Advancements in cholangiocarcinoma: evolving strategies for diagnosis, treatment, and palliation over three decades
Introduction
Cholangiocarcinomas (CCs) are malignant tumors originating from the epithelial cells of the biliary tree and gallbladder, presenting significant diagnostic and therapeutic challenges (1). The classification of CC into intrahepatic CC and extrahepatic CC (ECC) types, with further subdivision of ECC into perihilar CC (PCC) and distal CC (DCC), helps delineate treatment strategies based on tumor location. ICCs typically manifest as liver lesions, whereas ECCs often lead to obstructive jaundice. The increasing global incidence of CC demands a deep understanding of its pathophysiology, improved diagnostic techniques, and effective therapeutic interventions (2,3). This review aims to synthesize recent advances in CC research, highlighting developments in diagnosis, management, and palliative care, fostering a comprehensive approach to treatment.
Evidence acquisition
We conducted a comprehensive search across major databases including MEDLINE, Ovid MEDLINE In-Process, Cochrane Database of Systematic Reviews, EMBASE, PubMed, and the National Library of Medicine Gateway, covering literature from January 1990 to December 2023. The focus was on randomized controlled trials (RCTs) and prospective observational studies that address the epidemiology, diagnosis, therapy, and palliation of CC. Our methodology included using established systematic review tools such as the Jadad Scale for RCTs and the Downs and Black checklist for observational studies to ensure rigorous evaluation of study quality (4-6). To identify all potential papers, we searched medical subject headings reported in Table 1. Articles selected were restricted to those published in English, and the selection process was meticulously performed by a team of experts who independently reviewed titles and abstracts for relevance, followed by full-text reviews where necessary. Gallbladder cancer management was excluded from this review, as it has been extensively covered in other articles (7-10).
Table 1
Primary MeSH terms | Secondary MeSH terms (epidemiology, diagnosis) | Secondary MeSH terms (treatment, palliation) |
---|---|---|
Cholangiocarcinoma(s) | Epidemiology | Hepatectomy |
Adenocarcinoma(s) | Classification | Resection |
Carcinoma(s) | Diagnosis | Therapeutic(s) |
Bile duct neoplasm(s) | Differential diagnosis | Treatment outcome(s) |
Biliary tract neoplasm(s) | Early diagnosis | Surgery |
Common bile duct neoplasm(s) | Risk factor(s) | Transplantation |
Liver neoplasm(s) | Diagnostic imaging | Biliary tract |
Bile duct(s) | Magnetic resonance imaging endosonography ultrasonography | Surgical procedures |
Common bile duct | Emission computed tomography radionuclide imaging | Liver transplantation |
Intrahepatic bile duct(s) | Positron emission tomography | Organ transplantation |
Extrahepatic bile duct(s) | X-ray computed | Clinical trial |
Biliary tract disease(s) | Biopsy (needle) | Controlled clinical trial(s) |
Bile duct disease(s) | Biopsy (fine needle) | Randomized controlled trial(s) |
Cytology | Clinical trial (phase I) | |
Cytodiagnosis | Clinical trial (phase II) | |
Tumor markers (biological) antigen(s) | Clinical trial (phase III) | |
Carcinoembryonic antigen | Clinical trial (phase IV) | |
CA 19-9 antigen | Drug therapy | |
CA 125 antigen | Chemotherapy | |
Endoscopic retrograde cholangiopancreatography cholangiography | Adjuvant | |
In situ hybridization | Antineoplastic agent(s) combined modality therapy antineoplastic combined chemotherapy protocols neoadjuvant therapy | |
Fluorescence in situ hybridization nucleic acid hybridization | Radiotherapy | |
Computed assisted image processing | Adjuvant embolization | |
Portal vein embolization | ||
Drainage | ||
Cholestasis | ||
Obstructive jaundice |
CA, carbohydrate antigen.
Epidemiology
The global incidence of CC has seen a steady increase, positioning it as the second most prevalent primary liver malignancy after hepatocellular carcinoma (HCC). In the United States alone, the incidence of CC accounts for almost 3% of all gastrointestinal cancers, with an estimated 8,000 new cases diagnosed annually. This rise is not isolated to the U.S.; similar trends have been observed worldwide, with significant increases noted in both ICC and ECC across diverse nations (11). Factors contributing to this increase include improved diagnostic capabilities and possibly environmental and genetic predispositions. Studies have shown significant variations in incidence based on geographic and ethnic backgrounds, with notably higher rates in Eastern Asia, largely attributed to risk factors such as infections by liver flukes which are endemic in this region (1,2,12-21). The recent advancements in diagnosing and classifying CC subtypes are expected to improve our understanding of the disease’s epidemiology and facilitate the development of more effective treatments in the future.
ICC
ICC is classified into two types: small duct, characterized by non-mucin-producing cuboidal cells, and large duct, marked by mucin-producing columnar cells with aggressive growth and worse prognosis (22,23). Over the last five decades, the age-adjusted incidence rate of ICC in the U.S. has surged by 522%, from 0.32 per 100,000 in 1975–1979 to 1.99 per 100,000 in 2001–2017, comprising about 15% of all primary liver cancers. Similarly, mortality rates have increased, with the age-adjusted death rate rising from 0.07 per 100,000 in 1973 to 0.93 per 100,000 in 2015 (24). These trends are believed to be influenced by increasing obesity rates. Molecular studies of ICC have identified critical genetic alterations, including mutations in IDH1, ARID1A, BAP1, and TP53, and gene fusions involving FGFR2. Approximately one-quarter of ICC cases exhibit these genetic changes (25). Another study highlighted 32 significantly altered genes, such as ELF3, and further gene fusions including PRKACA/PRKACB (26).
ECC
In the U.S., the age-adjusted incidence of ECC has increase from 0.95 per 100,000 in 1973 to 1.02 per 100,000 in 2012 (27). Men are more frequently affected, with a current incidence of 1.2 per 100,000, compared to 0.8 per 100,000 in women (2,17). The mortality rate for ECC has significantly decreased from 0.6 per 100,000 in 1979 to 0.01 per 100,000 in 2015 (19,24,28).
Classification
Anatomical classification
CC is anatomically classified into ICC, PCC, and DCC. ICCs develop within the liver tissues, while ECCs originate from the biliary ducts, either in the hepatoduodenal ligament or more distally. Further subclassification of ECC distinguishes between hilar or distal tumors. Hilar cholangiocarcinomas (HiCC), also known as Klatskin tumors, are positioned within 2 cm of the bifurcation of the common bile duct (29). Bismuth and Corlette later introduced a clinical classification system based on the anatomical location of these tumors (Figure 1) (20). Approximately 60% to 70% of CCs occur are HiCC, 20% to 30% are ECC, and 5% to 10% are ICC (Figure 2) (21,30).
