What is the first-line chemotherapy regimen for a patient with metastatic gallbladder cancer to the liver?

First-Line Chemotherapy for Metastatic Gallbladder Cancer to the Liver

Gemcitabine plus cisplatin combined with durvalumab is the current standard of care for first-line treatment of metastatic gallbladder cancer to the liver, providing a median overall survival of 12.9 months compared to 11.3 months with chemotherapy alone (HR 0.76). 1, 2

Primary Treatment Regimen

The triplet combination of gemcitabine, cisplatin, and durvalumab should be offered to all eligible patients with metastatic gallbladder cancer. 1, 2

• Dosing schedule: Gemcitabine 1000 mg/m² plus cisplatin 25-30 mg/m² on days 1 and 8 every 3 weeks, combined with durvalumab 1, 2
• This regimen demonstrated superiority in the TOPAZ-1 trial with improved overall survival (HR 0.76,95% CI 0.64-0.91), response rates, and progression-free survival 1
• The addition of the PD-L1 inhibitor durvalumab to chemotherapy was approved by both FDA and EMA based on this evidence 1

Alternative First-Line Option

Gemcitabine plus cisplatin plus pembrolizumab represents an FDA/EMA-approved alternative, though the benefit in gallbladder cancer specifically was less pronounced than in intrahepatic cholangiocarcinoma (HR 0.99 for extrahepatic/gallbladder subgroup) 1, 2

• The Keynote-966 trial showed overall benefit across biliary tract cancers (HR 0.83,95% CI 0.72-0.95) 1
• This may be considered when durvalumab is unavailable or contraindicated 1, 2

Patient Selection Criteria

Only patients with ECOG performance status 0-1 (or 0-2 after biliary drainage optimization) should receive this intensive triplet therapy. 3, 2

• Patients with ECOG PS >2 should receive best supportive care only, as they derive no survival benefit and experience increased toxicity 3, 2
• Adequate organ function is required, particularly creatinine clearance for cisplatin-based therapy 3
• Biliary drainage must be optimized before chemotherapy initiation in jaundiced patients 3, 4

For Cisplatin-Ineligible Patients

When cisplatin is contraindicated due to renal impairment (GFR <60 mL/min), cardiac disease, or other comorbidities, carboplatin may be substituted, though with reduced efficacy 1, 5

• Gemcitabine plus carboplatin showed response rates of 42% in medically unfit patients, dropping to 26% in those with renal impairment 1
• Oxaliplatin may also be substituted for cisplatin when there is concern about renal function 1
• For very frail patients, gemcitabine monotherapy may be preferred 1

Treatment Duration and Monitoring

Continue treatment for a maximum of 6 cycles (approximately 6 months) depending on response and tolerance. 1, 5

• Re-evaluate patients after 2-3 cycles of chemotherapy 5
• Continue for 2 additional cycles in patients with response or stable disease 5
• Change treatment if no response is seen after 2 cycles or significant toxicity develops 5
• There is insufficient evidence to recommend continuous treatment beyond 6 months 1

Expected Outcomes

With modern first-line therapy, expect a median overall survival of 12.9 months and median progression-free survival of 5-6 months. 1, 2

• Disease control rate (complete response + partial response + stable disease) is approximately 60-85% 6, 7, 8
• Response rates range from 30-68% depending on the specific regimen and patient population 6, 7, 8
• Without treatment, median survival is only 3.9 months 2, 5

Prognostic Factors Specific to Liver Metastases

Liver metastases are an independent negative prognostic factor, associated with shorter overall survival (HR 1.63). 8

• Other poor prognostic factors include neutrophil-to-lymphocyte ratio ≥3 (HR 1.65), CEA ≥5 ng/mL (HR 1.50), and CA19-9 ≥500 U/mL (HR 1.59) 8
• Performance status remains the single most important prognostic factor determining treatment benefit 3, 5

Critical Pitfalls to Avoid

Do not delay chemotherapy in eligible patients waiting for further disease progression, as early initiation correlates with improved outcomes 3, 5

Do not proceed with chemotherapy before optimizing biliary drainage in jaundiced patients, as this increases toxicity and reduces efficacy 3, 4

Do not treat patients with ECOG PS >2, as they show no survival benefit and experience increased toxicity 3, 2

For patients with moderately elevated bilirubin due to endoluminal disease despite optimal stenting, cisplatin-gemcitabine can still be used safely with results similar to those with normal bilirubin, particularly in patients with luminal disease rather than extensive liver metastases 1, 4

Emerging Data

The combination of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) has shown promising results in phase II trials, with overall response rates of 67.6% and median event-free survival of 9.92 months 7

• This triplet is being evaluated in the phase III SWOG-1815 study compared to cisplatin-gemcitabine 1
• Until phase III data are available, this remains investigational 1, 7