Epidemiology, biomarkers, and therapeutic approach in early-stage biliary tract cancers

Introduction

Biliary tract cancer (BTC) is the second-most-common type of hepatobiliary cancer worldwide (1). BTC comprises a heterogeneous group of tumors with unique molecular characteristics, anatomic location, and demographics (2). They are commonly classified as intrahepatic cholangiocarcinoma (iCCA), perihilar/hilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA), and gallbladder cancer (GBC) (3). iCCAs classically arise above second-order bile ducts, whereas the anatomical point of distinction between pCCAs and dCCAs is the cystic duct. Extrahepatic cholangiocarcinoma (eCCA) includes both pCCA and dCCA. GBC arises from the gallbladder itself or from the cystic duct (Figure 1). BTC is difficult to diagnose at an early stage since most patients lack cancer-specific symptoms until they progress to advanced, unresectable disease. Ampulla of Vater cancers are excluded from this review (5). Only about 10–20% of BTC patients present at an early stage and are candidates for surgical resection (3,6-8). This review discusses epidemiology, risk factors, and staging of BTC, with a focus on systemic therapies in early-stage disease.

Figure 1 Types of biliary tract cancer with relevant targets and their corresponding frequencies and therapies. iCCAs classically arise above second-order bile ducts, whereas the anatomical point of distinction between pCCAs and dCCAs is the cystic duct. eCCA includes both pCCA and dCCA. Gallbladder cancer arises from the gallbladder itself or from the cystic duct. Frequencies in black font are drawn from data on metastatic patients, in which incidences of targets are more well-known. Early-stage frequencies in bolded, purple font are based on a group of 104 resectable BTC patients that underwent molecular testing (4). Therapies are not exhaustive. BTC, biliary tract cancer; CCA, cholangiocarcinoma; dCCA, distal cholangiocarcinoma; dMMR, mismatch repair deficiency; eCCA, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; iCCA, intrahepatic cholangiocarcinoma; MSI, microsatellite instability; pCCA, perihilar cholangiocarcinoma; T-DXd, trastuzumab deruxtecan.

Epidemiology

In the US, there are an estimated 12,610 new diagnoses (6,040 in men and 6,570 in women) and 4,400 deaths (1,950 in men and 2,450 in women) from BTCs in 2025 (9). At least 40% are GBC cases, making it the most common subtype of BTC (3,9).

The highest incidence of GBC is in South America, where the primary risk factor is symptomatic gallstone disease (3). The incidence of GBC is decreasing, possibly due to an increase in cholecystectomies (5).

Cholangiocarcinoma (CCA) includes pCCA (50–60%), dCCA (20–30%), and iCCA (10–20%) (10). The highest rates of CCA are found in Thailand, where infection with the liver fluke Opisthorchis viverrini (endemic to northeast Thailand), acquired by eating raw fish, is the strongest risk factor (3). Incidence of CCA is low in high-income countries (between 0.35 and 2 cases per 100,000 annually) compared to endemic regions, which can be up to 40 times higher (5). Globally, the number of cases and deaths from BTCs has been increasing, predominantly due to an increase in both eCCA and iCCA cases (1,5,11-15). Rising global incidence of iCCA may be linked to increases in type 2 diabetes, cirrhosis, alcoholic liver disease, and cholelithiasis.

Risk factors

Risk factors for BTC are diverse and vary by anatomical site. Inflammation due to infections has been strongly associated with iCCA, eCCA, and GBC and includes chronic infection with hepatotropic viruses (hepatitis B/C), liver fluke infections (Opisthorchis viverrini, Clonorchis sinensis), and chronic bacterial infections of the liver (Salmonella typhi) (10,16). Inflammation due to structural damage encompasses conditions such as choledochal cysts, Caroli’s disease, primary sclerosing cholangitis, hepatolithiasis, and gallstones (10,16). Inflammation due to toxins, such as alcohol and tobacco, has also been identified as a risk factor for BTC, while smoking is thought to increase the risk of all BTCs except for GBC (17).

Inflammation due to metabolic syndrome, including diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD), has also been linked to BTCs (17-20). Metabolic conditions have been linked to a pro-inflammatory and pro-carcinogenic environment in the hepatobiliary system (16,21). For example, diabetes is linked to increasing levels of IGF-1, which may accelerate oxidative stress, release of cytokines, and promotion of carcinogenesis. The rising global incidence of CCA may be linked to increases in type 2 diabetes, cirrhosis, alcoholic liver disease, and cholelithiasis (10).

Molecular profiling

BTC genetics

Some subtypes of BTC, particularly iCCA, are enriched in targetable genetic mutations, with up to 40% of iCCA patients estimated to harbor potentially actionable genetic alterations (22,23). For instance, the small duct subtype of iCCA often shows mutations in IDH1/2 and FGFR2, while the large duct type of iCCA is associated with mutations in KRAS and SMAD4 (24). One genomic analysis of a large cohort of BTC patients identified 32 genes as frequently altered, including KRAS, TP53, SMAD4, BAP1, FGFR2, IDH1, EGFR, and PIK3CA (25).

Molecular profiling guidelines

Guidelines for BTC management recommend that all patients with advanced CCA suitable for systemic treatment undergo molecular profiling via parallel next-generation sequencing (NGS) of several genes and biomarkers, including IDH1, FGFR2, NTRK, RET, KRAS, as well as high microsatellite instability (MSI-H), and mismatch repair deficiency (dMMR) (26-28).

While guidelines do not offer specific guidance on molecular profiling for early-stage, resectable BTCs, some evidence shows that the rate of actionable mutations may not significantly differ between advanced and early-stage BTCs. One study evaluating a cohort of patients with early-stage, resected CCA who underwent molecular profiling of their tumors found mutations in FGFR2, IDH1, HER2, and BRAF, as well as MSI-H and high tumor mutational burden (TMB-high) (4).

Potential therapeutic targets

FDA-approved targeted therapies are currently utilized for advanced BTCs harboring alterations in IDH1 or FGFR2 and suggest a potential role for molecular testing and molecularly targeted therapies in the setting of early-stage, resectable BTC. Tumor-agnostic targetable markers such as BRAF, HER2, and RET are quite rare in BTC, but patients with alterations in these targets tend to respond well to existing targeted drugs (29). Therefore, testing for these alterations in the setting of early-stage disease could still provide benefit to this subset of BTC patients. We suggest that a coordinated effort be taken to expand molecular testing to all BTC patients who could benefit from a molecularly-targeted therapy, regardless of stage.

Targeting tumor markers may have synergistic effects with other treatment modalities. For example, studies have suggested some targets, such as IDH1, not only target the oncogenic driver, but may also modulate the tumor microenvironment, potentially enhancing the response to immunotherapy (30). These studies may provide a rationale for the design of future clinical trials. Additionally, tumor marker targets may also be considered for second-line therapy for early-stage BTC (31).

Staging

Early-stage BTC refers to stages I, II, and III, as patients diagnosed at those stages often undergo curative treatment and tend to have a better prognosis compared to those with locally advanced or metastatic cancer. Tables 1,2 describe the T and N categories for each BTC subtype and those corresponding to each stage.

