICC remains controversial [89]. More recent data, however, suggest that acceptable outcomes may be achievable in carefully selected patients. A meta-analysis comparing LT with liver resection demonstrated similar 1-year survival but improved 3- and 5-year survival following LT–although this benefit depended on achieving R0 resection and favorable tumor biology [90]. In particular, “very-early” ICC (typically a solitary tumor ≤2 cm) have a reported 5-year survival approaching 60–70% following LT in selected cohorts [91].
An emerging strategy in Europe emphasizes biological selection, in which only patients with liver-confined ICC demonstrating radiologic stability or response after neoadjuvant therapy proceed to LT. In one Italian series using sequential systemic chemotherapy and transarterial radioembolization, four of thirteen patients ultimately underwent LT, and all remained alive and disease-free at last follow-up (8–73 months) [92]. The TESLA program and other European initiatives are prospectively evaluating LT for locally advanced, non-metastatic ICC after documented neoadjuvant response, and the UK National Health Service has recently introduced a pilot program offering LT to cirrhotic patients with very-early ICC not suitable for resection within a structured governance framework [93,94].
Despite these promising signals, standardized selection criteria and treatment algorithms are lacking, and current evidence remains largely limited to small series and registry studies [95,96,97]. LT for ICC should therefore be considered emerging and investigational, ideally restricted to specialized centers or prospective protocols while ongoing trials refine patient selection and define its true therapeutic role [4]. The overall treatment approach is summarized in Figure 1.

9. Future Directions

Despite advances in surgical technique and systemic therapy, outcomes for ICC remain mixed, underscoring the need for improved patient selection and more effective multimodal treatment strategies. Future progress will depend on better integration of tumor biology, advanced imaging, and personalized therapeutic approaches. Artificial intelligence–based imaging analysis has the potential to refine diagnosis, improve assessment of resectability, and predict recurrence risk by extracting quantitative features beyond conventional radiologic interpretation. Similarly, circulating biomarkers, including circulating tumor DNA and other liquid biopsy approaches, may enable earlier detection of recurrence, dynamic treatment monitoring, and improved risk stratification.
In parallel, ongoing efforts aim to expand and optimize systemic treatment strategies. Combination approaches incorporating chemotherapy, immunotherapy, and targeted agents are under active investigation, with the goal of improving response rates and durability of disease control. However, the marked molecular and clinical heterogeneity of ICC underscores the need for biomarker-driven trial design and rational treatment sequencing, rather than empiric escalation of therapy in unselected populations.
Advancing precision medicine in ICC will require coordinated, multi-institutional efforts to improve clinical trial enrollment, ensure representation of diverse patient populations, and expand access to high-quality biospecimens for molecular analysis. Such collaborative strategies are essential to identify actionable targets, validate predictive biomarkers, and translate emerging therapies into meaningful clinical benefit.

10. Conclusions

ICC remains a highly aggressive malignancy with recurrence being common even after curative-intent therapy. Surgical resection continues to represent the cornerstone of treatment for selected patients, yet recurrence is common and long-term survival remains suboptimal. Recent advances in systemic therapy, locoregional treatment, and transplant oncology have expanded the therapeutic landscape, but the optimal integration of these therapies into clinical practice has yet to be defined.
Future progress in ICC management will depend on biology-driven patient selection, multidisciplinary treatment planning, and continued innovation across surgical and non-surgical modalities. Well-designed clinical trials, collaborative data sharing, and advances in precision oncology will be critical to improve outcomes for patients with this challenging disease.

Author Contributions

Conceptualization, K.Y. and T.M.P.; investigation, K.Y.; writing—original draft preparation, K.Y.; writing—review and editing, M.A. and T.M.P.; supervision, T.M.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Saha, S.K.; Zhu, A.X.; Fuchs, C.S.; Brooks, G.A. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 2016, 21, 594–599. [Google Scholar] [CrossRef]
  2. Mavros, M.N.; Economopoulos, K.P.; Alexiou, V.G.; Pawlik, T.M. Treatment and Prognosis for Patients with Intrahepatic Cholangiocarcinoma: Systematic Review and Meta-Analysis. JAMA Surg. 2014, 149, 565–574. [Google Scholar] [CrossRef] [PubMed]
