Is chemotherapy or immunotherapy indicated and beneficial for advanced gallbladder cancer?

Treatment of Advanced Gallbladder Cancer with Chemotherapy and Immunotherapy

For patients with advanced, unresectable, or metastatic gallbladder cancer, combination chemotherapy with gemcitabine plus cisplatin PLUS immunotherapy (either durvalumab or pembrolizumab) is now the standard of care and provides significant survival benefit over chemotherapy alone. 1

First-Line Treatment: Chemoimmunotherapy

The treatment landscape for advanced gallbladder cancer has fundamentally changed based on recent phase III trial data:

Standard Regimen

• 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
• Continue combination therapy for up to 8 cycles, followed by durvalumab maintenance until disease progression or unacceptable toxicity 1, 2

Evidence Supporting Immunotherapy Addition

The TOPAZ-1 trial demonstrated that adding durvalumab to gemcitabine-cisplatin significantly improved outcomes: 1, 2

• Median overall survival: 12.9 months vs 11.3 months (HR 0.76,95% CI 0.64-0.91) 1
• 24-month survival rate: 24.9% vs 10.4% 2
• Progression-free survival: HR 0.75 (95% CI 0.63-0.89) 2
• Disease control rate: 59.5% in real-world data 3
• The safety profile was similar between durvalumab plus chemotherapy and chemotherapy alone 2

Alternative immunotherapy option: 1

• Pembrolizumab can be substituted for durvalumab based on the Keynote-966 trial, though the benefit was primarily driven by intrahepatic cholangiocarcinoma rather than extrahepatic disease 1
• For gallbladder cancer specifically, durvalumab appears to be the preferred immunotherapy agent based on stronger subgroup data 1

Real-World Outcomes

A case report demonstrated dramatic response with conversion to resectability: 4

• Patient with initially unresectable gallbladder cancer with peritoneal metastasis achieved near-complete pathological response (ypT1aN0) after 8 cycles of gemcitabine-cisplatin-durvalumab 4
• Successfully underwent R0 resection via minimally invasive surgery 4
• This highlights the potential for conversion surgery in select responders 4

Second-Line Treatment Options

Upon progression on first-line therapy, FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) should be offered as second-line therapy: 1

• Based on the ABC-06 trial showing median OS of 6.2 months vs 5.3 months with active symptom control alone (HR 0.69,95% CI 0.50-0.97) 1

Alternative second-line options include: 1

• Irinotecan-based regimens (based on phase II data) 1
• Liposomal irinotecan plus 5-fluorouracil 1

Historical Context: Chemotherapy Alone Era

Prior to immunotherapy approval, gemcitabine-cisplatin was the standard based on older data: 1

• Multiple phase II trials established gemcitabine-based regimens as active in biliary tract cancers 1
• The ABC-02 trial showed gemcitabine-cisplatin improved median OS to 11.7 months vs 8.1 months with gemcitabine alone 1
• Alternative chemotherapy combinations included gemcitabine-oxaliplatin, gemcitabine-capecitabine, capecitabine-oxaliplatin, and fluoropyrimidine-platinum combinations 1

However, these chemotherapy-only regimens are now obsolete for first-line treatment given the proven benefit of adding immunotherapy. 1

Prognostic Factors to Consider

Factors independently associated with worse overall survival include: 3

• Liver metastasis (HR 1.63,95% CI 1.11-2.40) 3
• Neutrophil-to-lymphocyte ratio ≥3 (HR 1.65,95% CI 1.09-2.49) 3
• CEA ≥5 ng/mL (HR 1.50,95% CI 1.02-2.19) 3
• CA19-9 ≥500 U/mL (HR 1.59,95% CI 1.01-2.50) 3

Emerging Approaches

Immunotherapy combined with tyrosine kinase inhibitors shows promise in small case series: 5

• Anti-PD-1 therapy (tislelizumab) plus lenvatinib combined with chemotherapy demonstrated responses in elderly patients with advanced gallbladder cancer 5
• Responses appeared better in patients with high tumor mutational burden or microsatellite instability 5
• This approach requires further validation but may represent a future treatment option 5

Critical Clinical Pitfalls

Do not use gemcitabine-cisplatin alone as first-line therapy - this is suboptimal care given the proven survival benefit of adding immunotherapy 1, 2

Do not use concurrent chemoradiation with gemcitabine - this has limited experience and excessive toxicity 1

Do not delay treatment initiation - median survival without chemotherapy is only 2.5-6 months 1

Assess for targetable alterations before initiating therapy - though not specifically mentioned for gallbladder cancer in the guidelines, molecular profiling may identify actionable mutations 1