What are the better management options for advanced gallbladder cancer with liver metastases?

Management of Advanced Gallbladder Cancer with Liver Metastases

For advanced gallbladder cancer with liver metastases, gemcitabine plus cisplatin plus durvalumab (or pembrolizumab) is the standard of care first-line treatment, providing superior survival compared to chemotherapy alone. 1, 2

First-Line Systemic Treatment

Standard Regimen: Chemoimmunotherapy

• Administer gemcitabine 1000 mg/m² plus cisplatin 25 mg/m² on days 1 and 8 of each 21-day cycle, combined with durvalumab 1500 mg on day 1 of each cycle 1, 2
• This combination achieved median overall survival of 12.9 months versus 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91) in the TOPAZ-1 trial 1
• Continue combination therapy for up to 8 cycles, followed by durvalumab maintenance until disease progression or unacceptable toxicity 2
• Pembrolizumab can be substituted for durvalumab based on the Keynote-966 trial, though the benefit was primarily driven by intrahepatic cholangiocarcinoma (HR 0.99 for extrahepatic disease, 95% CI 0.73-1.35) 1

Patient Selection Criteria

• Restrict chemoimmunotherapy to patients with ECOG performance status 0-2 1
• For patients with ECOG performance status >2, provide best supportive care only 1

Critical Pitfall to Avoid

• Do not use gemcitabine-cisplatin alone without immunotherapy as first-line treatment—this is now suboptimal care 2
• The historical ABC-02 trial established gemcitabine-cisplatin as superior to gemcitabine alone (median OS 11.7 vs 8.1 months), but this has been superseded by the addition of immunotherapy 1

Second-Line Systemic Treatment

Upon Disease Progression

• Offer FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) as second-line therapy 1, 2
• The ABC-06 trial demonstrated median OS of 6.2 months versus 5.3 months with active symptom control alone (HR 0.69,95% CI 0.50-0.97) 2
• Alternative second-line options include irinotecan-based regimens (based on phase II data) or liposomal irinotecan plus 5-fluorouracil 1, 2

Locoregional Treatment Options

Transarterial Therapies for Liver-Dominant Disease

• Consider transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) in selected patients with unresectable liver-dominant disease 1
• These procedures are feasible and safe but lack high-quality comparative data versus systemic therapy 1
• Reserve for patients who cannot tolerate systemic therapy or have isolated hepatic progression 1

Percutaneous Ablation

• Thermal ablation may be considered for small (<3 cm) liver metastases in patients who are not surgical candidates, with median overall survival ranging from 33 to 38.5 months in selected cases 1
• This approach has limited applicability in advanced metastatic disease 1

Radiation Therapy Considerations

External Beam Radiation

• Do not use radiotherapy alone for gallbladder cancer with liver metastases 1
• Concurrent chemoradiation with gemcitabine is specifically contraindicated due to excessive toxicity 1, 2
• If chemoradiation is considered for local control in non-metastatic disease, limit concurrent chemotherapy to 5-FU or capecitabine only 1

Supportive Care Measures

Biliary Drainage for Obstructive Jaundice

• Perform endoscopic stent insertion (ERCP) as first-line approach for obstructive jaundice, which has lower morbidity than percutaneous approaches 3
• Plastic stents are adequate for most patients; metal stents may be appropriate for those with better life expectancy 3
• Untreated obstructive jaundice may lead to biochemical derangements that preclude continuation of chemotherapy 3
• Administer perioperative antibiotics when injecting contrast into an obstructed duct to prevent cholangitis 3

Management of Pruritus

• Initiate ursodeoxycholic acid (UDCA) 10-15 mg/kg/day as first-line medication for cholestatic pruritus 4
• Second-line: cholestyramine (adsorb bile acids in intestine) 4
• Third-line: rifampicin (monitor for hepatotoxicity) 4

Monitoring Requirements

Baseline and Ongoing Assessments

• Obtain complete blood count with differential and platelet count prior to each chemotherapy dose 5
• Monitor for myelosuppression: Grade 3-4 neutropenia occurs in 25% with single-agent gemcitabine and 48-71% with combination regimens 5
• Assess renal function prior to initiation and periodically during treatment to detect hemolytic uremic syndrome (HUS), which occurs in 0.25% of patients 5
• Assess hepatic function prior to initiation and periodically during treatment, as drug-induced liver injury can occur 5

Toxicity Management

• Interrupt gemcitabine immediately if unexplained dyspnea develops, as pulmonary toxicity (interstitial pneumonitis, pulmonary fibrosis, ARDS) can be fatal 5
• Permanently discontinue if HUS, severe renal impairment, severe liver injury, capillary leak syndrome, or posterior reversible encephalopathy syndrome develops 5
• For capecitabine (if used in alternative regimens): interrupt for grade 2-3 hand-foot syndrome or grade 2+ diarrhea 6

Prognosis Without Treatment

• Median survival without chemotherapy is only 2.5-6 months, emphasizing the importance of prompt treatment initiation 2