Pathological classification
Well-to-moderately differentiated adenocarcinomas constitute over 90% of CCs (28,31). CCs often trigger desmoplastic reactions and early perineural invasion. In terms of appearance, ICCs may manifest as solid masses, infiltrate surrounding ductal tissues, or grow within the biliary ducts (32). Alternatively, ECCs commonly appear as nodular lesions, sclerosing strictures, or display papillary growth patterns. Within ECCs, sclerosing CCs are prevalent whereas papillary adenocarcinomas are infrequent and linked to a more favorable prognosis (29).
Mixed hepatocellular CC classification
Mixed hepatocellular CC combines features of both CC and HCC. These cancers exhibit a unique appearance in cross-sectional imaging studies, characterized by a prominent rim and an irregular shape on enhanced imaging modalities (32).
Risk factors for CC
Only a minority of patients with CC have known risk factors such as chronic biliary inflammation, cholestasis, or congenital abnormalities (Table 2) (33).
Table 2
General risk factors |
Old age (older than 65 years) |
Smoking |
Obesity |
Diabetes |
Post surgical |
Biliary-enteric anastomosis |
Chronic inflammatory diseases |
PSC |
Hepatolithiasis (oriental cholangiohepatitis) |
Hepatitis C |
Hepatitis B |
HIV |
Liver cirrhosis |
Parasitic infections |
Opisthorchis viverrini |
Clonorchis sinensis |
Congenital |
Choledochal cysts |
Caroli’s disease |
Congenital hepatic fibrosis |
Chemical agents |
Thorotrast |
Dioxin |
Nitrosamines |
Asbestos |
Medications |
Oral contraceptive pills |
Isoniazid |
PSC, primary sclerosing cholangitis; HIV, human immunodeficiency virus.
In Western countries, primary sclerosing cholangitis (PSC) is a significant risk factor, increasing the risk of CC by nearly 400 times compared to the general population. CC prevalence in PSC patients varies from 8% to 40%, with inflammatory bowel disease (IBD) further increasing this risk significantly (34-41). Diagnosis of CC in PSC patients is challenging and often occurs at advanced stages due to similar clinical and radiological presentations between these two conditions (42,43). Predictive factors include progressive jaundice, weight loss, dilation of bile ducts, elevated carbohydrate antigen (CA) 19-9 levels, and cellular dysplasia (44).
In Southeast Asia, liver fluke infestations from Opisthorchis viverrini and Clonorchis sinensis elevate CC risk, with prevalence rates, adjusted for age and gender, reaching up to 14% (3,39,45,46). These parasites cause biliary damage and inflammation, increasing CC risk through mechanisms like oxidative stress and DNA damage (47).
Recurrent pyogenic cholangiohepatitis, common in Southeast Asia, leads to a significant risk of ICC, with risk factors including age over 40 years and chronic hepatolithiasis (41,42,48,49). Early removal of choledochal cysts reduces CC risk, although the risk remains if not removed by age 20 years (50,51). Chronic inflammation from these cysts can lead to CC even after removal, indicating a possible genetic predisposition (51-53).
Cirrhosis and viral infections, notably hepatitis C virus (HCV) and hepatitis B virus (HBV), are major risk factors, with cirrhotic patients having a much higher likelihood of developing ICC. HCV and HBV are prevalent in CC patients (2,17,31,50,51,53-71).
Diagnosis
Clinical presentation
During physical examination, patients with CC may exhibit a palpable gallbladder (known as a Courvoisier sign), hepatomegaly, or signs of portal hypertension due to portal vein thrombosis caused by tumor invasion or compression (48,72). In the early stages, CCs are often clinically silent or present with nonspecific symptoms (Table 3) (73,74). ICCs are typically diagnosed through imaging tests rather than physical exams, as they often manifest as asymptomatic hepatic masses (37). As the disease progresses, patients may become symptomatic, with jaundice being the most common presenting symptom. ECCs usually present with painless jaundice and signs and symptoms related to biliary obstruction, such as itching, clay-colored stool, and dark urine. Only a minority of cases (10%) present with ascending cholangitis. Similarly to ICC, jaundice in ECC tends to be persistent and progressive, while patients with papillary lesions causing a ball-valve effect may experience intermittent biliary obstruction leading to recurrent episodes of jaundice.
Table 3
Symptoms | Percentage |
---|---|
Jaundice | 84 |
Weight loss | 35 |
Abdominal pain | 30 |
Nausea and vomiting | 20 |
Fever | 10 |
Serum tumor markers
Serum biochemical tests are supportive in diagnosing CC but are not diagnostic alone. Jaundice indicates possible obstruction of major biliary ducts, often showing increased bilirubin, alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) levels (48,75,76). Elevated ALP or GGT may occur without bilirubin increases in unilateral obstructions. Other signs include hypoalbuminemia and prolonged prothrombin time due to decreased hepatic function and vitamin K malabsorption (48). Tumor markers like CA 19-9 and carcinoembryonic antigen (CEA) help in diagnosis but lack specificity as they elevate in other cancers and benign conditions (77-79). For non-PSC patients, CA 19-9 above 100 U/mL offers 53% sensitivity and 75–90% specificity (80), while in PSC patients, it shows 75–89% sensitivity and 80–86% specificity (81,82). A Mayo Clinic study identified a CA 19-9 cutoff of 20 U/mL in PSC patients with 78% sensitivity and 67% specificity, and combining it with imaging tests increases sensitivity to 91–100% (83). CA 19-9 levels correlate with CC stage, with sensitivity varying based on tumor resectability (80). Combining CA 19-9 with CEA in PSC enhances detection, achieving 100% sensitivity and 78.4% specificity (72). New markers like MUC5AC, CYFRA 21-1, and MMP-7 are promising for diagnosis and survival prediction, showing sensitivities and specificities up to 71% and 90%, respectively (84,85).
Imaging modalities
Imaging techniques play a crucial role in diagnosing and planning treatment for patients with CC (86). The primary modalities used for CC diagnosis include computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and contrast-enhanced US (CEUS). Within this group, CT is currently the standard method for preoperative assessment (87).
Abdominal US
US is the first-line imaging tool for assessing biliary obstruction (88), with an 89% sensitivity for diagnosing ECC and accuracy ranging from 80% to 95% (79,80,86). Differentiating ICC from other liver masses can be challenging due to nonspecific US features (89,90). Duplex US with color Doppler enhances the evaluation of portal venous invasion, demonstrating high sensitivity (93%) and specificity (99%) (91,92). The technique’s effectiveness can vary with operator skill, often necessitating further tests for accurate staging (93). In cases with elevated CA 19-9, particularly in PSC patients, abdominal US sensitivity improves significantly, making it a valuable surveillance tool for early detection in high-risk regions (83,94).
CT
Triple-phase CT scan is a critical diagnostic tool in CC, providing essential insights into the tumor’s local spread, vascular and lymph node involvement, and potential distant metastases (83,95,96). ICCs on CT typically manifest as hypodense lesions with irregular margins and varying enhancement patterns, which are prognostic of the tumor’s aggressiveness (97). Common CT findings include dilatation and thickening of intrahepatic bile ducts and capsular retraction (98). ECCs may show focal ductal thickening with diverse enhancement patterns, often underestimating the longitudinal extent of the tumor compared to pathological specimens (89,90,99,100).
