What are the lines of management for metastatic gallbladder (biliary) adenocarcinoma?

Management of Metastatic Gallbladder Adenocarcinoma

For first-line treatment of metastatic gallbladder adenocarcinoma, gemcitabine plus cisplatin combined with durvalumab should be the standard of care, as this regimen demonstrated superior overall survival (12.9 vs 11.3 months, HR 0.76) in the TOPAZ-1 trial and is FDA/EMA approved. 1

First-Line Systemic Therapy

Standard Regimen

• Gemcitabine 1000 mg/m² plus cisplatin 25-30 mg/m² on days 1 and 8 every 3 weeks, combined with durvalumab (PD-L1 inhibitor), represents the current standard of care 1
• This triplet combination improved median overall survival to 12.9 months compared to 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91) 1
• Disease control rates with gemcitabine-cisplatin reach approximately 60%, with overall response rates of 15-25% 2, 3

Alternative First-Line Options

• Gemcitabine plus cisplatin plus pembrolizumab is an FDA/EMA-approved alternative, though the benefit in extrahepatic cholangiocarcinoma/gallbladder cancer subgroup was less clear (HR 0.99) compared to intrahepatic disease 1
• For patients with renal impairment (GFR <60 mL/min), substitute oxaliplatin for cisplatin, though this is less well-validated 1
• Gemcitabine monotherapy should be reserved only for patients with ECOG performance status 2 or significant comorbidities precluding platinum therapy 1

Patient Selection Criteria

• Only treat patients with ECOG performance status 0-1 (or 0-2 after biliary drainage optimization) 1, 4
• Patients with ECOG PS >2 should receive best supportive care only, as they derive no survival benefit and experience increased toxicity 4
• Optimize biliary drainage before initiating chemotherapy in jaundiced patients to prevent biochemical derangements and cholangitis 4, 5
• Ensure adequate renal function (creatinine clearance sufficient for cisplatin), hepatic function, and absence of rapidly deteriorating clinical status 4

Duration of Treatment

• Continue first-line therapy for up to 6 months or until disease progression, unacceptable toxicity, or patient preference 1
• There is insufficient evidence to recommend continuous treatment beyond 6 months 1

Second-Line Systemic Therapy

Standard Second-Line Regimen

• FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) should be offered as second-line therapy after progression on first-line gemcitabine-cisplatin 1
• The ABC-06 trial demonstrated median overall survival of 6.2 months with FOLFOX versus 5.3 months with active symptom control (HR 0.69, p=0.031) 1

Alternative Second-Line Options

• Liposomal irinotecan plus 5-fluorouracil (NalIRI+5FU) can be considered based on the NIFTY trial showing median OS of 8.6 months versus 5.3 months with 5-FU alone (HR 0.68) 1
• This option is supported by phase II data, though the NALIRICC study did not replicate these results 1

Supportive Care Measures

Biliary Drainage Management

• Endoscopic stent insertion (ERCP) is the preferred first-line approach for obstructive jaundice due to lower morbidity compared to percutaneous approaches 5
• Plastic stents are adequate for most patients; metal stents may be appropriate for those with better life expectancy 5
• Percutaneous transhepatic biliary drainage is reserved for failed endoscopic approaches 5
• Administer perioperative antibiotics when injecting contrast into obstructed ducts to prevent cholangitis 5

Pruritus Management

• First-line: ERCP with biliary drainage/stent placement achieves approximately 80% success for clinical improvement 6
• Second-line pharmacologic: Ursodeoxycholic acid 10-15 mg/kg/day improves pruritus and liver enzymes 6
• Third-line: Cholestyramine (adsorb bile acids) or rifampicin if cholestyramine fails 6

Treatment Algorithm Summary

Step 1: Confirm metastatic disease with pathologic diagnosis and staging imaging

Step 2: Assess ECOG performance status:

• PS 0-1: Proceed with systemic therapy
• PS 2: Consider gemcitabine monotherapy or best supportive care
• PS >2: Best supportive care only 1, 4

Step 3: Optimize biliary drainage if jaundiced before chemotherapy initiation 4, 5

Step 4: Initiate first-line therapy:

• Preferred: Gemcitabine + cisplatin + durvalumab 1
• Alternative: Gemcitabine + cisplatin + pembrolizumab 1
• If renal impairment: Gemcitabine + oxaliplatin 1

Step 5: Continue until progression, toxicity, or 6 months maximum 1

Step 6: Upon progression, offer second-line FOLFOX or NalIRI+5FU 1

Critical Pitfalls to Avoid

• Never delay chemotherapy in eligible patients waiting for further progression—early initiation correlates with improved outcomes 4
• Do not treat patients with ECOG PS >2 with chemotherapy, as they experience only toxicity without survival benefit 4
• Never proceed with chemotherapy before optimizing biliary drainage in jaundiced patients 4, 5
• Do not use radiation therapy as it has no proven survival benefit and carries significant toxicity 4
• Avoid liver transplantation outside of clinical trial protocols at specialized centers 4
• Recognize that stent occlusion (not progressive disease) is the usual cause of recurrent jaundice after initial drainage 5

Prognostic Factors

Poor prognostic indicators include:

• Liver metastases (HR 1.63) 2
• Neutrophil-to-lymphocyte ratio ≥3 (HR 1.65) 2
• CEA ≥5 ng/mL (HR 1.50) 2
• CA19-9 ≥500 U/mL (HR 1.59) 2

Expected Outcomes

• Median overall survival with modern first-line therapy: 12.9 months 1
• Median progression-free survival: 5-6 months 1, 2
• Disease control rate: Approximately 60% 2
• Median survival without treatment: 3.9 months 4