What are the recommended treatment options for cholangiocarcinoma by stage and anatomic location, including surgery, liver transplantation, adjuvant capecitabine, first‑line gemcitabine plus cisplatin, targeted therapy for FGFR2 fusions or IDH1 mutations, immunotherapy for MSI‑high/TMB‑high tumors, and second‑line regimens?

Cholangiocarcinoma Treatment Guidelines

Treatment by Stage and Anatomic Location

For resectable cholangiocarcinoma, surgical resection with tumor-free margins >5 mm is the only curative treatment, with the specific surgical approach determined by anatomic location: intrahepatic disease requires anatomic hepatic resection with lymphadenectomy, hilar tumors require en bloc bile duct resection ± hepatectomy based on Bismuth classification, and distal tumors require pancreatoduodenectomy. 1

Resectable Disease: Surgical Approaches

Intrahepatic Cholangiocarcinoma

• Anatomic hepatic resection of involved segments or lobe with regional portahepatis lymphadenectomy is the standard curative approach, achieving R0 resection with margins >5 mm 1, 2
• Expected median survival without hilar involvement is 18-30 months, with 5-year survival rates up to 40% 1, 2
• Major hepatic resection requires appropriate surgical and anesthetic experience, with postoperative mortality approximately 10% in Western referral centers 1, 2

Hilar (Perihilar) Cholangiocarcinoma

The surgical strategy follows the Bismuth-Corlette classification 1:

• Types I and II: En bloc resection of extrahepatic bile ducts and gallbladder, regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy 3
• Type III: As above plus right or left hepatectomy 3
• Type IV: As above plus extended right or left hepatectomy 3
• Segment 1 removal should be considered with stages II-IV, as it may preferentially harbor metastatic disease 1
• Median survival with perihilar tumor is 12-24 months, with 5-year survival approximately 20% 1

Distal Extrahepatic Cholangiocarcinoma

• Pancreatoduodenectomy is the standard operation, managed identically to ampullary or pancreatic head cancers 1
• Reported 5-year survival is currently 20-30% 1

Critical Preoperative Considerations

Mandatory Staging

Comprehensive preoperative staging is mandatory before surgical resection 1, 2:

• Chest imaging to exclude pulmonary metastases 1, 2
• CT abdomen or MRI/MRCP to assess local extent, liver involvement, vascular invasion, and lymphadenopathy 1, 2
• Staging laparoscopy to detect occult peritoneal or superficial liver metastases in patients considered resectable on imaging 3, 1, 2

Biliary Drainage

• Avoid routine preoperative biliary drainage except for acute cholangitis or severe malnutrition, as inadequate drainage increases sepsis risk and surgical complications 1, 2

Adjuvant Therapy for Resected Disease

Adjuvant capecitabine should be administered following curative-intent resection 4, 5:

• This is the standard postoperative treatment for resectable disease 4
• CCAs at early stages should undergo tumor resection surgery followed by postoperative treatment with capecitabine 5

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Advanced/Metastatic Disease: Systemic Therapy

First-Line Therapy

Gemcitabine plus cisplatin plus durvalumab is now the preferred first-line regimen for advanced/metastatic cholangiocarcinoma, showing modest but statistically significant improvement in median overall survival compared to gemcitabine-cisplatin alone 6, 7:

• Gemcitabine plus cisplatin alone remains acceptable if durvalumab is unavailable, providing a 3.6-month survival benefit over gemcitabine monotherapy 1, 2, 6

Molecular Profiling and Targeted Therapy

Molecular profiling via next-generation sequencing should be performed at initiation of first-line therapy to identify druggable mutations for targeted therapies 1, 7:

FGFR2 Fusions/Rearrangements

• FGFR inhibitors are indicated for FGFR2 fusion-positive cholangiocarcinoma after progression on first-line chemotherapy 6, 7, 5
• These targeted agents are generally preferable to second-line chemotherapy when molecular targets are detected 7

IDH1 Mutations

• Ivosidenib is an excellent option for IDH1-mutant cholangiocarcinoma that progressed on first-line chemotherapy, given its excellent tolerability and median overall survival benefit 6
• IDH1 inhibitors should be considered after failure of first-line treatment when IDH1 mutations are detected 7, 5

Other Molecular Targets

• MSI-high/TMB-high tumors: Immune checkpoint inhibitors are indicated 7
• BRAF V600E mutations: BRAF inhibitors should be considered 7
• NTRK fusions: NTRK inhibitors are appropriate 7
• HER2 amplifications: HER2-targeted therapy may be considered 6

Second-Line Chemotherapy

When targeted therapy is not available or after progression on targeted therapy 7, 5:

• FOLFOX (5-fluorouracil and oxaliplatin) has positive phase III data for second-line use 6, 7
• Nanoliposomal irinotecan plus 5-FU and leucovorin has shown encouraging results, though evidence is contradictory 6, 7
• Trifluridine/tipiracil plus irinotecan has shown encouraging results 6

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Unresectable Disease: Liver Transplantation

Liver transplantation is currently contraindicated for cholangiocarcinoma 3, 1, 2:

• It is usually associated with rapid recurrence of disease and death within 3 years 3
• 5-year survival rate is only 28% with 51% recurrence rate 2
• Liver transplantation following preoperative chemoirradiation may be appropriate within clinical trials for carefully selected patients 3

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Palliative Management

Biliary Drainage

Biliary stenting via ERCP is the preferred palliative treatment for biliary obstruction in unresectable disease 1:

• Stenting procedures resulting in adequate biliary drainage improve both survival and quality of life 1
• Metal stents are preferred over plastic stents in patients with life expectancy >6 months 1
• Surgical bypass has not been demonstrated to be superior to stenting 3

Other Palliative Options

• Fluoropyrimidine-based chemoradiation may be considered 2
• Locoregional therapies may be appropriate in select cases 2
• Clinical trial enrollment should be prioritized when available 2

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Prognostic Factors

R0 resection status with tumor-free margins and absence of lymphadenopathy are the most important positive prognostic indicators 1:

• Up to 50% of patients are lymph node positive at presentation, which significantly worsens surgical outcomes 1, 2
• Peritoneal and distant metastases are present in 10-20% of patients at presentation 3
• Bile duct cancers may be multifocal in 5% of cases 3

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Pathological Reporting Requirements

All surgical resection specimens must be systematically reported 1:

• Histological type and grade 1
• Extent of invasion (TNM system) 1
• Blood/lymphatic vessel invasion 1
• Perineural invasion (very common and associated with worse outcome) 3
• Margin status (margins must be adequately sampled as local recurrence relates to margin involvement) 3
• Regional lymph node status with specific identification of lymph node groups 3