The contrast-enhanced multidetector-row CT offers high accuracy (78.6% to 92.3%) and is particularly adept at diagnosing vascular invasions achieving 100% sensitivity for hepatic artery and 92.3% sensitivity for portal vein involvement (98,101). It also provides critical information on the resectability of CC, helping to project potential surgical outcomes with a general precision of 60% to 85% in assessing resectability (102,103).
CT cholangiography (CTC) further enhances diagnostic capabilities, excelling over traditional CT in visualizing the biliary tree and matching the efficacy of endoscopic retrograde cholangiopancreatography (ERCP) in certain studies (104,105). For patients with PSC, integrating serum CA 19-9 levels with CT significantly improves diagnostic accuracy, enabling more definitive assessment of tumor characteristics and guiding treatment planning (83).
MRI and magnetic resonance cholangiopancreatography (MRCP)
MRI with MRCP provides a non-invasive, three-dimensional view of the biliary tree, effectively assessing CC without the need for biliary instrumentation (101,106-108). MRCP’s diagnostic accuracy rivals that of more invasive techniques like ERCP and percutaneous transhepatic cholangiography (PTC), making it the preferred method for evaluating suspected CC cases (102,109-111).
MRCP excels in detailing the anatomy and extent of CC, including vascular invasions, lymph node enlargements, and metastases. It is advisable to perform MRCP before biliary decompression. In imaging, ICC appears as a dark lesion on T1-weighted images and bright on T2-weighted, with ECC presenting similar signal intensities and possible bile duct dilation (112-118).
A meta-analysis of 67 studies found MRCP to have an overall sensitivity of 88% and specificity of 95% (116). Specific studies noted its high accuracy in determining tumor length and the extent of biliary duct involvement, especially in cases of malignant obstruction at the liver hilum (119). Compared to CT, MRCP is less effective in assessing the relationship of ICC with nearby blood vessels and organs. However, its diagnostic performance increases dramatically when combined with elevated CA 19-9 levels in patients with PSC, achieving high sensitivity and specificity (113,120-122).
Cholangiography
ERCP and PTC provide dynamic, invasive imaging to detect biliary abnormalities and assess the extent of ECC within the biliary tree. The choice between ERCP and PTC depends on the expertise available and the specific anatomical challenges presented by the tumor (48,84,123). While ERCP may fail to visualize the proximal biliary tree in cases of complete obstruction, PTC might not reach the distal tumor extent. These techniques typically offer a sensitivity of 75–85% and a specificity of 70–75%, but their accuracy can reach up to 95% (120,121,124). However, their invasiveness can lead to complications like pancreatitis, infection, and bleeding (86,118,125). Both ERCP and PTC are valuable for collecting tissue samples for cytology and biopsy, although the desmoplastic reaction common in CC can reduce the sensitivity of these tests (11). In patients with PSC, ERCP’s diagnostic value improves significantly if the serum CA 19-9 level is elevated, enhancing both sensitivity and specificity (83). Routine cytology sensitivity varies widely, but combined cytologic techniques such as digitized image analysis (DIA) and fluorescence in situ hybridization (FISH) have been used to improve diagnostic yield, especially in PSC patients (86,126-128). Recent advancements include the use of peroral cholangioscopy (POCS) alongside ERCP, which can increase diagnostic sensitivity and specificity by allowing direct visualization and targeted biopsy of biliary strictures (83,119,125-131).
Endoscopic US (EUS)
EUS offers a unique advantage in closely examining tissues and organs near the stomach and duodenum, enhancing the ability to detect abnormalities not easily seen through percutaneous methods. It utilizes high-frequency US probes inserted into the endoscope. In studies on suspected CC, EUS demonstrated a sensitivity of 79% and specificity of 62% (120). This was corroborated by meta-analyses, which revealed a sensitivity of 78% and a specificity of 84% (132). Notably, EUS allows for guided fine needle aspirations (FNAs) of tumors, especially beneficial for patients with prior negative cytology. It also facilitates sampling of enlarged lymph nodes for staging (133-135). Recent research found EUS-FNA highly effective, with a sensitivity of 66% and specificity of 100% in diagnosing CC-related biliary strictures (136). However, caution should be applied in patients with potentially curative CC as this approach has a very low, but clinically significant risk of peritoneal seeding (81). In the evaluation of suspected HiCC, EUS-guided FNA showed a sensitivity and specificity of 89% and 100%, respectively, altering treatment plans for a majority of patients (137). Another prospective study reported an 86% sensitivity and 100% specificity for EUS-guided FNA in suspected CC cases, positively impacting treatment decisions for most patients (138).
Intraductal US (IDUS)
IDUS involves inserting high-frequency US probes into the common bile duct during ERCP (139). Malignant biliary strictures typically present as a hypoechoic infiltration of the ductal wall with irregular margins (140,141). Low echo areas invading proximal tissue are crucial for diagnosis, and assessing invasion longitudinally is vital before surgery (142). In a study with 62 patients, IDUS showed 90% sensitivity and 93% specificity for biliary strictures (143). Stavropoulos et al. conducted a study which determined that IDUS increased ERCP diagnostic accuracy from 58% to 90% in patients with biliary strictures and no visible mass on CT (144).
PET
PET, particularly when combined with CT (PET/CT), is a non-invasive method that detects 18F-fluorodeoxyglucose (FDG) uptake in cancer cells, making it a standard for staging various cancers, including CC (145,146). When integrated with abdominal MRI, PET/CT provides comprehensive anatomical and functional insights, enhancing both diagnosis and staging (147).
Studies have demonstrated PET’s high sensitivity (up to 92%) and specificity (up to 93%) for detecting CC, although its effectiveness varies depending on the tumor’s size and type. For instance, PET is more sensitive for tumors at least 1 cm in size compared to infiltrative forms of CC (148-153). Sensitivity also differs by CC stage—being lower for T2 stages and higher for T3 and T4 stages (154). For lymph node and distant metastasis detection, sensitivity and specificity range from 41.7% to 87.5% (155,156).
At the Memorial Sloan Kettering Cancer Center, PET/CT showed an overall sensitivity of 80% for identifying primary tumors, significantly impacting treatment management (154). Despite its utility, PET can yield unreliable results in patients with inflammatory biliary conditions like PSC or cholangitis due to false positives, and in mucinous CC where poor FDG uptake can lead to false negatives (155-158).
Optical coherence tomography (OCT)
OCT employs infrared light to create detailed cross-sectional images. It can provide high-resolution views of the biliary tree, which match to histological results (155,159). In the last decade, OCT has proven valuable in spotting early cancers and is expected to gain even more significance with the discovery of additional biomarkers (160).
