What is the recommended first‑line systemic chemotherapy (including dosing) for unresectable/metastatic cholangiocarcinoma, and what regimen should be used if the patient has impaired renal function?

First-Line Systemic Chemotherapy for Unresectable/Metastatic Cholangiocarcinoma

For patients with unresectable or metastatic cholangiocarcinoma and good performance status (ECOG 0-1), the standard first-line treatment is gemcitabine plus cisplatin combined with either durvalumab or pembrolizumab. 1, 2

Standard Dosing Regimen

The recommended dosing schedule is:

• Gemcitabine 1000 mg/m² IV on days 1 and 8
• Cisplatin 25-30 mg/m² IV on days 1 and 8
• Every 21 days (3-week cycles)
• Plus durvalumab 1500 mg IV every 3 weeks 1, 2

This triplet regimen provides a median overall survival of 12.9 months compared to 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91). 1, 2 Pembrolizumab combined with gemcitabine-cisplatin is an FDA/EMA-approved alternative, though the benefit in extrahepatic cholangiocarcinoma/gallbladder cancer was less clear (HR 0.99) compared to intrahepatic disease. 2

Critical Patient Selection Criteria

Only treat patients with ECOG performance status 0-1 (or 0-2 after biliary drainage optimization). 1, 2 Patients with ECOG PS >2 should receive best supportive care only, as they derive no survival benefit and experience increased toxicity from chemotherapy. 1

Management of Impaired Renal Function

For patients with impaired renal function who cannot tolerate cisplatin, gemcitabine plus oxaliplatin is the appropriate alternative backbone. 1 While the guidelines do not provide specific dosing for this scenario, the standard approach would be:

• Gemcitabine 1000 mg/m² IV on days 1 and 8
• Oxaliplatin 85-100 mg/m² IV on day 1
• Every 21 days

The addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine-oxaliplatin has not been formally studied in large trials, but extrapolation from the gemcitabine-cisplatin data supports its use in appropriate candidates. 1

Defining Impaired Renal Function

Cisplatin is contraindicated when creatinine clearance falls below 60 mL/min. 1 Calculate creatinine clearance using the Cockcroft-Gault equation before initiating therapy and monitor renal function before each cycle.

Common Pitfalls and Caveats

Do not use immunotherapy in patients with a history of immune-mediated hepatitis from prior checkpoint inhibitor therapy—this represents an absolute contraindication. 3 In such cases, use gemcitabine plus cisplatin chemotherapy alone without immunotherapy. 3

Ensure adequate biliary drainage before initiating chemotherapy. 1 Endoscopic stent insertion (ERCP) is the preferred first-line approach for obstructive jaundice due to lower morbidity compared to percutaneous approaches. 2 Optimize bilirubin levels and treat cholangitis before starting systemic therapy.

Obtain molecular profiling at diagnosis or during first-line therapy to identify actionable alterations (FGFR2 fusions, IDH1 mutations, HER2 amplification, MSI-high/dMMR, NTRK fusions, RET fusions, BRAF mutations). 1, 3 This information guides targeted therapy options in second-line or beyond, where targeted therapies take priority over cytotoxic chemotherapy when actionable mutations are present. 3, 4

Monitoring Requirements

Obtain complete blood counts before each chemotherapy cycle and at days 8 and 15 of each cycle. 3 Neutropenia is the most common grade ≥3 hematologic adverse event with gemcitabine-cisplatin combinations, occurring in 34.6-45.4% of patients, with nadir typically at 7-14 days after each cycle. 3

Check complete metabolic panel including liver function tests every 3 weeks during chemotherapy cycles to detect hepatotoxicity early. 3 Dose modifications or delays are typically required when absolute neutrophil count falls below 1,500/μL or platelets below 100,000/μL. 3

Duration of Therapy

Administer cisplatin for up to 8 cycles, with gemcitabine continuing beyond 8 cycles if tolerated and disease remains controlled. 3 Continue immunotherapy until disease progression or unacceptable toxicity. 1

Second-Line Options

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) is the standard second-line therapy after progression on first-line gemcitabine-cisplatin, with a median overall survival of 6.2 months (HR 0.69). 1, 2, 4 Alternative second-line options include FOLFIRI or nanoliposomal irinotecan plus 5-fluorouracil (NalIRI+5FU), though evidence is stronger for FOLFOX. 1