Overview of early-stage and late-stage BTC management

Early-stage BTC management

Even after curative-intent surgery, there are high rates of early-stage BTC recurrence with resection alone, with 5-year recurrence rates among all anatomical sites of BTC estimated to be 50–70% (33). One study found that, in patients with R0-resected pCCA, the presence of 2 or more risk factors (e.g., lymph node invasion, positive surgical margin, and perineural invasion) was associated with a 5-year recurrence rate of nearly 90% (34). Therefore, adjuvant chemotherapy is recommended as the first-line standard of care after curative resection of early-stage BTC: capecitabine is recommended for North American and European patients, while S-1 is recommended in Asian patients (7,26,27,35-37). A number of investigational localized therapies are also being explored in early-stage BTC, including liver transplant, hepatic arterial infusion (HAI), and chemoradiotherapy (38-41). Systemic therapies, including immunotherapy and molecularly targeted therapy, are generally reserved for advanced disease, but their role in the treatment of early-stage BTC is under active exploration for their potential to improve survival and lower rates of disease recurrence.

Advanced-stage BTC management

While surgical resection remains the primary curative-intent treatment for BTC, less than 35% of patients present with resectable disease at diagnosis (33). Therefore, a majority of patients diagnosed with BTC will be treated for advanced, unresectable disease. Unlike in early-stage BTC, there is no role for curative resection in advanced-stage BTC.

Chemotherapy is also utilized in the first-line for advanced-stage BTC: the combination of cisplatin and gemcitabine is considered a first-line treatment for advanced, unresectable BTC (42,43). Unlike in early-stage BTC, systemic treatment modalities other than chemotherapy, such as immunotherapy and targeted therapy, are approved as standard-of-care treatments for advanced, unresectable BTC (44,45). Immunotherapy in combination with chemotherapy is a preferred treatment modality for advanced, unresectable BTC: cisplatin and gemcitabine with either durvalumab or pembrolizumab are both approved as first-line treatment regimens (46,47). Currently, testing for targetable genetic alterations is considered standard of care for advanced, unresectable BTC, but this testing is not widely utilized for early-stage, resectable BTC (4). Patients with advanced BTC harboring mutations in genes including FGFR2, IDH1, HER2, BRAF, and KRAS also have targeted agents approved as treatments in the second-line, including the HER2-targeted bispecific antibody zanidatamab (44). Additionally, zenocutuzumab is a therapy targeting NRG1, which was recently granted breakthrough therapy designation by the FDA for advanced NRG1-mutated cholangiocarcinoma (48). A number of treatments for cancers exhibiting tumor-agnostic markers (e.g., NTRK, RET, MSI-H/dMMR) are also utilized in advanced BTC treatment, such as entrectinib (NTRK), selpercatinib (RET), and pembrolizumab with dostarlimab (MSI-H/dMMR) (45,49).

While non-chemotherapy systemic modalities are utilized as standard of care treatments in advanced, unresectable BTC, they remain only investigational perioperative agents for early-stage, resectable BTC. However, the use of novel, bispecific antibodies is being investigated in both early-stage and advanced-stage BTC. For example, spevatamig, a bispecific antibody targeting Claudin 18.2 and CD47, is currently being investigated as a treatment for advanced BTC (50). Table 3 provides an overview of current standard of care and select investigational treatment strategies for early-stage resectable BTC as well as advanced BTC.

Current and future perioperative treatments for early-stage BTC

Given the potential for cure in early-stage, resectable BTCs, much effort has been devoted to developing effective perioperative treatments that lower the risk for recurrence in patients who undergo curative-intent resection. We provide an overview of various current and future perioperative treatment regimens and modalities and examine the evidence in support of each. We will focus on treatments either currently utilized or being explored in early-stage, resectable BTC, since surgery is not a component of treatment for advanced-stage BTC, and there is no role for perioperative treatments in advanced-stage BTC.

Adjuvant therapy

Several clinical guidelines recommend capecitabine as first-line adjuvant therapy for North American and European patients who have undergone curative-intent resection for early-stage BTC (6,27,28,39,42). S-1 is currently approved for use in Asia but not North America or Europe, and the Pan-Asian adapted European Society for Medical Oncology (ESMO) consensus guidelines for the management of Asian patients with BTC strongly recommend adjuvant S-1 or capecitabine as standard of care in resectable BTC (37).

Evidence for adjuvant therapy

Early evidence

The earliest phase III randomized controlled trial (RCT) exploring adjuvant therapy for early-stage, resected BTCs compared an adjuvant chemotherapy regimen consisting of mitomycin C and 5-fluorouracil (5-FU) vs. postoperative observation alone for 508 patients with pancreaticobiliary carcinomas (51). In this Japan-based multi-center study, investigators enrolled patients with histologically confirmed pancreaticobiliary carcinoma, stage II-IV disease, and no previous cancer-directed therapy, among other criteria. The study had a primary endpoint of 5-year survival rate as well as secondary endpoints that included disease-free survival (DFS) and adverse events (AEs). Separate analyses were conducted for each subgroup of pancreaticobiliary carcinoma (e.g., pancreas, gallbladder, bile duct, or ampulla of Vater). The only statistically significant finding was a 5-year survival benefit in the adjuvant treatment group vs. observation alone (26% vs. 14.4%, P=0.0367) for patients with GBC (51). Toxicities which occurred at a significantly higher frequency in the adjuvant therapy group than the control group included leukopenia (12.9% vs. 3.0%), anorexia (22.4% vs. 13.9%), and nausea/emesis (12.9% vs. 6.9%) (51). Though we found that this study generally lacked rigorously supported conclusions, its findings were early evidence for clinical benefit from the use of adjuvant fluoropyrimidine treatment for early-stage, resected BTC.

BILCAP

Adjuvant fluoropyrimidine therapy for early-stage, resected BTCs was validated in the BILCAP study, a multi-center randomized, phase III RCT conducted in the United Kingdom that investigated adjuvant capecitabine vs. postoperative observation in 447 patients with early-stage, resected BTCs. The patient population included those with histologically confirmed CCA or muscle-invasive GBC, R0 or R1 resection, radical surgical treatment (liver resection, pancreatic resection, or both), and no previous chemotherapy or radiotherapy for BTC, among other criteria. Its primary endpoint was overall survival (OS), and it measured secondary endpoints including a per-protocol analysis of outcomes, recurrence-free survival (RFS), and toxicity. This study suggested a benefit in OS from adjuvant capecitabine vs. observation alone [adjusted hazard ratio (HR) 0.75, 95% confidence interval (CI): 0.58–0.97, P=0.028] in a prespecified per-protocol analysis showing a median OS (mOS) of 53 months (95% CI: 40 months to not reached) in the capecitabine group and 36 months (30,31,33-45) in the observation group (52). However, one limitation of the study is that the statistical design appears underpowered (53). Another is the lack of benefit in RFS beyond the 2-year period, with some noting that capecitabine may just delay instead of preventing recurrence (53). Notable AEs included grade 3 hand-foot syndrome (20%), diarrhea (8%), and fatigue (8%), as well as 1 patient with grade 4 cardiac ischemia/infarction (6). Updated 5-year survival outcomes for the BILCAP study noted similar results and conclusions to the initial study (6). Based mainly on the results of BILCAP, adjuvant capecitabine has become the standard of care for early-stage, resectable BTC in patients in North America or Europe (53).