Nondiagnostic work-up
In the presence of appropriate clinical and radiological findings, non-diagnostic cytology or biopsy results should not rule out CC (80). In the absence of alternative explanations for biliary strictures, patients should be managed as if they have CC. However, it is important to note that around 10% to 15% may have benign lesions upon further examination (158,161). Currently, there are no established surveillance programs for high-risk patients. Some suggest annual monitoring using non-invasive methods like tumor markers and imaging, with invasive procedures reserved for cases where cytology, biopsies, or stenting are warranted (162).
Tumor spread
The spread of CC is pivotal in planning treatment and determining staging. CC can spread in several ways including breaching the mucosa and submucosa, traveling through bile ducts, invading perineural and vascular tissues, affecting lymph nodes, spreading to neighboring structures, or forming distant metastases. The extent of spread, whether superficial mucosal extension or deeper submucosal infiltration, dictates the surgical margins required, with recommended margins exceeding 1 cm for infiltrative tumors and 2 cm for nodular or papillary types to ensure complete removal of cancerous cells (163,164).
Perineural invasion, a common occurrence in CC affecting about 75% of cases, typically indicates a poor prognosis, with survival rates notably lower for patients with this type of invasion (165-170). HiCC and distal ECC can directly invade liver tissue and nearby organs like the pancreas or duodenum, respectively. This pattern of direct or longitudinal extension along the biliary ducts is critical in understanding tumor behavior and planning surgical interventions such as partial hepatectomy with caudate lobectomy for improved survival outcomes (170-172).
Lymph node metastasis is a significant prognostic factor; about 45% of CC cases exhibit lymph node involvement. Surgical resection outcomes are better for patients with fewer lymph node metastases, highlighting the importance of accurate nodal assessment during staging (170,172-180).
Portal vein involvement is observed in roughly 30% of CC situated at the biliary confluence, frequently resulting in hepatic lobar atrophy with compensatory hypertrophy of the contralateral lobe (173,174,181). Distant metastases, when present at diagnosis, severely limit survival prospects, emphasizing the importance of comprehensive staging (181).
Staging
ICC and ECC are staged differently (87).
ICC
The American Joint Committee on Cancer (AJCC) staging system is commonly used to classify ICCs as primary liver malignancies using TNM (tumor, node, metastases) staging (Table 4) (182,183). Recently, the AJCC has included size as a prognostic factor, with a cutoff of 2 cm to identify very early tumors. The AJCC staging system for primary liver tumors was developed using data from patients with HCCs, which means it may not accurately reflect the characteristics of ICC (184). To address this, Nathan et al. (185) proposed a staging system for ICC based on factors like the number of tumors, vascular invasion, lymph node status, and presence of metastatic disease. Multiple tumors may indicate satellite neoplastic deposits or intrahepatic metastatic disease, and vascular and lymph node invasion are associated with poor survival.
Table 4
Stage | Tumor | Node | Metastasis |
---|---|---|---|
0 | Tis | N0 | M0 |
Ia | T1a | N0 | M0 |
Ib | T1b | N0 | M0 |
II | T2 | N0 | M0 |
IIIA | T3 | N0 | M0 |
IIIB | T4 | N0 | M0 |
IIIB | Any T | N1 | M0 |
IV | Any T | Any N | M1 |
AJCC, American Joint Committee on Cancer; Tis, tumor in situ; T1a, solitary tumor without vascular invasion ≤5 cm; T1b, solitary tumor without vascular invasion >5 cm; T2, solitary tumor with vascular invasion or multiple tumors; T3, tumor grown through the visceral peritoneum; T4, tumor with direct invasion of adjacent organs other than the; N0, no regional lymph node metastasis; N1, regional lymph node metastasis; M0, no distant metastasis; M1, distant metastasis.
ECC
As ECCs are situated near critical blood vessels such as the portal vein and hepatic artery. The assessment of vascular invasion aids in predicting the feasibility of surgery and the extent of tissue removal required to obtain negative margins. The AJCC staging system for ECC (Table 5) (186,187) is based on pathology findings that help predict the patient’s outlook. However, it does not offer much guidance in determining the feasibility of surgery (173). The Bismuth-Corlette classification effectively delineates the tumor location and its spread within the bile ducts, but it does not provide insight into surgical resectability. Additionally, the AJCC has developed a staging system for PCC outlined in Table 6 (188).
Table 5
Stage | Tumor | Node | Metastasis |
---|---|---|---|
0 | Tis | N0 | M0 |
I | T1 | N0 | M0 |
IIA | T2 | N0 | M0 |
IIA | T1 | N1 | M0 |
IIB | T2–T3 | N1 | M0 |
IIB | T3 | N0 | M0 |
IIIA | T1–T3 | N2 | M0 |
IIIB | T4 | Any N | M0 |
IV | Any T | Any N | M1 |
AJCC, American Joint Committee on Cancer; Tis, carcinoma in situ; T1, tumor confined to <5 mm into bile duct wall; T2, tumor confined to 5–12 mm into bile duct wall; T3, tumor >12 mm into bile duct wall; T4, tumor invades nearby blood vessels; N0, no regional lymph node metastasis; N1, regional lymph node metastasis; M0, no distant metastasis; M1, distant metastasis.
Table 6
Stage | Tumor | Node | Metastasis |
---|---|---|---|
0 | Tis | N0 | M0 |
I | T1 | N0 | M0 |
II | T2a or T2b | N0 | M0 |
IIIA | T3 | N0 | M0 |
IIIB | T4 | N0 | M0 |
IIIC | Any T | N1 | M0 |
IVA | Any T | N2 | M0 |
IVB | Any T | Any N | M1 |
AJCC, American Joint Committee on Cancer; Tis, carcinoma in situ; T1, tumor in deeper layers of bile duct wall; T2a, tumor grown through bile duct wall into fat tissue; T2b, tumor grown through bile duct wall into liver tissue; T3, tumor invaded blood vessels; T4, tumor invades main blood vessels; N0, no regional lymph node metastasis; N1, regional lymph node metastasis; M0, no distant metastasis; M1, distant metastasis.
Therapy
Surgical resection
Resection remains the sole potential cure for CC. For patients with unresectable disease, median survival typically ranges from 6 to 12 months. Despite surgery, the 5-year survival rate is only around 30%, a modest improvement that warrants careful consideration on a case-by-case basis, balancing benefits against post-operative risks (38,189). Resectable ICC and HiCC, as well as many cases of ECC, typically necessitate partial hepatectomy to optimize the chance of achieving negative resection margins. Prior to surgery, patients undergo a thorough evaluation to ensure they are fit for major surgery, have no evidence of metastatic disease, and have the potential for cancer-free resection margins (190). If any of these criteria are not met, surgical intervention is not recommended, and palliative care options should be explored.