  3. Bridgewater, J.; Galle, P.R.; Khan, S.A.; Llovet, J.M.; Park, J.-W.; Patel, T.; Pawlik, T.M.; Gores, G.J. Guidelines for the Diagnosis and Management of Intrahepatic Cholangiocarcinoma. J. Hepatol. 2014, 60, 1268–1289. [Google Scholar] [CrossRef] [PubMed]
  4. Alvaro, D.; Gores, G.J.; Walicki, J.; Hassan, C.; Sapisochin, G.; Komuta, M.; Forner, A.; Valle, J.W.; Laghi, A.; Ilyas, S.I.; et al. EASL-ILCA Clinical Practice Guidelines on the Management of Intrahepatic Cholangiocarcinoma. J. Hepatol. 2023, 79, 181–208. [Google Scholar] [CrossRef] [PubMed]
  5. Benson, A.B.; D’Angelica, M.I.; Abrams, T.; Ahmed, A.; Akce, M.; Anaya, D.A.; Anders, R.; Are, C.; Aye, L.; Bachini, M.; et al. Biliary Tract Cancers, Version 2.2025, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2025, 23, 403–418. [Google Scholar] [CrossRef]
  6. Tsilimigras, D.I.; Kurzrock, R.; Pawlik, T.M. Molecular Testing and Targeted Therapies in Hepatobiliary Cancers: A Review. JAMA Surg. 2025, 160, 576–585. [Google Scholar] [CrossRef] [PubMed]
  7. Caringi, S.; Delvecchio, A.; Casella, A.; Ferraro, V.; Dezio, M.; Marini, S.; Calbi, R.; Cortese, F.; Filippo, R.; Stasi, M.; et al. Hot Topics in the Surgical Treatment of Intrahepatic Cholangiocarcinoma: A Narrative Review of Current Managements. Cancers 2025, 17, 3127. [Google Scholar] [CrossRef] [PubMed]
  8. Vithayathil, M.; Khan, S.A. Current Epidemiology of Cholangiocarcinoma in Western Countries. J. Hepatol. 2022, 77, 1690–1698. [Google Scholar] [CrossRef] [PubMed]
  9. Clements, O.; Eliahoo, J.; Kim, J.U.; Taylor-Robinson, S.D.; Khan, S.A. Risk Factors for Intrahepatic and Extrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. J. Hepatol. 2020, 72, 95–103. [Google Scholar] [CrossRef]
  10. Ruff, S.M.; Pawlik, T.M. Clinical Management of Intrahepatic Cholangiocarcinoma: Surgical Approaches and Systemic Therapies. Front. Oncol. 2024, 14, 1321683. [Google Scholar] [CrossRef]
  11. Kawashima, J.; Akabane, M.; Woldesenbet, S.; Tsilimigras, D.I.; Endo, Y.; Sahara, K.; Cauchy, F.; Aucejo, F.; Marques, H.P.; Lopes, R.; et al. Oncological Resectability Criteria for Intrahepatic Cholangiocarcinoma: A Preoperative Framework for Multidisciplinary Management. Ann. Surg. Oncol. 2025, 32, 7141–7151. [Google Scholar] [CrossRef]
  12. Chun, Y.S.; Pawlik, T.M.; Vauthey, J.-N. 8th Edition of the AJCC Cancer Staging Manual: Pancreas and Hepatobiliary Cancers. Ann. Surg. Oncol. 2018, 25, 845–847. [Google Scholar] [CrossRef] [PubMed]
  13. Childers, B.G.; Denbo, J.W.; Kim, R.D.; Hoffe, S.E.; Glushko, T.; Qayyum, A.; Anaya, D.A. Intrahepatic Cholangiocarcinoma: Role of Imaging as a Critical Component for Multi-Disciplinary Treatment Approach. Abdom. Radiol. 2025, 50, 4110–4124. [Google Scholar] [CrossRef] [PubMed]
  14. Dong, Y.; Podrascanin, V.; Li, Z.; Santol, J.; Ammann, M.; Fonkoua, L.A.K.; Graham, R.P.; Conboy, C.B.; Tran, N.H.; Warner, S.G.; et al. Real-World Single-Center Experience with Neoadjuvant Gemcitabine, Cisplatin, and Durvalumab in Borderline Resectable Cholangiocarcinoma. Ann. Surg. Oncol. 2025, 32, 7228–7239. [Google Scholar] [CrossRef]
  15. Matsuyama, R.; Mori, R.; Ota, Y.; Homma, Y.; Yabusita, Y.; Hiratani, S.; Murakami, T.; Sawada, Y.; Miyake, K.; Shimizu, Y.; et al. Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma. Ann. Surg. Oncol. 2022, 29, 2393–2405. [Google Scholar] [CrossRef]
  16. Vogel, A.; Ducreux, M. ESMO Clinical Practice Guideline Interim Update on the Management of Biliary Tract Cancer. ESMO Open 2024, 10, 104003. [Google Scholar] [CrossRef] [PubMed]
  17. Kubota, K.; Makuuchi, M.; Kusaka, K.; Kobayashi, T.; Miki, K.; Hasegawa, K.; Harihara, Y.; Takayama, T. Measurement of Liver Volume and Hepatic Functional Reserve as a Guide to Decision-Making in Resectional Surgery for Hepatic Tumors. Hepatology 1997, 26, 1176–1181. [Google Scholar] [CrossRef]
  18. Vauthey, J.-N.; Chaoui, A.; Do, K.-A.; Bilimoria, M.M.; Fenstermacher, M.J.; Charnsangavej, C.; Hicks, M.; Alsfasser, G.; Lauwers, G.; Hawkins, I.F.; et al. Standardized Measurement of the Future Liver Remnant Prior to Extended Liver Resection: Methodology and Clinical Associations. Surgery 2000, 127, 512–519. [Google Scholar] [CrossRef] [PubMed]
  19. Shoup, M.; Gonen, M.; D’Angelica, M.; Jarnagin, W.R.; DeMatteo, R.P.; Schwartz, L.H.; Tuorto, S.; Blumgart, L.H.; Fong, Y. Volumetric Analysis Predicts Hepatic Dysfunction in Patients Undergoing Major Liver Resection. J. Gastrointest. Surg. 2003, 7, 325–330. [Google Scholar] [CrossRef]
  20. Takamoto, T.; Hashimoto, T.; Ichida, A.; Shimada, K.; Maruyama, Y.; Makuuchi, M. Surgical Strategy Based on Indocyanine Green Test for Chemotherapy-Associated Liver Injury and Long-Term Outcome in Colorectal Liver Metastases. J. Gastrointest. Surg. 2018, 22, 1077–1088. [Google Scholar] [CrossRef]