ASCOT

Further evidence for the clinical benefit of adjuvant fluoropyrimidine treatment in early-stage, resected BTCs came from the ASCOT study, which was a randomized, multi-center, phase III RCT based in Japan that showed a significant OS benefit for the intervention group receiving S-1 (tegafur, gimeracil, and oteracil potassium) compared to the control group (observation alone) (HR 0.69, 95% CI: 0.51–0.94, one sided P=0.0080) (54). The 440 enrolled patients included those with histologically confirmed CCA/GBC/ampullary carcinoma, tumor stage I-III, and R0 or R1 resection, among other criteria. The primary endpoint was OS, and notable secondary endpoints included RFS, AEs, and the proportion of treatment completion. Notable grade 3 or 4 AEs in the S-1 group were decreased neutrophil count (14%) and biliary tract infection (7%), with 2 grade 4 events considered related to S-1 (i.e., myocardial infarction and Guillain-Barré syndrome) (55). A statistically significant survival benefit from adjuvant S-1 therapy was maintained in a 5-year follow-up of outcomes from ASCOT (55). Based mainly on the results of ASCOT, adjuvant S-1 has become the standard of care for early-stage, resectable BTC in patients in Asia.

Ongoing adjuvant therapy research

Chemotherapy

There are several ongoing phase III studies investigating whether adjuvant chemotherapy regimens besides capecitabine can provide benefit for resected BTC (56-58). This includes studies exploring chemotherapy by itself and in combination with other modalities.

(I) ACTICCA-1 (gemcitabine-cisplatin vs. capecitabine)

ACTICCA-1 (NCT02170090) is a global phase III RCT randomizing an expected 440 patients to either adjuvant gemcitabine-cisplatin or observation alone in patients who have undergone curative-intent resections for BTC, with a primary endpoint of 24-month DFS (59). Of note, this study included separate cohorts for CCA and GBC, which were separately randomized between intervention and control groups. The patients will also be randomized in a stratified manner according to iCCA vs. eCCA localization and lymph node status. The study was paused after initial presentation of results from BILCAP and was resumed with a protocol adjustment randomizing patients to either gemcitabine-cisplatin or capecitabine, which was a reasonable strategy to adapt to the changing clinical landscape at the time (33).

(II) BilGemCap and AdBTC-1 (gemcitabine-capecitabine vs. capecitabine alone)

There are two phase III RCTs—BilGemCap (NCT04401709) and AdBTC-1 (NCT03779035)— investigating the effectiveness of gemcitabine-capecitabine combination therapy compared to capecitabine monotherapy for patients with resected BTC (60). BilGemCap plans to enroll 490 patients across South Korea, while AdBTC plans to enroll 460 patients across China. The studies differ slightly in capecitabine dosing in the intervention group, and BilGemCap includes GBC cases while AdBTC-1 excludes such cases. Both studies will measure 24-month DFS as their respective primary endpoint.

(III) GEMOXICC (oxaliplatin-gemcitabine vs. capecitabine)

Another China-based phase III RCT—GEMOXICC (NCT02548195)—is comparing adjuvant oxaliplatin-gemcitabine to capecitabine alone. It will measure its primary endpoint of 36-month RFS in an expected 286 patients with histologically confirmed iCCA treated by R0 or R1 resection. Notably, the study protocol lists certain risk factors, such as lymph node metastasis, lymphatic or blood vessel invasion, or tumor size >5 cm, as inclusion criteria, suggesting selection toward higher-risk patients.

(IV) GECICCA (gemcitabine-cisplatin vs. gemcitabine alone)

The Thailand-based phase III RCT—GECICCA (HE591330)—will expect to randomize 320 patients between an interventional gemcitabine-cisplatin group and a control group receiving gemcitabine alone. It will compare them based on its primary outcome of 3-year OS. Patient inclusion criteria include histologically proven CCA, R0 or R1 resection, and no radiotherapy or chemotherapy before surgery. It would be interesting to observe whether the distinct risk factors for BTC in Thailand (i.e., endemic liver fluke infections) influence response to therapy.

(V) HAI

HAI utilizes a surgically implanted subcutaneous infusion pump connected to a catheter placed into the hepatic arterial system that allows for administration of high concentrations of chemotherapy directly to hepatic tumors while reducing systemic toxicity. It has been studied in advanced BTCs as a viable option for disease control, suggesting its potential in adjuvant therapy for early-stage iCCA. One phase II study utilizing first-HAI for advanced pCCA showed an objective response rate (ORR) of 67.6% (38). Another phase II study utilizing HAI for locally advanced iCCA in the first or second line of treatment showed an ORR of 44% (39). A phase II (NCT06888063) trial is currently investigating the use of HAI to deliver adjuvant floxuridine in patients with iCCA.

Chemoradiotherapy

(I) SWOG S0809

The SWOG S0809 trial was a single-arm phase II study investigating the effectiveness of combination chemotherapy with concurrent radiotherapy-chemoradiotherapy in 79 patients with resected GBC and eCCA. The patients first underwent a course of adjuvant combination gemcitabine-capecitabine prior to adjuvant chemoradiotherapy (capecitabine and radiation to the upper abdomen). This regimen showed a greater than expected 2-year survival of 65% (compared to an expected 2-year survival of 55% for R0 resection without adjuvant treatment) (40).

(II) Ongoing phase III RCT investigating chemoradiotherapy

The use of concurrent chemoradiotherapy in the adjuvant setting for resected BTCs is being further explored in a China-based phase III RCT (NCT02798510) investigating the efficacy of adjuvant chemoradiotherapy assessed according to its primary endpoint of 24-month OS in patients with R0 or R1-resected GBC, pCCA, or dCCA. An expected 140 patients will be randomized to the intervention group, receiving an initial adjuvant chemotherapy regimen of gemcitabine-capecitabine followed by concurrent capecitabine and radiotherapy, or the control group, which will only receive adjuvant gemcitabine-capecitabine.

Targeted therapy with chemotherapy

While molecularly targeted therapies have been explored in advanced BTC, their efficacy in resectable disease is less well-understood (61). Several ongoing trials (NCT03609489, NCT05833815) are investigating the addition of targeted therapies—including the vascular endothelial growth factor (VEGF) 2 receptor inhibitor, apatinib—to standard of care chemotherapy in the adjuvant setting (62). These targeted therapies have shown promise in the advanced BTC setting and have the potential to improve outcomes in the early-stage setting, especially since some evidence suggests that the rate of actionable mutations does not significantly differ between advanced and resectable BTCs (4,63,64). The growth of directed efforts toward molecular testing and targeted therapy in early-stage BTC holds great promise.