Preoperative patient preparation
Many patients are deemed unsuitable for surgery due to comorbidities or advanced age. A thorough assessment of overall health and medical conditions is critical before considering surgery (170). Studies have shown that low preoperative serum albumin levels (<3 g/dL) and high bilirubin levels (>10 mg/dL) are linked to increased postoperative mortality and reduced survival (191,192). The efficacy of preoperative biliary drainage (PBD) in jaundiced patients is debated, as it might increase infection risk and extend hospital stays without clear benefits, although it may be considered under specific conditions such as cholangitis or severe malnutrition (133,193). PBD is suggested when major liver resections are planned or in cases with coagulation disorders, generally requiring a delay in surgery to improve liver function (172,194,195). PBD has been noted to decrease postoperative liver insufficiency in patients with high bilirubin levels (196). For extensive liver resections, preoperative volumetric or functional liver studies are advisable to prevent liver failure due to insufficient liver remnant (172).
Assessment of resectability
A systematic analysis of all available clinical and radiological information is crucial to assess whether surgery is feasible and to avoid unnecessary procedures. Despite advancements in diagnostic methods, roughly 16–25% of patients have more advanced disease at the time of their abdominal exploration, which prohibits resection at the time of laparotomy (197). The main factors influencing resectability include the tumor’s extent within the bile ducts, involvement of hepatic tissue, degree of vascular invasion, hepatic lobar atrophy, and presence of metastatic disease (198). Research on 294 cases of CC revealed that tumors located more distally are associated with higher resectability rates (84). Determining resectability is particularly challenging in patients with HiCC, with about half of them considered unresectable upon exploration. Radiological criteria defining unresectability in HiCC patients are outlined in Table 7 (173,174). Distal ECC and ICC with AJCC stages III and IV are typically deemed unresectable (Table 8) (73,199-209).
Table 7
Local tumor invasion |
(I) Bilateral hepatic duct involvement up to secondary biliary radicles |
(II) Encasement or occlusion of the main portal vein |
(III) Unilateral tumor extension to secondary biliary radicles with contralateral portal vein or hepatic artery encasement or occlusion |
(IV) Hepatic lobar atrophy with contralateral portal vein or hepatic artery encasement or occlusion |
(V) Hepatic lobar atrophy with contralateral tumor extension to secondary biliary radicles |
Metastatic disease |
(I) Lymph node metastases beyond the hepatoduodenal ligament (N2 lymph nodes)† |
(II) Distant metastasis (e.g., lung, liver, peritoneal) |
†, peripancreatic, periduodenal, periportal, celiac, or superior mesenteric lymph nodes.
Table 8
Author, year | Resections, n | Overall 5-year survival (%) | R0 5-year survival (%) |
---|---|---|---|
Yin et al., 2021 (199) | 151 | 12.91 | NR |
Buettner et al., 2019 (200) | 1,013 | 43.3 | NR |
Si et al., 2017 (201) | 251 | 32.3 | NR |
Doussot et al., 2015 (202) | 188 | 45 | NR |
DeOliveira et al., 2007 (73) | 34 | 40 | 63 |
Miwa et al., 2006 (203) | 41 | 29 | 36 |
Jan et al., 2005 (204) | 81 | 15 | NR |
Ohtsuka et al., 2003 (205) | 50 | 23 | NR |
Uenishi et al., 2001 (206) | 28 | 27 | 67 |
Inoue et al., 2000 (207) | 52 | 36 | 55 |
Yamamoto et al., 1999 (208) | 83 | 23 | 53 |
Madariaga et al., 1998 (209) | 34 | 35 | 41 |
NR, not reported.
Invasion of the main portal vein or the blood vessels supplying the planned hepatic remnant is a contraindication for surgery. However, recent findings suggest that in highly selective cases, en-bloc resection with vascular reconstruction may achieve negative margins and potential cure, with only a 10% perioperative mortality rate (175,186). Staging laparoscopy is increasingly recommended to reduce unnecessary laparotomies by identifying metastatic lesions in the liver and peritoneal cavity (210). Laparoscopy detects unresectability in about 25% of patients initially deemed suitable for surgery based on preoperative imaging, with an overall accuracy of 50% (211,212). Additionally, laparoscopy allows for intraoperative hepatic US, which can improve diagnostic accuracy by up to 42% (191). One of the limitations of laparoscopy is its limitation in detecting vascular or nodal involvement (208,209). Peritoneal washings to obtain cytology specimens have not been shown to predict occult metastasis (193). Ultimately, true resectability is determined after a complete abdominal exploration.
Operative procedures and survival
Surgical goals aim for complete tumor removal with clear histological margins (known as R0 resection), which significantly improves survival compared to surgeries with positive margins (R1 or R2 resection) (174,194,198). To confirm histologically negative margins, many authors advocate the use of intraoperative frozen section to examine the state of the bile ducts at the resection sites (173). A recent important study from the Memorial Sloan Kettering Cancer Center (MSKCC) assessed the clinical significance of these frozen sections in HiCC patients (213). The study aimed to determine their role in planning the extent of surgical dissection. Frozen sections were obtained from 101 patients, with 20 (19.8%) showing positive margins. Among those with negative results, 8 (9.8%) were later found to have positive margins on final histopathology. This study found the intraoperative frozen section to be 71.4% sensitive, 100% specific, with a positive predictive value of 100% and a negative predictive value of 80.2% (214).
ICC
Surgical therapy for ICC is based on the same principles used for hepatic resections performed for HCCs or secondary tumors. The operative approach should be aimed at ensuring R0 resection margins whenever it is possible. Lymph node dissection during resection of ICC is not recommended as it does not improve patients’ survival (215,216). Recent outcomes after surgical resection have improved, with 5-year survival rates now ranging from 20% to 40% (Table 9) (73,169,195,217-226). Poor prognostic indicators include positive resection margins, lymphatic and vascular invasion, and periductal infiltrating disease (227,228). Recurrence most commonly occurs within the liver (229).
Table 9
Author, year | Resections, n | Liver resection (%) | R0 resection (%) | Overall 5-year survival (%) | R0 5-year survival (%) |
---|---|---|---|---|---|
Geers et al., 2020 (217) | 88 | NR | NR | 33 | NR |
Juntermanns et al., 2019 (218) | 76 | NR | 69 | 43 | 30 |
Hasegawa et al., 2007 (219) | 49 | 92 | 78 | 40 | 50 |
DeOliveira et al., 2007 (73)† | 173 | 20 | 19 | 10 | 30 |
Dinant et al., 2006 (220) | 99 | 38 | 31 | 27 | 33 |
Hemming et al., 2005 (221) | 53 | 98 | 80 | 35 | 45 |
Rea et al., 2004 (222) | 46 | 100 | 80 | 26 | 30 |
Kawasaki et al., 2003 (195) | 79 | 96 | 68 | NR | 40 |
Kawarada et al., 2002 (223) | 87 | 75 | 64 | 26 | NR |
Jarnagin et al., 2001 (169) | 80 | 78 | 78 | 37 | NR |
Tabata et al., 2000 (224) | 75 | 71 | 60 | 23 | 40 |
Kosuge et al., 1999 (225) | 65 | 88 | 52 | 35 | 52 |
Miyazaki et al., 1998 (226) | 76 | 86 | 71 | 26 | 40 |
†, 5-year survival for patients with R1 resection is 6%. NR, not reported.