  21. Smet, H.; Martin, D.; Uldry, E.; Duran, R.; Girardet, R.; Schaefer, N.; Prior, J.O.; Denys, A.; Halkic, N.; Demartines, N.; et al. Tc-99m Mebrofenin Hepatobiliary Scintigraphy to Assess Future Liver Remnant Function before Major Liver Surgery. J. Surg. Oncol. 2023, 128, 1312–1319. [Google Scholar] [CrossRef]
  22. Robinson, S.M.; Wilson, C.H.; Burt, A.D.; Manas, D.M.; White, S.A. Chemotherapy-Associated Liver Injury in Patients with Colorectal Liver Metastases: A Systematic Review and Meta-Analysis. Ann. Surg. Oncol. 2012, 19, 4287–4299. [Google Scholar] [CrossRef]
  23. Vigano, L.; De Rosa, G.; Toso, C.; Andres, A.; Ferrero, A.; Roth, A.; Sperti, E.; Majno, P.; Rubbia-Brandt, L. Reversibility of Chemotherapy-Related Liver Injury. J. Hepatol. 2017, 67, 84–91. [Google Scholar] [CrossRef]
  24. Ribero, D.; Abdalla, E.K.; Madoff, D.C.; Donadon, M.; Loyer, E.M.; Vauthey, J.-N. Portal Vein Embolization before Major Hepatectomy and Its Effects on Regeneration, Resectability and Outcome. Br. J. Surg. 2007, 94, 1386–1394. [Google Scholar] [CrossRef] [PubMed]
  25. Li, J.; Moustafa, M.; Linecker, M.; Lurje, G.; Capobianco, I.; Baumgart, J.; Ratti, F.; Rauchfuss, F.; Balci, D.; Fernandes, E.; et al. ALPPS for Locally Advanced Intrahepatic Cholangiocarcinoma: Did Aggressive Surgery Lead to the Oncological Benefit? An International Multi-Center Study. Ann. Surg. Oncol. 2020, 27, 1372–1384. [Google Scholar] [CrossRef] [PubMed]
  26. Chaouch, M.A.; Mazzotta, A.; da Costa, A.C.; Hussain, M.I.; Gouader, A.; Krimi, B.; Panaro, F.; Guiu, B.; Soubrane, O.; Oweira, H. A Systematic Review and Meta-Analysis of Liver Venous Deprivation versus Portal Vein Embolization before Hepatectomy: Future Liver Volume, Postoperative Outcomes, and Oncological Safety. Front. Med. 2024, 10, 1334661. [Google Scholar] [CrossRef]
  27. Yang, L.; Yang, M.; Wang, T.; Qiu, Y.; Yang, Y.; Wang, W. Comparison of Liver Venous Deprivation with Portal Vein Embolization Alone in Patients Undergoing Major Liver Resection: A Systematic Review and Meta-Analysis. HPB 2024, 26, 1329–1338. [Google Scholar] [CrossRef]
  28. Jiang, C.; Hou, G.-M.; Zhang, Z.-H.; Qiang, Z.-Y.; Wang, H.-C.; Zhou, J.; Zeng, Y. Anatomic versus Nonanatomic Resection for Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. Int. J. Surg. 2025, 111, 1440–1453. [Google Scholar] [CrossRef] [PubMed]
  29. Si, A.; Li, J.; Yang, Z.; Xia, Y.; Yang, T.; Lei, Z.; Cheng, Z.; Pawlik, T.M.; Lau, W.Y.; Shen, F. Impact of Anatomical Versus Non-Anatomical Liver Resection on Short- and Long-Term Outcomes for Patients with Intrahepatic Cholangiocarcinoma. Ann. Surg. Oncol. 2019, 26, 1841–1850. [Google Scholar] [CrossRef]
  30. Jiang, J.-H.; Fang, D.-Z.; Hu, Y.-T. Influence of Surgical Margin Width on Survival Rate after Resection of Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. BMJ Open 2023, 13, e067222. [Google Scholar] [CrossRef]
  31. Liu, H.; Lin, L.; Lin, Z.; Chen, Y.; Huang, Q.; Ding, L.; Lou, J.; Zheng, S.; Bi, X.; Wang, J.; et al. Impact of Surgical Margin Width on Long-Term Outcomes for Intrahepatic Cholangiocarcinoma: A Multicenter Study. BMC Cancer 2021, 21, 840. [Google Scholar] [CrossRef]
  32. Zhang, X.-F.; Beal, E.W.; Bagante, F.; Chakedis, J.; Weiss, M.; Popescu, I.; Marques, H.P.; Aldrighetti, L.; Maithel, S.K.; Pulitano, C.; et al. Early versus Late Recurrence of Intrahepatic Cholangiocarcinoma after Resection with Curative Intent. Br. J. Surg. 2018, 105, 848–856. [Google Scholar] [CrossRef] [PubMed]
  33. Bagante, F.; Spolverato, G.; Weiss, M.; Alexandrescu, S.; Marques, H.P.; Aldrighetti, L.; Maithel, S.K.; Pulitano, C.; Bauer, T.W.; Shen, F.; et al. Defining Long-Term Survivors Following Resection of Intrahepatic Cholangiocarcinoma. J. Gastrointest. Surg. 2017, 21, 1888–1897. [Google Scholar] [CrossRef]
  34. Dai, Y.-S.; Hu, H.-J.; Lv, T.; Hu, Y.-F.; Zou, R.-Q.; Li, F.-Y. The Influence of Resection Margin Width in Patients with Intrahepatic Cholangiocarcinoma: A Meta-Analysis. World J. Surg. Oncol. 2023, 21, 16. [Google Scholar] [CrossRef]
  35. Bowlus, C.L.; Arrivé, L.; Bergquist, A.; Deneau, M.; Forman, L.; Ilyas, S.I.; Lunsford, K.E.; Martinez, M.; Sapisochin, G.; Shroff, R.; et al. AASLD Practice Guidance on Primary Sclerosing Cholangitis and Cholangiocarcinoma. Hepatology 2023, 77, 659. [Google Scholar] [CrossRef]
  36. Zhu, J.; Liu, C.; Li, H.; Ren, H.; Cai, Y.; Lan, T.; Wu, H. Adequate Lymph Node Dissection Is Essential for Accurate Nodal Staging in Intrahepatic Cholangiocarcinoma: A Population-based Study. Cancer Med. 2023, 12, 8184–8198. [Google Scholar] [CrossRef] [PubMed]
  37. Yu, J.; Zhou, F.; Tan, X.-G.; Guo, J.; Feng, W. Impact of Lymph Node Dissection on the Prognosis of Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. Front. Oncol. 2025, 15, 1590019. [Google Scholar] [CrossRef]