Immunotherapy

The success of immunotherapy in several cancer types has spurred exploration into the effectiveness of adjuvant immunotherapy for the treatment of early-stage BTC. Numerous ongoing clinical trials (NCT06406816, NCT06730009) are exploring adjuvant immunotherapy in combination with various novel agents and anti-cancer modalities (61,65). Utilizing immunotherapy in early-stage BTC treatment remains a promising therapeutic strategy to enhance clinical outcomes beyond what is achievable with chemotherapy alone.

(I) Immunotherapy with chemotherapy

TOPAZ-1 and KEYNOTE-966 are large, phase III RCTs demonstrating that the addition of immune checkpoint inhibition (ICI) with agents such as durvalumab or pembrolizumab to chemotherapy (gemcitabine-cisplatin) has improved overall response rate (ORR) and OS compared to chemotherapy alone for advanced, metastatic BTC (66,67). Following this success in the metastatic setting are several ongoing trials using similar approaches for early-stage BTC.

One notable study is the ADJUBIL trial, a phase II study that studied an adjuvant regimen combining durvalumab and tremelimumab (anti-PD-L1 and anti-CTLA-4, respectively) compared to the same regimen with concurrent capecitabine (68). The patients who received dual ICI alone showed non-inferiority and experienced fewer toxicities compared to the dual ICI plus capecitabine group. A multitude (NCT06490107, NCT05430698, NCT06717464) of other ongoing clinical trials are investigating the effectiveness of ICI combined with various chemotherapy regimens for the adjuvant treatment of resectable BTCs (69,70).

(II) Bispecific antibody (ARTEMIDE-Biliary01)

ARTEMIDE-Biliary01 is a global (21 countries/regions), phase III RCT comparing the use of the novel bispecific antibody rilvegostomig with concurrent chemotherapy compared to adjuvant chemotherapy alone in 750 patients with resected BTCs (71). This study offers 3 adjuvant chemotherapy options: S-1, capecitabine, or gemcitabine-cisplatin. Patients will include those with histologically confirmed CCA or muscle-invasive GBC and R0 or R1 resection. This study will measure a primary endpoint of 5-year RFS as well as OS as one of the secondary endpoints. Rilvegostomig is a monovalent, bispecific, humanized, IgG1 monoclonal antibody targeted against human PD-1 and TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain) (71).

The results of this study will demonstrate the potential of synergy between immunotherapy acting on PD-1/TIGIT and chemotherapy in adjuvant BTC. Excitingly, this study will complete accrual faster than anticipated.

(III) Anti-TIGIT and PD-1/PD-L1 pathway

The PD-1/PD-L1 pathway inhibits T cell function when activated, and inhibition of this pathway has been shown to have a strong anti-tumor effect (72). Monotherapy with PD-1 inhibitors can lead to compensatory upregulation of TIGIT, a receptor that is part of an immunomodulatory signaling pathway, which can limit the efficacy of PD-1 therapy by maintaining immunosuppression and T cell exhaustion (73,74). Emerging clinical data suggest that the dual blockade of both the PD-1 and TIGIT pathways may be synergistic without additional toxicity (74-76). Preliminary results from a study of rilvegostomig in non-small-cell lung cancer (NSCLC) patients showed a favorable safety profile and encouraging preliminary efficacy in patients with a PD-L1 tumor proportion score (TPS) ≥1%, providing a degree of clinical validation to this treatment approach (77).

(IV) Immunotherapy with chemoradiotherapy (ACCORD)

The phase II, randomized ACCORD trial compared combined immunotherapy and chemoradiotherapy vs. observation alone in 93 patients with resected eCCA or GBC. The treatment regimen consisted of initial monotherapy with camrelizumab (anti-PD-1) followed by chemoradiotherapy concurrent with immunotherapy. It showed a benefit in 3-year survival for the treatment group (58.2%) compared to observation alone (30.5%) (HR 0.43, 95% CI: 0.24–0.79, P=0.004) (78). The treatment regimen was well tolerated, with 100% of the intervention group completing treatment.

Results from the ACCORD trial promote combination immunotherapy and chemoradiotherapy as a promising regimen treatment, and another recently initiated single-arm prospective study (NCT06997913) will explore the efficacy of adjuvant chemoradiotherapy (radiotherapy with capecitabine) with concurrent immunotherapy (tislelizumab, PD-1 inhibitor) for patients with resected eCCA.

(V) Immunotherapy, chemoradiotherapy, and targeted therapy

Some ongoing studies (NCT05254847, NCT06280508) are exploring the efficacy of a regimen combining chemotherapy, immunotherapy, and targeted therapy. The combination of immunotherapy with a targeted agent inhibiting VEGF in these studies is particularly interesting, as VEGF-driven angiogenesis promotes an immunosuppressive microenvironment and limits T-cell infiltration of a tumor (79). Inhibition of VEGF by targeted agents may potentiate the effectiveness of immunotherapy in BTC. This therapeutic approach has been validated in the treatment of advanced hepatocellular carcinoma, for which the combination of atezolizumab and bevacizumab is recommended as a first-line systemic therapy (80). Additionally, studies in advanced-stage cancers have suggested potential synergy between immunotherapy and targeted IDH1 therapy (30).

(VI) Antibody-drug conjugates (ADCs)

ADCs are targeted cancer therapies composed of a monoclonal antibody linked to a cytotoxic agent, allowing for greater selectivity for cancer cells and reduced systemic toxicity (81). The first ADC approved by the FDA for the treatment of solid tumors was ado-trastuzumab emtasine (T-DM1) for the treatment of HER2-positive metastatic breast cancer (82). BTCs overexpress a number of tumor-associated antigens, especially HER2 and TROP2, which are attractive targets for ADC therapy, especially given the existence of FDA-approved ADCs targeting both of these tumor-associated antigens (83). While ADCs are an emerging therapeutic modality in the treatment of BTC, they are exclusively limited to advanced, unresectable BTC and are therefore largely outside of the scope of this review (84). However, it is worth noting that particularly in BTCs overexpressing TROP2, TROP2-targeted ADCs such as sacituzumab govitecan and OBI902 have shown early promise (85,86).

Summary

Surgical resection and adjuvant chemotherapy are the current standard of care for early-stage, resectable BTC, and this approach has been validated in phase III RCTs (Table 4). While immunotherapy and targeted therapy are currently utilized for advanced BTC, their role in early-stage BTC is the subject of investigation in many ongoing clinical trials (Table 5). Additional therapies that incorporate novel agents, such as immunotherapy and targeted treatment, will hopefully enhance the benefit of chemotherapy, improve overall outcomes in BTCs, and broaden the number of options available to providers and patients. The emerging treatment landscape for adjuvant BTC management is advancing at an exciting pace, expanding possibilities for both clinicians and patients alike.

Neoadjuvant therapy

Neoadjuvant chemotherapy (NAC) is not currently recommended as standard of care for most patients, and no randomized studies have been conducted comparing NAC followed by surgery with resection alone (26). A number of retrospective studies suggest that neoadjuvant therapy can be used to downstage tumors and improve long-term outcomes, most often in patients with disease initially staged as locally advanced or unresectable (87). Among those with iCCA, 351 patients who underwent neoadjuvant therapy had higher rates of R1 resection (ranging from 24% to 67%) compared to 2,732 patients who immediately underwent surgical resection (ranging from 5% to 49%). Han et al. found that NAC is the most effective neoadjuvant therapy for patients with resectable iCCA, associated with an average OS of 40.3 months compared to 32.8 months (HR 0.78, 95% CI: 0.64–0.94, P=0.01) (88).