PCC
Curative surgery of HiCC usually requires the excision of the extrahepatic bile duct, regional lymphadenectomy, cholecystectomy, and often partial hepatectomy (214). The rationale behind performing partial hepatectomies in HiCC is to ensure histologically negative margins. Several studies have shown that this strategy increases R0 resections in up to 80% of patients (173,205,221). Extended lymphadenectomy is not recommended as there is no evidence showing survival advantage (172,175).
Radical resection of HiCC carries a perioperative mortality rate of 5–10%, especially with extended hepatectomy involving five or more segments (222,229,230), primarily due to the increased risk of postoperative liver failure. Portal vein embolization (PVE) is a beneficial preoperative measure when extensive liver resections are anticipated as it induces compensatory hypertrophy of the remaining liver parenchyma by occluding the main portal vein branch to the lobe slated for resection (231). This can increase the volume of the remaining liver by 12–20%, reducing the risk of postoperative liver dysfunction. PVE is particularly useful when the expected liver remnant volume is less than 20–25% of the total liver volume in patients with normal liver function, or when it is 40% or less in patients with compromised liver function (232,233). Favorable outcomes are associated with R0 resections, absence of lymph node metastasis, no perineural invasion, and well-differentiated histological grade (173,191).
ECC
The aim of achieving negative resection margins also applies to ECC. Resectability rates of up to 90% have been reported for distal extrahepatic tumors (84,234). Complete removal of distal ECC typically requires a pancreaticoduodenectomy (Whipple procedure) (80,235,236). However, extended lymphadenectomy is not recommended as it does not improve survival and is linked to increased perioperative morbidity (221). Segmental bile duct excision is rarely feasible, except for cases of CC located in the middle of the common duct without periductal invasion or spread to surrounding structures. Only 10% of patients undergoing bile duct excision alone achieve curative resection margins on final pathology (233,237). When managing patients with CC originating midway along the extrahepatic duct, surgeons need to decide whether a pancreaticoduodenectomy or a partial hepatectomy is more appropriate depending on the tumor’s extent.
The 5-year survival rates for these patients following curative resections are detailed in Table 10 (73,157,234,237-248). Key factors associated with poor outcomes include positive surgical margins and lymph node involvement (249,250). Other unfavorable prognostic factors include pancreatic and duodenal invasion, perineural invasion, and poorly differentiated histology (249).
Table 10
Author, year | Resections, n | Overall 5-year survival (%) | R0 5-year survival (%) |
---|---|---|---|
Tjaden et al., 2023 (238) | 196 | 40 | 52† |
Kurahara et al., 2022 (239) | 59 | NR | 51† |
Kamarajah et al., 2021 (240) | 6,318 | 27 | NR |
Tawarungruang et al., 2021 (241) | 80 | 35 | NR |
Strijker et al., 2019 (242) | 620 | 22 | NR |
Kim et al., 2017 (243) | 132 | 48 | NR |
Komaya et al., 2017 (244) | 370 | 41 | NR |
Miura et al., 2015 (245) | 133 | 33 | NR |
van der Gaag et al., 2012 (246) | 175 | 26 | NR |
DeOliveira et al., 2007 (73) | 229 | 23 | 27 |
Cheng et al., 2007 (234) | 112 | 25 | 26 |
Murakami et al., 2007 (247) | 36 | 50 | 62 |
Nagorney et al., 2006 (157) | 49 | 43 | NR |
Yoshida et al., 2002 (248) | 26 | 37 | 44 |
Fong et al., 1996 (237) | 45 | 27 | 54† |
†, patients had node negative tumors as well. NR, not reported.
Liver transplantation (LT) for Klatskin tumors
LT is emerging as a treatment option for unresectable CC in patients without evidence of metastatic disease (251). Suitable candidates are those who require total hepatectomy to achieve clear margins or those with liver failure precluding hepatic resection. Early transplantations for CC showed early recurrence rates exceeding 50% and a 5-year survival of 10–20% (252-254). However, recent studies have shown promising outcomes in highly selected patients undergoing neoadjuvant protocols. For instance, Sudan et al. (255) reported a 45% tumor-free survival in patients who received neoadjuvant chemoradiation before transplantation with a median follow-up of 7.5 years before transplantation. Similarly, Becker et al. and Sotiropoulos et al. observed 5-year survival rates of 45% and 33%, respectively, in patients diagnosed with CC (249,256). At the Mayo Clinic, Rosen et al. (257,258) developed a LT protocol for HiCC, achieving a disease-free 5-year survival of 82%. This protocol is also applicable to unresectable CC in PSC patients. Patients eligible for this protocol undergo neoadjuvant chemoradiation therapy, followed by staging laparotomy to rule out metastatic disease, and then receive living-related or cadaveric LT. Currently, LT for CC is limited to highly selected patients in specialized centers.
LT for intra-hepatic CC
LT for ICC is outlined in recent recommendations by the International Liver Transplantation Society Transplant Oncology Consensus Conference. It suggests LT as an option for early-stage ICC in cirrhotic livers and for advanced ICC in noncirrhotic livers after neoadjuvant therapy, emphasizing adherence to protocols due to moderate evidence levels (259,260). Ziogas et al. reviewed 18 studies involving 355 LT patients for ICC, showing 1-, 3-, and 5-year overall survival rates at 75%, 56%, and 42%, and recurrence-free rates at 70%, 49%, and 38%, respectively. Superior outcomes were noted in patients with single, small tumors (≤2 cm) (261). Additionally, Huang et al. used Surveillance, Epidemiology, and End Results (SEER) database data for a propensity-score matched analysis comparing liver resection and LT outcomes in ICC patients. They reported significantly better survival rates with LT over resection, and highlighted particularly favorable results in early-stage tumors and in those treated with neoadjuvant chemotherapy (262).
Biologics and immunotherapy
Cancers employ various strategies to evade immune responses, including modifying the tumor microenvironment, expressing immune checkpoint proteins, and reducing major histocompatibility complex (MHC) expression. Scientists are exploring several biomarkers to predict how well immunotherapy will work. For instance, PD-L1 expression is linked to better responses to immune checkpoint inhibitors in specific subtypes cancers. When analyzing CC samples, researchers found that 62% of tumor-associated macrophages and 72% of the tumor front tested positive for PD-L1. Another important biomarker is neoantigen load, which can predict how well patients will respond to checkpoint inhibitors. Approximately 6% of CCs exhibit hypermutation, and 2% have microsatellite instability (263). In a study evaluating pembrolizumab, an anti-PD-1 monoclonal antibody, in patients with microsatellite instability CC, the disease control rate was 100%, with one patient achieving a complete response (264,265). However, there is limited clinical evidence regarding the efficacy of immune checkpoint inhibitors in microsatellite stable CCs. The KEYNOTE-028 basket trial investigated pembrolizumab’s safety and effectiveness in patients with PD-L1 positive biliary tract cancers. The overall response rate was 13%, with response duration ranging from 5.4 to 9.3 months (264,265). A larger phase II study, KEYNOTE-158, included 104 patients with biliary tract cancers that had either progressed or were intolerant to standard therapy. Preliminary results showed that six patients achieved a partial response, and 17 had stable disease. Median overall survival was 7.2 months in patients with a PD-L1 combined positive score <1, compared to 9.6 months in those with a PD-L1 combined positive score ≥1 (265,266). Nivolumab, another anti-PD-1 monoclonal antibody, has gained attention in recent years and was evaluated in a phase II trial. Out of 45 evaluable patients, 10 achieved a partial response, and 17 had stable disease. The disease control rate was 60%. Notably, all responders had microsatellite stable tumors, with 6- and 12-month overall survival rates of 71.4% and 52.3%, respectively, and 6- and 12-month progression-free survival rates of 35.2% and 24.1%, respectively (267,268).
