Treatment Selection for Advanced Gallbladder Cancer
For advanced gallbladder cancer, the standard of care is combination chemoimmunotherapy with gemcitabine plus cisplatin plus either durvalumab or pembrolizumab—not chemotherapy or immunotherapy alone, but both together. 1, 2
First-Line Treatment: Chemoimmunotherapy is Standard
The treatment paradigm has fundamentally shifted based on two landmark phase III trials (TOPAZ-1 and Keynote-966) that demonstrated superior survival with the addition of immune checkpoint inhibitors to chemotherapy. 3
Recommended regimen:
- Gemcitabine 1000 mg/m² plus cisplatin 25 mg/m² on days 1 and 8 of each 21-day cycle 1
- PLUS durvalumab 1500 mg on day 1 of each cycle 1
- Continue for up to 8 cycles, followed by durvalumab maintenance until progression 1
Evidence supporting this approach:
- In the TOPAZ-1 trial, the addition of durvalumab to gemcitabine/cisplatin improved median overall survival from 11.3 to 12.9 months (HR 0.76,95% CI 0.64-0.91) 3, 1
- For gallbladder cancer specifically, the hazard ratio was even more favorable at 0.61 (95% CI 0.41-0.91) 3
- This combination is FDA and EMA approved and represents the current standard of care 3
Alternative immunotherapy option:
- Pembrolizumab can substitute for durvalumab based on the Keynote-966 trial, though the benefit was primarily driven by intrahepatic cholangiocarcinoma rather than gallbladder cancer specifically 1
Critical Pitfall: Chemotherapy Alone is Suboptimal
Using gemcitabine-cisplatin without immunotherapy is now considered suboptimal care given the proven survival benefit of adding checkpoint inhibitors. 1 The historical standard of gemcitabine-cisplatin alone (from the ABC-02 trial) has been superseded by chemoimmunotherapy. 3
Patient Selection Criteria
Eligible patients must have:
- WHO/ECOG performance status 0-2 (preferably 0-1) 4
- Adequate organ function, particularly creatinine clearance for cisplatin 4
- Optimized biliary drainage before treatment initiation 4
Ineligible patients (ECOG >2) should receive best supportive care only, as they show no survival benefit and experience increased toxicity. 4
Second-Line Treatment After Progression
FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) is the preferred second-line option based on the ABC-06 trial showing median OS of 6.2 vs 5.3 months with active symptom control alone (HR 0.69,95% CI 0.50-0.97). 1, 2
Alternative second-line options include irinotecan-based regimens or liposomal irinotecan plus 5-fluorouracil. 3, 1
Common Clinical Pitfalls to Avoid
- Never use immunotherapy as monotherapy—it is only approved and effective in combination with chemotherapy 2
- Never delay treatment waiting for further progression in eligible patients—early initiation correlates with improved outcomes 4
- Never proceed without optimizing biliary drainage in jaundiced patients 4
- Never use concurrent chemoradiation with gemcitabine due to excessive toxicity 1
Real-World Evidence Supporting This Approach
Recent case reports demonstrate dramatic responses with chemoimmunotherapy, including conversion of initially unresectable disease to R0 resection with near-complete pathological response. 5 Retrospective series show disease control rates of 59.5% with chemotherapy alone 6, but combination approaches with immunotherapy achieve higher response rates of 79-90% in early months. 7, 8