There is little research on neoadjuvant radiotherapy, immunotherapy, and targeted therapy, but ongoing trials are promising, often focusing on high-recurrence-risk BTC, defined as disease exhibiting any of the following: single tumor >5 cm, tumor stage T2 or higher, major vascular invasion, or regional lymph node involvement.

Chemotherapy

NAC has been investigated mostly in patients with iCCA. Sutton et al. administered NAC gemcitabine-cisplatin to 10 patients from a cohort of 52 with resectable iCCA (89). The NAC group had an 80% 5-year OS compared to only 37% of those who did not receive NAC (HR 0.16, P=0.01).

A phase II feasibility trial of neoadjuvant gemcitabine-cisplatin and nab-paclitaxel was conducted on 30 patients with resectable, high-recurrence-risk iCCA (90). The mOS was 24 months, and the R0 rate was 73%, suggesting that NAC is feasible and does not adversely affect resection. However, 33% of patients experienced grade 3 or higher toxicities, and 50% of patients required at least one dose reduction.

Immunotherapy and chemotherapy

Following in the success of the TOPAZ-1 and KEYNOTE-966 studies are several ongoing trials exploring neoadjuvant immunotherapy and chemotherapy.

Randomized studies

A phase II randomized study (NCT05672537) is evaluating the efficacy of durvalumab (PD-L1 inhibitor) and gemcitabine-cisplatin prior to resection compared to resection alone. Another phase II randomized study (NCT06721286) is instead using toripalimab (PD-1 inhibitor) in combination with gemcitabine-cisplatin as neoadjuvant therapy. Both studies aim to measure effects on RFS in patients with resectable, high-recurrence-risk iCCA.

Single-arm studies

Other studies, such as NCT05557578 and NCT06903273, are phase II, single-arm, prospective studies investigating tislelizumab in combination with various chemotherapies prior to resection, measuring ORR and R0 rate in patients with resectable, high-recurrence-risk iCCA.

Targeted therapy with immunotherapy and chemotherapy

A phase I, single-arm trial (NCT06181032) aims to evaluate the efficacy and safety of using adebrelimab (PD-L1 inhibitor), apatinib, and gemcitabine-cisplatin as neoadjuvant treatment of resectable, high-recurrence-risk BTC. This follows a number of small studies evaluating the efficacy of apatinib in treating advanced or metastatic BTC that did not respond to chemotherapy, with and without immunotherapy (91,92). The median progression-free survival (mPFS) was 4.4 (95% CI: 2.4–6.3) and 2.7 months (95% CI: 1.74–3.72), and the mOS was 13.1 (95% CI: 8.1–18.2) and 4.81 months (95% CI: 3.16–10.9), respectively.

Summary

Although there are no large studies validating the success of the neoadjuvant approach in BTCs, the introduction of systemic therapy prior to surgery has the benefit of improved R0 resection and potential elimination of micro-metastatic disease and should be explored in future research.

Perioperative therapies

An area of interest in BTC treatment is perioperative treatment, which includes neoadjuvant therapy, surgery, and adjuvant therapy. Neoadjuvant therapy is hypothesized to make the tumor smaller and reduce the extent of surgery, and help improve the R0 resection rate, while adjuvant therapy would kill any remaining tumor cells.

Chemotherapy

One open-label phase III clinical trial, GAIN, included 68 patients with localized or locally advanced resectable non-metastatic BTC and compared patients randomized to receive perioperative chemotherapy (3 cycles of gemcitabine-cisplatin) with adjuvant therapy according to the investigator’s choice. The trial results were encouraging; neoadjuvant therapy improved OS (27.8 vs. 14.6 months), R0 resection rate (62.5% vs. 33.3%), and reduced 30-day mortality rate (4.2% vs. 24%) and 90-day mortality rate (4.2% vs. 28%) (93). However, this study closed early due to poor accrual, so the data must be interpreted with caution and is not conclusion-generating. The trial was initially recruiting 300 patients; however, recruitment was halted at 68 patients in 2024 because of slow enrollment. This is still intriguing data that warrants further exploration using chemotherapy in the perioperative setting.

There are a number of pending clinical trials exploring the benefit of perioperative therapy, including a phase II/III trial (NCT04559139) with the ECOG-ACRIN Cancer Research Group comparing patients given neoadjuvant gemcitabine-cisplatin prior to re-resection, followed by adjuvant gemcitabine-cisplatin, compared to patients who receive only adjuvant gemcitabine-cisplatin after re-resection for incidental GBC.

Immunotherapy and chemotherapy

Some trials are utilizing immunotherapies in conjunction with chemotherapy as perioperative therapy. A phase II trial in Canada, NEOLANGIO (NCT06569225), is assessing the efficacy of gemcitabine, cisplatin, nab-paclitaxel, and rilvegostomig treatment in a pre-surgical setting for upfront resectable iCCA, followed by adjuvant gemcitabine-cisplatin and rilvegostomig. The chemotherapy in the study utilized a triple therapy because trials among advanced BTCs have shown that administration of nab-paclitaxel plus gemcitabine-cisplatin can prolong mPFS and OS (7).

Another phase II clinical trial (NCT06001658) at Johns Hopkins plans to evaluate perioperative treatment with gemcitabine, cisplatin, and pembrolizumab with the primary outcome of microenvironment involving CD8+ T cells and immunosuppressive tumor-associated macrophages in patients with a major pathologic response versus pathologic non-responders, as well as secondary outcomes of R0 resection rate and major pathologic response.

Another phase IIb/III trial in the Netherlands that has not started recruiting (NEODISCO, NCT06923475) will assess whether neoadjuvant gemcitabine-cisplatin plus perioperative pembrolizumab improves event-free survival in patients with resectable and borderline resectable pCCA and dCCA.

A phase II trial in Korea (NCT04308174) that has recruited 45 patients is studying the addition of immunotherapy with durvalumab to gemcitabine-cisplatin neoadjuvantly, compared with patients who receive only gemcitabine-cisplatin in the neoadjuvant setting. Both patient groups are planned to receive adjuvant therapy with durvalumab.

Targeted therapy with immunotherapy and/or chemotherapy

Recently, targeted therapy has emerged as an important therapeutic option for the treatment of malignant tumors. Another phase II trial, NeoBrave CCA in China (NCT06739252), is evaluating neoadjuvant therapy with three cycles of HAI chemotherapy with atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) and adjuvant therapy with two cycles of HAI chemotherapy with atezolizumab and bevacizumab.

Another area of interest in targeted therapy is a single-arm, prospective clinical study enrolling 20 patients (NCT06417606) on lenvatinib and adebrelimab with gemcitabine-oxaliplatin in the perioperative treatment of potentially resectable iCCA. Lenvatinib is a multiple receptor tyrosine kinase inhibitor, which targets VEGF receptor 1–3, leading to inhibition of angiogenesis and modulation of the tumor microenvironment. The primary endpoint is ORR and DFS.