Adjuvant therapy
Given the high local and distant recurrence rate after radical resections, there has been a concerted effort to explore the efficacy of chemotherapy, radiotherapy, or chemoradiation therapy in the neo-adjuvant and adjuvant settings. However, there is a lack of a universally endorsed standard protocol for adjuvant therapy for CCs.
Neoadjuvant therapy
Neoadjuvant therapy has shown to be associated with enhanced patient outcomes and extended median overall survival in comparison to surgical resection alone (269). Preoperative chemoradiation therapy’s role has been scrutinized in a limited study of patients with ECC (250). In a study by McMasters et al., involving nine subjects subjected to neoadjuvant therapy, three individuals exhibited a pathological complete response, with all subjects achieving negative resection margins (250,270). However, further trials are imperative to comprehensively evaluate its therapeutic efficacy.
Adjuvant radiotherapy
The efficacy of adjuvant radiotherapy in influencing patient outcomes remains uncertain. Studies investigating postoperative external beam radiation, with or without intraoperative radiotherapy and intraluminal radiotherapy (brachytherapy), in the adjuvant setting have not yielded significant benefits following R0 resections (271,272). Conversely, some research suggests potential benefits for patients with positive resection margins (273,274). Research conducted by Todoroki et al. demonstrated a 5-year survival rate of 34% among patients with R1 resections who received adjuvant radiotherapy (intraoperative and external beam), compared to 14% among those who underwent surgery alone (275). However, the effectiveness of adjuvant radiotherapy appears to vary across different types of CC, with some studies suggesting potential benefits for ECC. Nonetheless, the overall impact of adjuvant radiotherapy on patient outcomes remains ambiguous (276).
Adjuvant chemotherapy
Previously, postoperative chemotherapy failed to demonstrate significant survival benefits (277,278). A multicenter RCT evaluated the impact of postoperative chemotherapy, using mitomycin C and 5-fluorouracil (5FU), compared to surgery alone in patients with pancreatic and biliary duct cancers (279). Among 508 patients who underwent R0 resection, including 139 with CC, no survival advantage was observed in patients who received chemotherapy (280). A recent retrospective chart review corroborated these findings, indicating that adjuvant chemotherapy did not improve patient survival and was associated with a 20% increased risk of adverse events (281). However, the phase III trial BILCAP conducted in 2019 demonstrated improved outcomes in patients treated with capecitabine compared to those in the observational group. Although the trial did not meet its primary endpoint in the intention-to-treat analysis (282), a long-term analysis by the same authors highlighted the role of capecitabine as the standard post-resection therapy, as it continued to enhance long-term patient survival (283).
Adjuvant chemoradiation therapy
The potential of chemotherapeutic agents to enhance the effectiveness of radiotherapy has been explored in the adjuvant setting, showing positive outcomes solely for distal ECC. In a retrospective cohort study involving 94 individuals who underwent resection for CC, 34% received postoperative chemoradiation (284). Patients who received adjuvant therapy showed longer survival compared to those who underwent surgery alone, with a median survival of 41 versus 24 months, respectively (285). Similar findings were reported in other retrospective studies, indicating that patients with distal ECC experienced better survival outcomes following adjuvant therapy compared to those with more proximal CC (286,287). Hughes et al. observed a slight survival advantage at 5 years in patients receiving postoperative chemoradiation therapy for distal ECC compared to those undergoing surgical resection alone [35% versus 27% (288)]. Furthermore, Figueras et al. revealed that adjuvant chemoradiation therapy did not significantly improve survival in cases of HiCC (289). Larger-scale studies are needed to validate these findings.
Evidence supporting the use of adjuvant chemoradiation therapy for ICC is scarce. In a recent retrospective study involving 3,839 patients, Shinohara et al. found significant differences in overall survival rates among groups receiving different treatments: surgery alone, surgery plus adjuvant radiation therapy (P=0.014), radiation therapy alone, and no treatment (P<0.0001) (280). The combination of surgery and adjuvant radiation therapy showed the most substantial benefit in terms of overall survival [hazard ratio (HR) =0.40; 95% confidence interval (CI): 0.3–0.47], followed by surgery alone (HR =0.49; 95% CI: 0.44–0.54) and radiation therapy alone (HR =0.68; 95% CI: 0.59–0.77) compared to no treatment. However, there is a notable absence of RCTs assessing the effectiveness of adjuvant therapy following R0 resections of CC. Additionally, most current studies are limited by their small sample sizes and retrospective nature, often combining CC cases with those of gallbladder and pancreatic cancers.
Palliation
Approximately half of patients diagnosed with CC, are deemed suitable only for palliative treatments. This classification often results from either the advanced stage of the disease upon diagnosis or the presence of substantial comorbidities that render surgical intervention unfeasible (72,173). Consequently, palliative care assumes a crucial role. The principal objective of palliative interventions is to enhance the quality of life by alleviating symptoms and extending survival through the prevention of cholestatic liver failure. When confronted with incurable CC, obtaining tissue diagnosis whenever feasible is imperative for guiding the planning of palliative interventions.
Biliary drainage
Alleviating biliary obstruction is a primary concern for the palliation of CC patients. The aim of biliary decompression is to resolve obstructive jaundice, pain, and itching while also preventing complications like cholangitis and liver failure (290). There are various methods for draining the bile system, such as endoscopic, percutaneous, and surgical bypass. The best approach for palliative biliary decompression should be effective, long-lasting, and carry minimal risks.
Biliary endoprosthesis (stenting)
Biliary stenting, essential for managing unresectable CC, can be performed via endoscopic or percutaneous approaches. Endoscopic stenting is more common, but percutaneous stenting is used when endoscopic methods are not feasible, offering internal, external, or combined configurations. While external percutaneous stents facilitate bile drainage, they can cause discomfort and electrolyte imbalances due to the lack of enteric recycling (291,292).