  38. Umeda, Y.; Takagi, K.; Matsuda, T.; Fuji, T.; Kojima, T.; Satoh, D.; Hioki, M.; Endo, Y.; Inagaki, M.; Oishi, M.; et al. Clinical Implications and Optimal Extent of Lymphadenectomy for Intrahepatic Cholangiocarcinoma: A Multicenter Analysis of the Therapeutic Index. Ann. Gastroenterol. Surg. 2022, 7, 512–522. [Google Scholar] [CrossRef] [PubMed]
  39. Hyder, O.; Marques, H.; Pulitano, C.; Marsh, J.W.; Alexandrescu, S.; Bauer, T.W.; Gamblin, T.C.; Sotiropoulos, G.C.; Paul, A.; Barroso, E.; et al. A Nomogram to Predict Long-Term Survival After Resection for Intrahepatic Cholangiocarcinoma: An Eastern and Western Experience. JAMA Surg. 2014, 149, 432–438. [Google Scholar] [CrossRef]
  40. Tsilimigras, D.I.; Sahara, K.; Paredes, A.Z.; Moro, A.; Mehta, R.; Moris, D.; Guglielmi, A.; Aldrighetti, L.; Weiss, M.; Bauer, T.W.; et al. Predicting Lymph Node Metastasis in Intrahepatic Cholangiocarcinoma. J. Gastrointest. Surg. 2021, 25, 1156–1163. [Google Scholar] [CrossRef]
  41. Jansson, H.; Villard, C.; Nooijen, L.E.; Ghorbani, P.; Erdmann, J.I.; Sparrelid, E. Prognostic Influence of Multiple Hepatic Lesions in Resectable Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. Eur. J. Surg. Oncol. 2023, 49, 688–699. [Google Scholar] [CrossRef]
  42. Spolverato, G.; Kim, Y.; Alexandrescu, S.; Popescu, I.; Marques, H.P.; Aldrighetti, L.; Gamblin, T.C.; Miura, J.; Maithel, S.K.; Squires, M.H.; et al. Is Hepatic Resection for Large or Multifocal Intrahepatic Cholangiocarcinoma Justified? Results from a Multi-Institutional Collaboration. Ann. Surg. Oncol. 2015, 22, 2218–2225. [Google Scholar] [CrossRef]
  43. Buettner, S.; Ten Cate, D.W.G.; Bagante, F.; Alexandrescu, S.; Marques, H.P.; Lamelas, J.; Aldrighetti, L.; Gamblin, T.C.; Maithel, S.K.; Pulitano, C.; et al. Survival after Resection of Multiple Tumor Foci of Intrahepatic Cholangiocarcinoma. J. Gastrointest. Surg. 2019, 23, 2239–2246. [Google Scholar] [CrossRef]
  44. Yin, L.; Zhao, S.; Zhu, H.; Ji, G.; Zhang, X. Primary Tumor Resection Improves Survival in Patients with Multifocal Intrahepatic Cholangiocarcinoma Based on a Population Study. Sci. Rep. 2021, 11, 12166. [Google Scholar] [CrossRef]
  45. Valle, J.; Wasan, H.; Palmer, D.H.; Cunningham, D.; Anthoney, A.; Maraveyas, A.; Madhusudan, S.; Iveson, T.; Hughes, S.; Pereira, S.P.; et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N. Engl. J. Med. 2010, 362, 1273–1281. [Google Scholar] [CrossRef]
  46. Lamarca, A.; Ross, P.; Wasan, H.S.; Hubner, R.A.; McNamara, M.G.; Lopes, A.; Manoharan, P.; Palmer, D.; Bridgewater, J.; Valle, J.W. Advanced Intrahepatic Cholangiocarcinoma: Post Hoc Analysis of the ABC-01, -02, and -03 Clinical Trials. J. Natl. Cancer Inst. 2020, 112, 200–210. [Google Scholar] [CrossRef] [PubMed]
  47. Oh, D.-Y.; He, A.R.; Bouattour, M.; Okusaka, T.; Qin, S.; Chen, L.-T.; Kitano, M.; Lee, C.; Kim, J.W.; Chen, M.-H.; et al. Durvalumab or Placebo plus Gemcitabine and Cisplatin in Participants with Advanced Biliary Tract Cancer (TOPAZ-1): Updated Overall Survival from a Randomised Phase 3 Study. Lancet Gastroenterol. Hepatol. 2024, 9, 694–704. [Google Scholar] [CrossRef] [PubMed]
  48. Kelley, R.K.; Ueno, M.; Yoo, C.; Finn, R.S.; Furuse, J.; Ren, Z.; Yau, T.; Klümpen, H.-J.; Chan, S.L.; Ozaka, M.; et al. Pembrolizumab in Combination with Gemcitabine and Cisplatin Compared with Gemcitabine and Cisplatin Alone for Patients with Advanced Biliary Tract Cancer (KEYNOTE-966): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet 2023, 401, 1853–1865. [Google Scholar] [CrossRef] [PubMed]
  49. Shroff, R.T.; King, G.; Colby, S.; Scott, A.J.; Borad, M.J.; Goff, L.; Matin, K.; Mahipal, A.; Kalyan, A.; Javle, M.M.; et al. SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers. J. Clin. Oncol. 2025, 43, 536–544. [Google Scholar] [CrossRef]
  50. Primrose, J.N.; Fox, R.P.; Palmer, D.H.; Malik, H.Z.; Prasad, R.; Mirza, D.; Anthony, A.; Corrie, P.; Falk, S.; Finch-Jones, M.; et al. Capecitabine Compared with Observation in Resected Biliary Tract Cancer (BILCAP): A Randomised, Controlled, Multicentre, Phase 3 Study. Lancet Oncol. 2019, 20, 663–673. [Google Scholar] [CrossRef]
  51. Nakachi, K.; Ikeda, M.; Konishi, M.; Nomura, S.; Katayama, H.; Kataoka, T.; Todaka, A.; Yanagimoto, H.; Morinaga, S.; Kobayashi, S.; et al. Adjuvant S-1 Compared with Observation in Resected Biliary Tract Cancer (JCOG1202, ASCOT): A Multicentre, Open-Label, Randomised, Controlled, Phase 3 Trial. Lancet 2023, 401, 195–203. [Google Scholar] [CrossRef]
  52. Lamarca, A.; Palmer, D.H.; Wasan, H.S.; Ross, P.J.; Ma, Y.T.; Arora, A.; Falk, S.; Gillmore, R.; Wadsley, J.; Patel, K.; et al. Second-Line FOLFOX Chemotherapy versus Active Symptom Control for Advanced Biliary Tract Cancer (ABC-06): A Phase 3, Open-Label, Randomised, Controlled Trial. Lancet Oncol. 2021, 22, 690–701. [Google Scholar] [CrossRef]