A combination of lenvatinib and anti-PD-L1 therapies is currently being studied in advanced biliary cancers (94,95). For example, a phase II clinical trial of patients with advanced iCCA treated with gemcitabine-oxaliplatin chemotherapy in combination with the anti-PD-1 antibody toripalimab and lenvatinib as first-line therapy found a mPFS of 10.0 months and ORR of 80% (96).

Summary

These studies suggest that a perioperative approach is a great strategy for BTC, with the advantage of neoadjuvant treatment to improve R0 resection and elimination of micrometastatic disease. The results of the clinical trials discussed above for perioperative therapy are of high interest and should be considered with more data. In addition, it allows immunotherapy to provide additional benefit in the adjuvant setting.

Future directions

Though still rare, the increasing incidence of BTC worldwide underscores the importance of furthering advancements in our understanding of this disease. Molecular profiling revealing new subtypes of BTC and the development of novel biomarkers will likely play a significant role in improvements in BTC diagnosis, prognosis, and management. The BILCAP and ASCOT trials have established the standard of care in early-stage, resected BTC as adjuvant oral fluoropyrimidine therapy: capecitabine (in North America and Europe) and S-1 (in Asia).

While the current standard of care therapy is adjuvant capecitabine or S-1, there remain high rates of long-term recurrence (97). Current ongoing studies are investigating the use of various chemotherapy regimens, as well as modalities such as immunotherapy and radiotherapy in a neoadjuvant, adjuvant, or perioperative setting. Immunotherapy and targeted therapies have shown efficacy in advanced BTCs and may hold promise for early-stage BTCs. Neoadjuvant strategies may improve rates of R0 resection and potentially reduce the need for surgeries. Although no studies in early-stage BTCs have included a biomarker-based approach, the extremely high ORR for both IDH1 and FGFR2 pathway blockade in the metastatic setting makes them attractive targets. Additional tumor agnostic biomarkers, such as dMMR and NTRK can be beneficial in resectable BTCs.

The future of early-stage BTC therapy is focused on using perioperative approaches to introduce tailored therapies guided by clinically validated biomarkers. Perioperative chemotherapy is a foundational backbone for the treatment of early-stage BTC. For patients who express biomarkers (for example, HER2 or IDH1), incorporating corresponding targeted therapy should be a highly prioritized investigational pathway. For other patients, the introduction of immunotherapy in the perioperative setting should be highly prioritized, given the synergy between immunotherapy and chemotherapy seen in prior clinical studies.

Conclusions

To effectively evaluate studies on perioperative treatment strategies, future early-stage BTC should adopt clear, achievable milestones and long-term endpoints. Pathological complete response (pCR) is the absence of viable tumor cells in the resected tumor specimen after neoadjuvant therapy. pCR has been associated with better prognostic outcomes in other studies (98,99). It will also be important to evaluate long-term survival outcomes from clinical trials, including 3-year and 5-year survival rates. Additionally, integrating the Cachexia Index (CXI) can be important to integrate into clinical trials and treatments for patients, as low CXI has been associated with low OS and progression-free survival (100).