Endoscopic stents come in metallic and plastic (polyethylene) varieties. Metallic stents, both uncovered and covered, provide better patency and require fewer changes than plastic stents, which typically need replacement every 2 to 3 months. Metallic stents can last up to 9 months or more, making them a preferable choice for patients expected to survive longer than 5 months due to their cost-effectiveness and reduced need for hospital interventions (292-296). RCTs have shown that metallic stents, especially self-expanding ones, are superior in palliating both ECC and HiCC due to their larger diameters and longer patency (297-299).
Draining approximately 25% of the hepatic parenchyma is generally sufficient to relieve symptoms without infection risks. However, stents, particularly those in the hilar region, may require reintervention due to blockage, with about 30% of cases needing further attention (270,285,300-302). Covered stents tend to have higher patency rates but can increase the risk of cholecystitis by 5% due to cystic duct occlusion (292,303).
Surgical biliary drainage
The biliary-enteric anastomosis can be conducted via an open or laparoscopic approach. Comparative studies between surgical and non-surgical biliary drainage have revealed similar overall palliative effects, albeit with heightened perioperative morbidity and mortality rates (304,305). Surgical drainage presents the benefit of higher patency rates and eliminates the requirement for recurrent stent exchanges due to clogging, a common issue with endoscopic or percutaneous stent usage (295). Presently, prime candidates for surgical drainage encompass patients diagnosed with unresectable CC during exploration, individuals unsuitable for repeat endoscopic or percutaneous stent exchanges, and those anticipated to have prolonged survival and deemed fit for surgery (296).
Palliative radiotherapy
Palliative radiotherapy can offer benefits to patients with locally advanced unresectable CC or those who have undergone palliative bypass, especially if distant metastases are absent. This treatment approach can help alleviate pain, maintain biliary patency, and improve overall patient survival (306,307). The two primary radiotherapy methods employed are external beam radiation, typically delivering doses of 30 to 50 Gy, and intraluminal brachytherapy, administering 10 to 20 Gy, either individually or in combination. Intraluminal brachytherapy employs iridium-192 seeds mounted on a catheter, which is positioned across the tumor via an endoscopic or percutaneous approach (308). This method allows for more precise delivery of radiation without harming surrounding organs. Studies have shown that a combination of both modalities tends to yield the most favorable outcomes, with median patient survival ranging from 9 to 14 months (303,309-311). Palliative radiotherapy is associated with increased risks of complications such as cholangitis, gastroduodenitis, and prolonged hospitalizations compared to best supportive care, leading to its limited use in some centers (312). Additionally, higher radiation doses (exceeding 55 Gy) may be necessary for improved survival but come with elevated toxicity rates (313). Further controlled studies are needed to thoroughly assess the efficacy and safety of these palliative interventions. For ICC, brachytherapy can be delivered via radioembolization using yttrium-90 microspheres (314). This method has demonstrated partial response in 27% of patients and stable disease in 68%, with minimal side effects. Consequently, it has emerged as a leading palliative modality in centers equipped with this technology (315).
Palliative chemotherapy
Chemotherapy for CC has historically seen limited success in improving survival rates. Initially, 5FU alone showed modest 10% response rates. Combining 5FU with agents like leucovorin, interferon-alpha, cisplatin, and oxaliplatin later improved response rates to 25–55%, with median survival between 6 to 12 months (316-319). Oral prodrugs of 5FU, such as uracil-tegafur and capecitabine, were also tested, with capecitabine and cisplatin achieving 41% response rates and 12-month median survival (320-322). Gemcitabine, either alone or in combination with cisplatin and oxaliplatin, reported response rates up to 36% and survival of 10 to 15 months (323-326). Analysis of studies from 1985 to 2006 highlighted gemcitabine plus platinum compounds as the most effective, showing the highest patient response rates (327,328). Techniques like transcatheter arterial chemoembolization (TACE) and transcatheter arterial chemoinfusion (TACI) were explored for unresectable ICC but lacked demonstrable survival benefits, calling for more evidence (329-331). Recently, the TOPAZ-1 trial showed that durvalumab with gemcitabine and cisplatin extended survival significantly compared to chemotherapy alone (332,333). KEYNOTE-966 also found benefits in combining pembrolizumab with gemcitabine and cisplatin, extending median survival to 12.7 months from 10.9 months (334). Additionally, trials like ClarIDHy and a phase II study on pemigatinib have focused on chemotherapy-refractory patients with specific genetic alterations, offering new therapeutic possibilities for targeted subgroups (335).
Photodynamic therapy (PDT)
PDT is an emerging palliative approach that entails intravenous administration of photosensitizing agents with an affinity for malignant cells. Following administration, specific light wavelengths activate the photosensitizer, inducing necrosis in tumor cells (336). The depth of tumor necrosis typically ranges from 4 to 6 mm. Currently, PDT is employed as a palliative adjunct alongside biliary stenting for nonresectable CCs. Several case series have documented enhanced quality of life, biliary drainage, and survival rates in patients with advanced CCs following PDT (322). Morover, a RCT compared PDT combined with endoscopic stenting to stenting alone in unresectable CC patients (337). The trial was prematurely halted due to the marked superiority of PDT over simple stenting. The PDT group exhibited prolonged median survival (493 versus 98 days), improved biliary drainage, and enhanced quality of life compared to the stenting-alone group. In recent investigations, PDT was explored as a neoadjuvant approach preceding surgical resection of advanced HiCC in seven patients (338). All patients achieved tumor-free resection margins, with a 1-year recurrence-free survival rate of 83%. Another study corroborated the safety of PDT as a neoadjuvant therapy, demonstrating its efficacy in downstaging tumors from unresectable to resectable (339). Primary side effects of PDT include photosensitivity due to photosensitizer administration and cholangitis related to biliary instrumentation (340).
Other palliative measures
Several alternative palliative approaches have demonstrated efficacy in specific patient cohorts. Radiofrequency ablation (RFA) has been utilized for patients deemed unsuitable for surgery, particularly those with small ICC (341). In a single-center cohort study of individuals with unresectable ICC, TACE has exhibited an increased survival benefit compared to best supportive care, with a median survival of 23 months (342). Hepatic arterial chemotherapy infusion enables targeted delivery of chemotherapy to the tumor site and has been established as a safe modality (343). Similarly, localized ablation of tumor cells via high-intensity intraductal US has shown promise (344). Another avenue of interest is the use of molecular targeting agents for CC chemoprevention and adjuvant therapy, such as cyclooxygenase-2 and nitric oxide inhibitors (345). However, the clinical applicability of these emerging therapies necessitates further investigation before widespread adoption can be justified.
Conclusions
Over the last few years, several advances have occurred concerning the diagnosis, treatment, and palliation of CC. The diagnosis, staging, and further management of patients affected by this disease is complex and requires the expertise of different disciplines. Therefore, a multidisciplinary approach is recommended to optimize the outcome of patients with suspected or proven CC.
Acknowledgments
Funding: None.
Footnote
Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-144/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-144/coif). M.M. serves as an unpaid editorial board member of Chinese Clinical Oncology from April 2024 to March 2026. The other 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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