  53. Abou-Alfa, G.K.; Sahai, V.; Hollebecque, A.; Vaccaro, G.; Melisi, D.; Al-Rajabi, R.; Paulson, A.S.; Borad, M.J.; Gallinson, D.; Murphy, A.G.; et al. Pemigatinib for Previously Treated, Locally Advanced or Metastatic Cholangiocarcinoma: A Multicentre, Open-Label, Phase 2 Study. Lancet Oncol. 2020, 21, 671–684. [Google Scholar] [CrossRef] [PubMed]
  54. Goyal, L.; Meric-Bernstam, F.; Hollebecque, A.; Valle, J.W.; Morizane, C.; Karasic, T.B.; Abrams, T.A.; Furuse, J.; Kelley, R.K.; Cassier, P.A.; et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N. Engl. J. Med. 2023, 388, 228–239. [Google Scholar] [CrossRef]
  55. Abou-Alfa, G.K.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.; Borad, M.J.; Bridgewater, J.; et al. Ivosidenib in IDH1-Mutant, Chemotherapy-Refractory Cholangiocarcinoma (ClarIDHy): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Study. Lancet Oncol. 2020, 21, 796–807. [Google Scholar] [CrossRef] [PubMed]
  56. Sahai, V.; Catalano, P.J.; Zalupski, M.M.; Lubner, S.J.; Menge, M.R.; Nimeiri, H.S.; Munshi, H.G.; Benson, A.B., III; O’Dwyer, P.J. Nab-Paclitaxel and Gemcitabine as First-Line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018, 4, 1707–1712. [Google Scholar] [CrossRef]
  57. Maithel, S.K.; Keilson, J.M.; Cao, H.S.T.; Rupji, M.; Mahipal, A.; Lin, B.S.; Javle, M.M.; Cleary, S.P.; Akce, M.; Switchenko, J.M.; et al. NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma. Ann. Surg. Oncol. 2023, 30, 6558–6566. [Google Scholar] [CrossRef]
  58. Le Roy, B.; Gelli, M.; Pittau, G.; Allard, M.-A.; Pereira, B.; Serji, B.; Vibert, E.; Castaing, D.; Adam, R.; Cherqui, D.; et al. Neoadjuvant Chemotherapy for Initially Unresectable Intrahepatic Cholangiocarcinoma. Br. J. Surg. 2018, 105, 839–847. [Google Scholar] [CrossRef] [PubMed]
  59. Sutton, T.L.; Billingsley, K.G.; Walker, B.S.; Enestvedt, C.K.; Dewey, E.N.; Orloff, S.L.; Mayo, S.C. Neoadjuvant Chemotherapy Is Associated with Improved Survival in Patients Undergoing Hepatic Resection for Intrahepatic Cholangiocarcinoma. Am. J. Surg. 2021, 221, 1182–1187. [Google Scholar] [CrossRef]
  60. Ejaz, A.; Pawlik, T.M. Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Potential Paradigm Shift in Treatment Sequencing. Ann. Surg. Oncol. 2023, 30, 6304–6305. [Google Scholar] [CrossRef]
  61. Reames, B.N.; Bagante, F.; Ejaz, A.; Spolverato, G.; Ruzzenente, A.; Weiss, M.; Alexandrescu, S.; Marques, H.P.; Aldrighetti, L.; Maithel, S.K.; et al. Impact of Adjuvant Chemotherapy on Survival in Patients with Intrahepatic Cholangiocarcinoma: A Multi-Institutional Analysis. HPB 2017, 19, 901–909. [Google Scholar] [CrossRef]
  62. Ebata, T.; Hirano, S.; Konishi, M.; Uesaka, K.; Tsuchiya, Y.; Ohtsuka, M.; Kaneoka, Y.; Yamamoto, M.; Ambo, Y.; Shimizu, Y.; et al. Randomized Clinical Trial of Adjuvant Gemcitabine Chemotherapy versus Observation in Resected Bile Duct Cancer. Br. J. Surg. 2018, 105, 192–202. [Google Scholar] [CrossRef]
  63. Edeline, J.; Benabdelghani, M.; Bertaut, A.; Watelet, J.; Hammel, P.; Joly, J.-P.; Boudjema, K.; Fartoux, L.; Bouhier-Leporrier, K.; Jouve, J.-L.; et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J. Clin. Oncol. 2019, 37, 658–667. [Google Scholar] [CrossRef]
  64. Yoo, C.; Kim, K.-P.; Jeong, J.H.; Kim, I.; Kang, M.J.; Cheon, J.; Kang, B.W.; Ryu, H.; Lee, J.S.; Kim, K.W.; et al. Liposomal Irinotecan plus Fluorouracil and Leucovorin versus Fluorouracil and Leucovorin for Metastatic Biliary Tract Cancer after Progression on Gemcitabine plus Cisplatin (NIFTY): A Multicentre, Open-Label, Randomised, Phase 2b Study. Lancet Oncol. 2021, 22, 1560–1572. [Google Scholar] [CrossRef]
  65. Vogel, A.; Saborowski, A.; Wenzel, P.; Wege, H.; Folprecht, G.; Kretzschmar, A.; Schütt, P.; Jacobasch, L.; Ziegenhagen, N.; Boeck, S.; et al. Nanoliposomal Irinotecan and Fluorouracil plus Leucovorin versus Fluorouracil plus Leucovorin in Patients with Cholangiocarcinoma and Gallbladder Carcinoma Previously Treated with Gemcitabine-Based Therapies (AIO NALIRICC): A Multicentre, Open-Label, Randomised, Phase 2 Trial. Lancet Gastroenterol. Hepatol. 2024, 9, 734–744. [Google Scholar] [CrossRef]
  66. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the Management of Extrahepatic Cholangiocarcinoma. J. Hepatol. 2025, 83, 211–238. [Google Scholar] [CrossRef]
  67. Ozer, M.; Sahin, I. The Evolving Landscape of Biliary Tract Cancers: Comparing French and US National Comprehensive Cancer Network Guidelines. Hepatobiliary Surg. Nutr. 2024, 13, 850–853. [Google Scholar] [CrossRef] [PubMed]
  68. Rimassa, L.; Lamarca, A.; O’Kane, G.M.; Edeline, J.; McNamara, M.G.; Vogel, A.; Fassan, M.; Forner, A.; Kendall, T.; Adeva, J.; et al. New Systemic Treatment Paradigms in Advanced Biliary Tract Cancer and Variations in Patient Access across Europe. Lancet Reg. Health–Eur. 2025, 50, 101170. [Google Scholar] [CrossRef]
  69. Kawashima, J.; Akabane, M.; Endo, I.; Pawlik, T.M. Recent Advances in the Treatment of FGFR-Altered Cholangiocarcinoma. Expert Opin. Pharmacother. 2025, 26, 1973–1983. [Google Scholar] [CrossRef] [PubMed]