Biomarker-guided and perioperative studies should be important priorities in future investigations for early-stage BTCs.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-103/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-103/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Kehmann L, Jördens M, Loosen SH, et al. Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets. ESMO Open 2024;9:103706. [Crossref] [PubMed]
2. Jusakul A, Cutcutache I, Yong CH, et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov 2017;7:1116-35. [Crossref] [PubMed]
3. Marcano-Bonilla L, Mohamed EA, Mounajjed T, et al. Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol 2016;5:61. [Crossref] [PubMed]
4. Oppat KM, Warren EA, Bennett FJ, et al. Incidence and prognostic value of actionable mutations in early-stage resectable cholangiocarcinoma. J Clin Oncol 2024;42:545.
5. Valle JW, Kelley RK, Nervi B, et al. Biliary tract cancer. Lancet 2021;397:428-44. [Crossref] [PubMed]
6. Bridgewater J, Fletcher P, Palmer DH, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol 2022;40:2048-57. [Crossref] [PubMed]
7. Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J Clin Oncol 2019;37:1015-27. [Crossref] [PubMed]
8. Lamarca A, Kapacee Z, Breeze M, et al. Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers. J Clin Med 2020;9:2854. [Crossref] [PubMed]
9. Key Statistics for Gallbladder Cancer [Internet]. [cited 2025 Aug 13]. Available online: https://www.cancer.org/cancer/types/gallbladder-cancer/about/key-statistics.html
10. Clements O, Eliahoo J, Kim JU, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis. J Hepatol 2020;72:95-103. [Crossref] [PubMed]
11. Tsilimigras DI, Sahara K, Wu L, et al. Very Early Recurrence After Liver Resection for Intrahepatic Cholangiocarcinoma: Considering Alternative Treatment Approaches. JAMA Surg 2020;155:823-31. [Crossref] [PubMed]
12. Jiang Y, Jiang L, Li F, et al. The epidemiological trends of biliary tract cancers in the United States of America. BMC Gastroenterol 2022;22:546. [Crossref] [PubMed]
13. Turkes F, Carmichael J, Cunningham D, et al. Contemporary Tailored Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res Pract 2019;2019:7698786. [Crossref] [PubMed]
14. Lamarca A, Barriuso J, McNamara MG, et al. Molecular targeted therapies: Ready for "prime time" in biliary tract cancer. J Hepatol 2020;73:170-85. [Crossref] [PubMed]
15. Florio AA, Ferlay J, Znaor A, et al. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012. Cancer 2020;126:2666-78. [Crossref] [PubMed]
16. Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019;19:185. [Crossref] [PubMed]
17. McGee EE, Jackson SS, Petrick JL, et al. Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies. J Natl Cancer Inst 2019;111:1263-78. [Crossref] [PubMed]
18. Zhan ZQ, Chen YZ, Huang ZM, et al. Metabolic syndrome, its components, and gastrointestinal cancer risk: a meta-analysis of 31 prospective cohorts and Mendelian randomization study. J Gastroenterol Hepatol 2024;39:630-41. [Crossref] [PubMed]
19. Lamabadusuriya DA, Jayasena H, Bopitiya AK, et al. Obesity-driven inflammation and cancer risk: A comprehensive review. Semin Cancer Biol 2025;114:256-66. [Crossref] [PubMed]
20. Thomas JA, Kendall BJ, El-Serag HB, et al. Hepatocellular and extrahepatic cancer risk in people with non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2024;9:159-69. [Crossref] [PubMed]
21. Zhang S, Shen Y, Liu H, et al. Inflammatory microenvironment in gastric premalignant lesions: implication and application. Front Immunol 2023;14:1297101. [Crossref] [PubMed]
22. Bekaii-Saab TS, Bridgewater J, Normanno N. Practical considerations in screening for genetic alterations in cholangiocarcinoma. Ann Oncol 2021;32:1111-26. [Crossref] [PubMed]
23. Verdaguer H, Saurí T, Acosta DA, et al. ESMO Scale for Clinical Actionability of Molecular Targets Driving Targeted Treatment in Patients with Cholangiocarcinoma. Clin Cancer Res 2022;28:1662-71. [Crossref] [PubMed]
24. Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel) 2024;16:1761. [Crossref] [PubMed]
25. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet 2015;47:1003-10. [Crossref] [PubMed]
26. Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:127-40. [Crossref] [PubMed]
27. Mateo J, Chakravarty D, Dienstmann R, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol 2018;29:1895-902. [Crossref] [PubMed]
28. Benson AB, D'Angelica MI, Abrams T, et al. NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023. J Natl Compr Canc Netw 2023;21:694-704. [Crossref] [PubMed]
29. Farha N, Dima D, Ullah F, et al. Precision Oncology Targets in Biliary Tract Cancer. Cancers (Basel) 2023;15:2105. [Crossref] [PubMed]
30. Brandi G, Rizzo A. IDH Inhibitors and Immunotherapy for Biliary Tract Cancer: A Marriage of Convenience? Int J Mol Sci 2022;23:10869. [Crossref] [PubMed]
31. Rizzo A, Ricci AD, Tober N, et al. Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow. Anticancer Res 2020;40:3013-30. [Crossref] [PubMed]
32. Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
33. Kefas J, Bridgewater J, Vogel A, et al. Adjuvant therapy of biliary tract cancers. Ther Adv Med Oncol 2023;15:17588359231163785. [Crossref] [PubMed]
34. Nakahashi K, Ebata T, Yokoyama Y, et al. How long should follow-up be continued after R0 resection of perihilar cholangiocarcinoma? Surgery 2020;168:617-24. [Crossref] [PubMed]
35. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol 2023;79:181-208. [Crossref] [PubMed]
36. EASL Clinical Practice Guidelines on the management of extrahepatic cholangiocarcinoma. J Hepatol 2025;83:211-38. [Crossref] [PubMed]
37. Chen LT, Vogel A, Hsu C, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with biliary tract cancer. ESMO Open 2024;9:103647. [Crossref] [PubMed]
38. Wang X, Hu J, Cao G, et al. Phase II Study of Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Perihilar Cholangiocarcinoma. Radiology 2017;283:580-9. [Crossref] [PubMed]
39. Cercek A, Boerner T, Tan BR, 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;6:60-7. [Crossref] [PubMed]
40. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol 2015;33:2617-22. [Crossref] [PubMed]
41. Anteby R, Vierra BM, Shah SA. Liver transplant for intrahepatic cholangiocarcinoma: current evidence and clinical practice recommendations. J Gastrointest Surg 2025;29:102211. [Crossref] [PubMed]
42. Rizzo A, Brandi G. First-line Chemotherapy in Advanced Biliary Tract Cancer Ten Years After the ABC-02 Trial: "And Yet It Moves!". Cancer Treat Res Commun 2021;27:100335. [Crossref] [PubMed]
43. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
44. Rimassa L, Lamarca A, O'Kane GM, 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. [Crossref] [PubMed]
45. Benson AB 3rd, D'Angelica MI, Abrams T, et al. Biliary Tract Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw 2025;23:403-18. [Crossref] [PubMed]
46. Finn RS, Ueno M, Yoo C, et al. Three-year follow-up data from KEYNOTE-966: Pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) compared with gem/cis alone for patients (pts) with advanced biliary tract cancer (BTC). J Clin Oncol 2024;42:4093.
47. Oh DY, He AR, Qin S, et al. Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase III TOPAZ-1 study. J Hepatol 2025;83:1092-101. [Crossref] [PubMed]
48. Schram AM, Goto K, Kim DW, et al. Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. N Engl J Med 2025;392:566-76. [Crossref] [PubMed]
49. Boilève A, Hilmi M, Delaye M, et al. Biomarkers in Hepatobiliary Cancers: What is Useful in Clinical Practice? Cancers (Basel) 2021;13:2708. [Crossref] [PubMed]
50. Overman MJ, Laeufle R, Singh H, et al. 1531TiP TWINPEAK phase I/II study, PT886 a bispecific antibody targeting claudin 18.2 and CD47 in combination with chemotherapy and/or pembrolizumab in gastric/GEJ-carcinomas or PDAC. Ann Oncol 2024;35:S933-4.
51. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95:1685-95. [Crossref] [PubMed]
52. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019;20:663-73. [Crossref] [PubMed]
53. Rizzo A, Brandi G. BILCAP trial and adjuvant capecitabine in resectable biliary tract cancer: reflections on a standard of care. Expert Rev Gastroenterol Hepatol 2021;15:483-5. [Crossref] [PubMed]
54. Nakachi K, Ikeda M, Konishi M, 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. [Crossref] [PubMed]
55. Nakachi K, Ikeda M, Konishi M, et al. Adjuvant S-1 vs. observation for resected biliary tract cancer: 5-year follow-up of the JCOG1202/ASCOT. J Clin Oncol 2024;42:4119.
56. Luvira V, Satitkarnmanee E, Pugkhem A, et al. Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma. Cochrane Database Syst Rev 2021;9:CD012814. [Crossref] [PubMed]
57. Ioka T, Shindo Y, Ueno M, et al. Current progress in perioperative chemotherapy for biliary tract cancer. Ann Gastroenterol Surg 2023;7:565-71. [Crossref] [PubMed]
58. Rizzo A, Brandi G. Adjuvant systemic treatment in resected biliary tract cancer: State of the art, controversies, and future directions. Cancer Treat Res Commun 2021;27:100334. [Crossref] [PubMed]
59. Stein A, Arnold D, Bridgewater J, et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial. BMC Cancer 2015;15:564. [Crossref] [PubMed]
60. Park JO, Park JS, Lee C, et al. A randomized, multi-center phase III trial of adjuvant chemotherapy with gemcitabine and capecitabine (GemCap) compared to capecitabine (Cap) alone in curatively resected biliary tract cancer (BilGemCap Study): KCSG HB20-14. J Clin Oncol 2023;41:TPS633.
61. Nakachi K, Gotohda N, Hatano E, et al. Adjuvant and neoadjuvant chemotherapy for biliary tract cancer: a review of randomized controlled trials. Jpn J Clin Oncol 2023;53:1019-26. [Crossref] [PubMed]
62. Yang M, Zhao Y, Li Y, et al. Afatinib in combination with GEMOX chemotherapy as the adjuvant treatment in patients with ErbB pathway mutated, resectable gallbladder cancer: study protocol for a ctDNA-based, multicentre, open-label, randomised, controlled, phase II trial. BMJ Open 2023;13:e061892. [Crossref] [PubMed]
63. Zhang G, Gong S, Pang L, et al. Efficacy and Safety of Apatinib Treatment for Advanced Cholangiocarcinoma After Failed Gemcitabine-Based Chemotherapy: An Open-Label Phase II Prospective Study. Front Oncol 2021;11:659217. [Crossref] [PubMed]
64. Gruenberger B, Schueller J, Heubrandtner U, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010;11:1142-8. [Crossref] [PubMed]
65. Lo JH, Agarwal R, Goff LW, et al. Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies. Cancers (Basel) 2023;15:3312. [Crossref] [PubMed]
66. Kelley RK, Ueno M, Yoo C, 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;401:1853-65. [Crossref] [PubMed]
67. Oh DY, Ruth He A, Qin S, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid 2022;1:EVIDoa2200015.
68. Goetze T, Eickhoff R, Pons M, et al. ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer. J Clin Oncol 2024;42:TPS583.
69. Wei X, Jiang Y, Zhou J, et al. Efficacy and safety of combining tislelizumab with capecitabine compared to capecitabine alone in the adjuvant treatment of biliary tract cancers: rationale and protocol design for a randomized clinical trial. BMC Cancer 2025;25:938. [Crossref] [PubMed]
70. Li X, Li C, Cheng Y, et al. A phase 2, randomized, multicenter study of adjuvant adebrelimab plus capecitabine in resected cholangiocarcinoma with high-risk factors: ACHIEVE. J Clin Oncol 2025;43:TPS4220. [Crossref] [PubMed]
71. Fan J, Bekaii-Saab TS, Aldrighetti LA, et al. A phase 3, randomized study of adjuvant rilvegostomig plus chemotherapy in resected biliary tract cancer: ARTEMIDE-Biliary01. J Clin Oncol 2024;42:TPS4199.
72. Chai LF, Prince E, Pillarisetty VG, et al. Challenges in assessing solid tumor responses to immunotherapy. Cancer Gene Ther 2020;27:528-38. [Crossref] [PubMed]
73. Manieri NA, Chiang EY, Grogan JL. TIGIT: A Key Inhibitor of the Cancer Immunity Cycle. Trends Immunol 2017;38:20-8. [Crossref] [PubMed]
74. Rudin CM, Liu SV, Soo RA, et al. SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2024;42:324-35. [Crossref] [PubMed]
75. Rohrberg KS, Brandao M, Castanon Alvarez E, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01. J Clin Oncol 2023;41:9050.
76. Finn RS, Ryoo BY, Hsu CH, et al. Results from the MORPHEUS-liver study: Phase Ib/II randomized evaluation of tiragolumab (tira) in combination with atezolizumab (atezo) and bevacizumab (bev) in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC). J Clin Oncol 2023;41:4010.
77. Hiltermann TJN, Izumi H, Cho BC, et al. OA11.03 Efficacy and Safety of Rilvegostomig, an Anti-PD-1/TIGIT Bispecific, for CPI-naïve Metastatic NSCLC with PD-L1 1-49% or ≥50%. J Thorac Oncol 2024;19:S33.
78. Kuang M, Peng Z, Shen SL, et al. Adjuvant chemoradiation combined with immunotherapy for patients with high-risk resectable extrahepatic cholangiocarcinoma and gallbladder cancer: A phase II, multicenter, randomized controlled trial (ACCORD trial). J Clin Oncol 2025;43:570.
79. Schirizzi A, De Leonardis G, Lorusso V, et al. Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues. Cancers (Basel) 2023;15:2376. [Crossref] [PubMed]
80. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
81. Yao X, Lu Y, Shi S, et al. Antibody-drug conjugates (ADCs): "Smart Missiles" targeting cancer therapy. Colloids Surf B Biointerfaces 2026;257:115161. [Crossref] [PubMed]
82. Tarantino P, Tolaney SM. The Dawn of the Antibody-Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors. Cancer Res 2022;82:3659-61. [Crossref] [PubMed]
83. Kuwatani M, Sakamoto N. Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives. Cancers 2023;15:3686. [Crossref] [PubMed]
84. Ocker M, Mayr C, Huber-Cantonati P, et al. New frontiers in the pharmacological management of biliary tract carcinomas: the emerging role of drug conjugates. Expert Opin Pharmacother 2025;26:887-96. [Crossref] [PubMed]
85. Hsu RY, Lu CH, Shia CS, et al. Abstract 4356: OBI-902, a novel TROP2 targeted antibody-drug conjugate via GlycOBI® platform, has favorable pharmacokinetics and sustained antitumor activities in challenging solid tumors. Cancer Res 2025;85:4356.
86. Kasi A, Al-Rajabi RMT, Li H, et al. A phase II open-label study of sacituzumab govitecan in patients with previously treated locally advanced, recurrent, or metastatic cholangiocarcinoma (SIGNA). J Clin Oncol 2025;43:TPS651.
87. Cremen S, Kelly ME, Gallagher TK. The role of neo-adjuvant therapy in cholangiocarcinoma: A systematic review. Front Oncol 2022;12:975136. [Crossref] [PubMed]
88. Han R, Song P, Tang W, et al. Advances in neoadjuvant therapy for resectable intrahepatic cholangiocarcinoma: An invited commentary. Oncol Transl Med 2025;11:1-4.
89. Sutton TL, Billingsley KG, Walker BS, et al. Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma. Am J Surg 2021;221:1182-7. [Crossref] [PubMed]
90. Maithel SK, Keilson JM, Cao HST, 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;30:6558-66. [Crossref] [PubMed]
91. Wang C, Huang M, Geng Q, et al. Apatinib for patients with metastatic biliary tract carcinoma refractory to standard chemotherapy: results from an investigator-initiated, open-label, single-arm, exploratory phase II study. Ther Adv Med Oncol 2021;13:17588359211039047. [Crossref] [PubMed]
92. Wang D, Yang X, Long J, et al. The Efficacy and Safety of Apatinib Plus Camrelizumab in Patients With Previously Treated Advanced Biliary Tract Cancer: A Prospective Clinical Study. Front Oncol 2021;11:646979. [Crossref] [PubMed]
93. Goetze TO, Vogel A, Pratschke J, et al. Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone followed adjuvant therapy in biliary tract cancer: Final results from the phase III AIO/CALGP/ACO-GAIN-Trial. J Clin Oncol 2025;43:4008.
94. Zhu C, Xue J, Wang Y, et al. Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer. Front Immunol 2023;14:1109292. [Crossref] [PubMed]
95. Shi C, Li Y, Yang C, et al. envatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China. Front Immunol 2022;13:946861. [Crossref] [PubMed]
96. Jian Z, Fan J, Shi GM, et al. Gemox chemotherapy in combination with anti-PD1 antibody toripalimab and lenvatinib as first-line treatment for advanced intrahepatic cholangiocarcinoma: A phase 2 clinical trial. J Clin Oncol 2021;39:4094.
97. Akkus E, Lamarca A. Adjuvant chemotherapy compared to observation in resected biliary tract cancers: Survival meta-analysis of phase-III randomized controlled trials. Eur J Cancer 2025;220:115342. [Crossref] [PubMed]
98. Leong T, Smithers BM, Michael M, et al. Preoperative Chemoradiotherapy for Resectable Gastric Cancer. N Engl J Med 2024;391:1810-21. [Crossref] [PubMed]
99. Schrag D, Shi Q, Weiser MR, et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med 2023;389:322-34. [Crossref] [PubMed]
100. Bas O, Sahin TK, Karahan L, et al. Prognostic significance of the cachexia index (CXI) in patients with cancer: A systematic review and meta-analysis. Clin Nutr ESPEN 2025;68:240-7. [Crossref] [PubMed]