  70. Subbiah, V.; Lassen, U.; Élez, E.; Italiano, A.; Curigliano, G.; Javle, M.; de Braud, F.; Prager, G.W.; Greil, R.; Stein, A.; et al. Dabrafenib plus Trametinib in Patients with BRAFV600E-Mutated Biliary Tract Cancer (ROAR): A Phase 2, Open-Label, Single-Arm, Multicentre Basket Trial. Lancet Oncol. 2020, 21, 1234–1243. [Google Scholar] [CrossRef] [PubMed]
  71. Inoue, K.; Nakamura, Y.; Caughey, B.; Zheng-Lin, B.; Ueno, M.; Furukawa, M.; Kawamoto, Y.; Itoh, S.; Umemoto, K.; Sudo, K.; et al. Clinicomolecular Profile and Efficacy of Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Therapy for HER2-Amplified Advanced Biliary Tract Cancer. JCO Precis. Oncol. 2025, 9, e2400718. [Google Scholar] [CrossRef] [PubMed]
  72. Normanno, N.; Martinelli, E.; Melisi, D.; Pinto, C.; Rimassa, L.; Santini, D.; Scarpa, A. Role of Molecular Genetics in the Clinical Management of Cholangiocarcinoma. ESMO Open 2022, 7, 100505. [Google Scholar] [CrossRef]
  73. Yang, X.; Lian, B.; Zhang, N.; Long, J.; Li, Y.; Xue, J.; Chen, X.; Wang, Y.; Wang, Y.; Xun, Z.; et al. Genomic Characterization and Immunotherapy for Microsatellite Instability-High in Cholangiocarcinoma. BMC Med. 2024, 22, 42. [Google Scholar] [CrossRef]
  74. Hwang, S.; Woo, S.; Kang, B.; Kang, H.; Kim, J.S.; Lee, S.H.; Kwon, C.I.; Kyung, D.S.; Kim, H.-P.; Kim, G.; et al. Concordance of ctDNA and Tissue Genomic Profiling in Advanced Biliary Tract Cancer. J. Hepatol. 2025, 82, 649–657. [Google Scholar] [CrossRef]
  75. Lowery, M.A.; Ptashkin, R.; Jordan, E.; Berger, M.F.; Zehir, A.; Capanu, M.; Kemeny, N.E.; O’Reilly, E.M.; El-Dika, I.; Jarnagin, W.R.; et al. Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention. Clin. Cancer Res. 2018, 24, 4154–4161. [Google Scholar] [CrossRef]
  76. Nakamura, H.; Arai, Y.; Totoki, Y.; Shirota, T.; Elzawahry, A.; Kato, M.; Hama, N.; Hosoda, F.; Urushidate, T.; Ohashi, S.; et al. Genomic Spectra of Biliary Tract Cancer. Nat. Genet. 2015, 47, 1003–1010. [Google Scholar] [CrossRef]
  77. Incyte Corporation. A Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Chemotherapy in Unresectable or Metastatic Cholangiocarcinoma (FIGHT-302). Available online: https://clinicaltrials.gov/study/NCT03656536 (accessed on 27 December 2025).
  78. Oh, D.-Y.; Lee, K.-H.; Lee, D.-W.; Yoon, J.; Kim, T.-Y.; Bang, J.-H.; Nam, A.-R.; Oh, K.-S.; Kim, J.-M.; Lee, Y.; et al. Gemcitabine and Cisplatin plus Durvalumab with or without Tremelimumab in Chemotherapy-Naive Patients with Advanced Biliary Tract Cancer: An Open-Label, Single-Centre, Phase 2 Study. Lancet Gastroenterol. Hepatol. 2022, 7, 522–532. [Google Scholar] [CrossRef]
  79. Kemeny, N.; Huang, Y.; Cohen, A.M.; Shi, W.; Conti, J.A.; Brennan, M.F.; Bertino, J.R.; Turnbull, A.D.M.; Sullivan, D.; Stockman, J.; et al. Hepatic Arterial Infusion of Chemotherapy after Resection of Hepatic Metastases from Colorectal Cancer. N. Engl. J. Med. 1999, 341, 2039–2048. [Google Scholar] [CrossRef] [PubMed]
  80. Kemeny, N.E.; Gonen, M. Hepatic Arterial Infusion after Liver Resection. N. Engl. J. Med. 2005, 352, 734–735. [Google Scholar] [CrossRef] [PubMed]
  81. Franssen, S.; Rousian, M.; Filipe, W.F.; Buisman, F.E.; Ten Haaft, B.H.E.A.; Swijnenburg, R.-J.; Mostert, B.; Haj Mohammad, N.; Hagendoorn, J.; Doukas, M.; et al. Hepatic Arterial Infusion Pump Chemotherapy in Patients with Unresectable Intrahepatic Cholangiocarcinoma-PUMP-2 Trial. J. Clin. Oncol. 2026, 44, 455–465. [Google Scholar] [CrossRef]
  82. Cercek, A.; Boerner, T.; Tan, B.R.; Chou, J.F.; Gönen, M.; Boucher, T.M.; Hauser, H.F.; Do, R.K.G.; Lowery, M.A.; Harding, J.J.; et al. Assessment of Hepatic Arterial Infusion of Floxuridine in Combination with Systemic Gemcitabine and Oxaliplatin in Patients with Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2020, 6, 60–67. [Google Scholar] [CrossRef]
  83. Jarnagin, W.R.; Schwartz, L.H.; Gultekin, D.H.; Gönen, M.; Haviland, D.; Shia, J.; D’Angelica, M.; Fong, Y.; DeMatteo, R.; Tse, A.; et al. Regional Chemotherapy for Unresectable Primary Liver Cancer: Results of a Phase II Clinical Trial and Assessment of DCE-MRI as a Biomarker of Survival. Ann. Oncol. 2009, 20, 1589–1595. [Google Scholar] [CrossRef] [PubMed]
  84. Kemeny, N.E.; Schwartz, L.; Gönen, M.; Yopp, A.; Gultekin, D.; D’Angelica, M.I.; Fong, Y.; Haviland, D.; Gewirtz, A.N.; Allen, P.; et al. Treating Primary Liver Cancer with Hepatic Arterial Infusion of Floxuridine and Dexamethasone: Does the Addition of Systemic Bevacizumab Improve Results. Oncology 2011, 80, 153–159. [Google Scholar] [CrossRef] [PubMed]
  85. Hepatic Arterial Infusion (HAI) with Floxuridine (FUDR) and Dexamethasone (Dex) Combined with Systemic Gemcitabine and Oxaliplatin in Patients with Unresectable Intrahepatic Cholangiocarcinoma (ICC). Available online: https://clinicaltrials.gov/study/NCT01862315 (accessed on 25 December 2025).
  86. Moris, D.; Palta, M.; Kim, C.; Allen, P.J.; Morse, M.A.; Lidsky, M.E. Advances in the Treatment of Intrahepatic Cholangiocarcinoma: An Overview of the Current and Future Therapeutic Landscape for Clinicians. CA Cancer J. Clin. 2023, 73, 198–222. [Google Scholar] [CrossRef]
  87. Meyer, C.G.; Penn, I.; James, L. Liver Transplantation for Cholangiocarcinoma: Results in 207 Patients. Transplantation 2000, 69, 1633–1637. [Google Scholar] [CrossRef] [PubMed]
  88. Robles, R.; Figueras, J.; Turrión, V.S.; Margarit, C.; Moya, A.; Varo, E.; Calleja, J.; Valdivieso, A.; Valdecasas, J.C.G.; López, P.; et al. Spanish Experience in Liver Transplantation for Hilar and Peripheral Cholangiocarcinoma. Ann. Surg. 2004, 239, 265–271. [Google Scholar] [CrossRef]
  89. Breuer, E.; Mueller, M.; Doyle, M.B.; Yang, L.; Darwish Murad, S.; Anwar, I.J.; Merani, S.; Limkemann, A.; Jeddou, H.; Kim, S.C.; et al. Liver Transplantation as a New Standard of Care in Patients with Perihilar Cholangiocarcinoma? Results from an International Benchmark Study. Ann. Surg. 2022, 276, 846–853. [Google Scholar] [CrossRef]
  90. Chen, Y.; Shen, H.; Xu, R.; Zhu, J.; Zhu, Y.; Zou, H. Comparative Prognosis of Liver Transplantation versus Liver Resection in Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis. Chin. Clin. Oncol. 2025, 14, 3. [Google Scholar] [CrossRef]
  91. Ma, K.W.; Chok, K.S.H.; She, W.H.; Cheung, T.T.; Chan, A.C.Y.; Dai, W.C.; Fung, J.Y.Y.; Lo, C.M. Hepatocholangiocarcinoma/Intrahepatic Cholangiocarcinoma: Are They Contraindication or Indication for Liver Transplantation? A Propensity Score-Matched Analysis. Hepatol. Int. 2018, 12, 167–173. [Google Scholar] [CrossRef]
  92. Maspero, M.; Sposito, C.; Bongini, M.A.; Cascella, T.; Flores, M.; Maccauro, M.; Chiesa, C.; Niger, M.; Pietrantonio, F.; Leoncini, G.; et al. Liver Transplantation for Intrahepatic Cholangiocarcinoma After Chemotherapy and Radioembolization: An Intention-To-Treat Study. Transpl. Int. 2024, 37, 13641. [Google Scholar] [CrossRef]
  93. Yaqub, S.; Busund, S.; Smedman, T.M.; Syversveen, T.; Khan, A.; Solheim, J.M.; Folseraas, T.; Wiencke, K.; Lassen, K.; Dueland, S.; et al. Liver Transplantation for Locally Advanced Non-Resectable Intrahepatic Cholangiocarcinoma Treated with Neoadjuvant Therapy: Early Results from the TESLA Trial. Br. J. Surg. 2025, 112, znaf054. [Google Scholar] [CrossRef]
  94. Hakeem, A.R.; Isaac, J.; Thorburn, D.; Heaton, N.; Prasad, R. The Role of Liver Transplant for Intrahepatic Cholangiocarcinoma: The UK NHSBT Liver Advisory Group Pilot Programme. Hepatoma Res. 2023, 9, 38. [Google Scholar] [CrossRef]
  95. Hoogwater, F.J.H.; Kuipers, H.; de Meijer, V.E.; Maulat, C.; Muscari, F.; Polak, W.G.; van Hoek, B.; Jézéquel, C.; Alwayn, I.P.J.; Ijzermans, J.N.M.; et al. Role of Neoadjuvant Chemoradiotherapy in Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma: Multicentre, Retrospective Cohort Study. BJS Open 2023, 7, zrad025. [Google Scholar] [CrossRef] [PubMed]
  96. Sapisochin, G.; Facciuto, M.; Rubbia-Brandt, L.; Marti, J.; Mehta, N.; Yao, F.Y.; Vibert, E.; Cherqui, D.; Grant, D.R.; Hernandez-Alejandro, R.; et al. Liver Transplantation for “Very Early” Intrahepatic Cholangiocarcinoma: International Retrospective Study Supporting a Prospective Assessment. Hepatology 2016, 64, 1178–1188. [Google Scholar] [CrossRef] [PubMed]
  97. De Abreu Neto, I.P.; Pugliese, V.; Massarollo, P.C.B.; Benini, B.B.; Marta, M.M.M.; Takenaka, V.S.; Monteiro, F.; Pessoa, J.L.E.; De Azevedo Neto, R.S.; Gonzalez, A.M. Retrospective Comparative Analyses of Liver Transplantation for Intrahepatic Cholangiocarcinoma and Combined Hepatocellular Cholangiocarcinoma versus Hepatocellular Carcinoma in Brazil. HPB 2025, 27, 640–648. [Google Scholar] [CrossRef]
Livers 06 00024 g001
Figure 1. Proposed treatment algorithm for intrahepatic cholangiocarcinoma. This algorithm outlines a multidisciplinary, biology-driven approach to the management of intrahepatic cholangiocarcinoma. Patients undergo initial staging with cross-sectional imaging and assessment of liver function, tumor biology, and performance status. For liver-confined disease, upfront resection with regional lymphadenectomy is recommended when complete (R0) resection is feasible with adequate future liver remnant, followed by adjuvant capecitabine. Patients with borderline or high-risk resectable disease may benefit from portal vein embolization and/or neoadjuvant systemic therapy with reassessment in a multidisciplinary setting. Unresectable liver-dominant disease may be treated with locoregional therapy, ideally in combination with systemic therapy. Systemic therapy remains the mainstay for metastatic disease, with targeted or immunotherapy options in biomarker-defined subsets. Liver transplantation is considered investigational and may be appropriate only for highly selected patients with very-early intrahepatic cholangiocarcinoma in cirrhosis within structured protocols or clinical trials. Abbreviations: ICC, intrahepatic cholangiocarcinoma; FLR, future liver remnant; MDT, multidisciplinary team.
Figure 1. Proposed treatment algorithm for intrahepatic cholangiocarcinoma. This algorithm outlines a multidisciplinary, biology-driven approach to the management of intrahepatic cholangiocarcinoma. Patients undergo initial staging with cross-sectional imaging and assessment of liver function, tumor biology, and performance status. For liver-confined disease, upfront resection with regional lymphadenectomy is recommended when complete (R0) resection is feasible with adequate future liver remnant, followed by adjuvant capecitabine. Patients with borderline or high-risk resectable disease may benefit from portal vein embolization and/or neoadjuvant systemic therapy with reassessment in a multidisciplinary setting. Unresectable liver-dominant disease may be treated with locoregional therapy, ideally in combination with systemic therapy. Systemic therapy remains the mainstay for metastatic disease, with targeted or immunotherapy options in biomarker-defined subsets. Liver transplantation is considered investigational and may be appropriate only for highly selected patients with very-early intrahepatic cholangiocarcinoma in cirrhosis within structured protocols or clinical trials. Abbreviations: ICC, intrahepatic cholangiocarcinoma; FLR, future liver remnant; MDT, multidisciplinary team.
Livers 06 00024 g001
Table 1. Key clinical trials of systemic therapies for biliary tract cancer, including intrahepatic cholangiocarcinoma.
Table 1. Key clinical trials of systemic therapies for biliary tract cancer, including intrahepatic cholangiocarcinoma.
Setting/LineRegimen
(Arm A vs. Arm B)		Trial (Phase; Design)Population
(Key Notes)		Key Efficacy (OS/PFS)Notes (ICC-Relevance)
Advanced/metastatic
(1L)		GemCis vs. GemABC-02
(phase III; RCT) [45,46]		Advanced BTCOS: 11.7 vs. 8.1 mo; HR 0.64 (95% CI 0.52–0.80).
PFS: 8.0 vs. 5.0 mo; HR 0.63 (95% CI 0.51–0.77).		Established cytotoxic backbone across BTC (includes ICC).
Advanced/metastatic
(1L)		Durva + GemCis
vs. GemCis		TOPAZ-1
(phase III; RCT) [47]		Advanced BTCOS: 12.9 vs. 11.3 mo; HR 0.76 (95% CI 0.64–0.91).
24-mo OS: 23.6% vs. 11.5%.
PFS: 7.2 vs. 5.7 mo; HR 0.75 (95% CI 0.63–0.89).		Supports chemo-immunotherapy as a 1L standard in BTC; ICC subset included.
Advanced/metastatic
(1L)		Pembro + GemCis
vs. GemCis		KEYNOTE-966
(phase III; RCT) [48]		Advanced BTCOS: 12.7 vs. 10.9 mo; HR 0.83 (95% CI 0.72–0.95).
PFS: 6.5 vs. 5.6 mo; HR 0.86 (95% CI 0.75–1.00).		Another BTC chemo-ICI option; direct comparisons across regimens are indirect.
Advanced/metastatic
(1L)		GAP vs. GemCisSWOG S1815
(phase III; RCT) [49]		Advanced BTCOS: 14.0 vs. 13.6 mo; HR 0.91 (95% CI 0.72–1.14).
PFS: 7.5 vs. 6.3 mo; HR 0.89 (95% CI 0.71–1.12).		No OS benefit; higher toxicity reported despite promising phase II data.
Adjuvant
(post-resection)		Capecitabine
vs. observation		BILCAP
(phase III; RCT) [50]		Resected BTCOS (ITT): 51.1 vs. 36.4 mo; HR 0.81 (95% CI 0.63–1.04).
OS (PP): 53 vs. 36 mo; HR 0.75 (95% CI 0.58–0.97).		Supports adjuvant capecitabine as common standard; includes ICC.
Adjuvant
(post-resection)		S-1 vs. observationJCOG1202 (ASCOT)
(phase III; RCT) [51]		Resected BTC3-yr OS: 77.1% vs. 67.6%; HR 0.69 (95% CI 0.51–0.94).Practice-changing mainly in Asia; includes ICC.
Advanced/metastatic (2L)FOLFOX vs. best supportive careABC-06 (phase III; RCT) [52]Advanced BTC after GemCisOS: 6.2 vs. 5.3 mo; HR 0.69 (95% CI 0.50–0.97). Low ORR, modest benefit.Standard second-line cytotoxic option; applies broadly to ICC without actionable alterations.
Molecular (≥2L)Pemigatinib (single-arm)FIGHT-202
(phase II; single-arm) [53]		FGFR2 fusion/rearranged ICCORR: 35.5%; PFS 6.9 mo; OS 21.1 mo.First-in-class FGFR2 inhibitor; ICC-specific; approved post–first-line.
Molecular (≥2L)Futibatinib (single arm)FOENIX-CCA2
(phase II; single-arm) [54]		FGFR2 fusion/rearranged ICCORR: 42%. PFS: 9.0 mo. OS: 21.7 mo.ICC-specific (FGFR2-altered); typically post–first-line.
Molecular (≥2L)Ivosidenib vs. placeboClarIDHy
(phase III; RCT) [55]		IDH1-mutant cholangiocarcinomaOS: 10.3 vs. 7.5 mo; HR 0.79 (95% CI 0.56–1.12).
PFS: 2.7 vs. 1.4 mo; HR 0.37 (95% CI 0.25–0.54).		Targeted option for IDH1-mutant disease; crossover affects unadjusted OS interpretation.
Abbreviations: OS, overall survival; PFS, progression-free survival; ICC, intrahepatic cholangiocarcinoma; 1L, first-line therapy; ≥2L, second-line or later therapy; BTC, biliary tract cancer; Gem, gemcitabine; Cis, cisplatin; GemCis, gemcitabine–cisplatin; RCT, randomized controlled trial; HR, hazard ratio; CI, confidence interval; Durva, durvalumab; mo, months; Pembro, pembrolizumab; GAP, gemcitabine–cisplatin–nab-paclitaxel; ITT, intention-to-treat; PP, per-protocol; FOLFOX, leucovorin (folinic acid), fluorouracil, and oxaliplatin; FGFR2, fibroblast growth factor receptor 2; ORR, objective response rate; IDH1, isocitrate dehydrogenase 1.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yuza, K.; Akabane, M.; Pawlik, T.M. Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy. Livers 2026, 6, 24. https://doi.org/10.3390/livers6020024

AMA Style

Yuza K, Akabane M, Pawlik TM. Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy. Livers. 2026; 6(2):24. https://doi.org/10.3390/livers6020024

Chicago/Turabian Style

Yuza, Kizuki, Miho Akabane, and Timothy M. Pawlik. 2026. "Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy" Livers 6, no. 2: 24. https://doi.org/10.3390/livers6020024

APA Style

Yuza, K., Akabane, M., & Pawlik, T. M. (2026). Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy. Livers, 6(2), 24. https://doi.org/10.3390/livers6020024

Article Metrics

Back to TopTop