What are the treatment options for advanced gallbladder cancer, including chemotherapy (chemo) and immunotherapy (immuno), and their survival benefits?

Survival Benefit of Chemotherapy and Immunotherapy in Advanced Gallbladder Cancer

For advanced gallbladder cancer, combination chemoimmunotherapy with gemcitabine plus cisplatin plus durvalumab (or pembrolizumab) is now the standard of care, providing a median overall survival of 12.9 months compared to 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91). 1

First-Line Treatment: The New Standard

Chemoimmunotherapy is superior to chemotherapy alone and should be used in all eligible patients with advanced, unresectable, or metastatic gallbladder cancer. 1 The evidence supporting this comes from the TOPAZ-1 trial (durvalumab) and KEYNOTE-966 trial (pembrolizumab), which demonstrated significant survival benefits when immunotherapy was added to standard gemcitabine-cisplatin chemotherapy.

Recommended Regimen

The standard first-line regimen consists of: 1

• Gemcitabine 1000 mg/m² on days 1 and 8
• Cisplatin 25 mg/m² on days 1 and 8
• Durvalumab 1500 mg on day 1 (or pembrolizumab 200 mg on day 1 as alternative) 2
• 21-day cycles, continuing for up to 8 cycles of chemotherapy, followed by durvalumab maintenance until progression or unacceptable toxicity 1

Survival Outcomes with Chemoimmunotherapy

The addition of immunotherapy to chemotherapy provides: 1

• Median overall survival: 12.9 months (vs 11.3 months with chemotherapy alone)
• Hazard ratio for death: 0.76 (95% CI 0.64-0.91)
• This represents approximately a 24% reduction in the risk of death

For pembrolizumab specifically in biliary tract cancers (which includes gallbladder cancer), KEYNOTE-966 showed: 2

• Median overall survival: 12.7 months (vs 10.9 months with placebo plus chemotherapy)
• Hazard ratio: 0.83 (95% CI 0.72-0.95, p=0.0034)
• Objective response rate: 29% in both arms, but duration of response was longer with pembrolizumab (8.3 vs 6.8 months)

Historical Context: Chemotherapy Alone Era

Before immunotherapy became standard, gemcitabine-cisplatin was the backbone of treatment: 3

• Median overall survival with gemcitabine-cisplatin: approximately 11.7 months (from ABC-02 trial)
• Response rates: 30-50% with gemcitabine-cisplatin combinations 3
• Disease control rate: 59.5% in real-world cohorts 4

Single-agent gemcitabine showed inferior outcomes: 3

• Response rates: 20-30% with gemcitabine alone
• Survival benefit of adding cisplatin: approximately 3-4 months 3

Second-Line Treatment Options

When disease progresses on first-line therapy: 1

• FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) is the recommended second-line regimen
• Median overall survival with FOLFOX: 6.2 months vs 5.3 months with active symptom control alone (HR 0.69,95% CI 0.50-0.97)
• Alternative options include irinotecan-based regimens or liposomal irinotecan plus 5-FU

Emerging Data: Triplet Chemotherapy

Recent phase 2 data suggest that adding nab-paclitaxel to gemcitabine-cisplatin may further improve outcomes: 5, 6

• Median progression-free survival: 11.8 months with gemcitabine-cisplatin-nab-paclitaxel
• Median overall survival: 19.2 months in the phase 2 trial 5
• Objective response rate: 45-67.6% 5, 6
• However, this requires phase 3 validation and is not yet standard of care

The triplet regimen showed particular promise in potentially converting unresectable disease to resectable: 7, 6

• 34% of locally advanced patients underwent surgery after triplet chemotherapy 6
• Case reports demonstrate complete pathological responses with conversion to R0 resection 7

Critical Clinical Pitfalls to Avoid

Do NOT use chemotherapy alone as first-line treatment

Using gemcitabine-cisplatin without immunotherapy is now suboptimal care given the proven survival benefit of adding durvalumab or pembrolizumab. 1 This represents a fundamental shift in the treatment paradigm that occurred in 2022-2023.

Do NOT use concurrent chemoradiation with gemcitabine

Chemoradiation with gemcitabine has excessive toxicity and limited experience. 3 If chemoradiation is needed for local control in non-metastatic disease, use 5-FU or capecitabine as the radiosensitizer instead. 3

Do NOT delay treatment initiation

Median survival without chemotherapy is only 2.5-6 months. 1 Patients who are relatively healthy and stable should be treated early rather than waiting for disease progression. 3 Performance status is the most important prognostic factor—patients with Karnofsky status ≥50 who are not rapidly deteriorating are suitable for treatment. 3

Do NOT ignore quality of life as a primary endpoint

Quality of life should be the primary focus, with survival as a secondary endpoint. 3 Good symptom control requires multidisciplinary team input throughout treatment. 3 Achieving stable disease has value that translates into both length and quality of life. 3

Patient Selection and Prognostic Factors

Factors associated with worse overall survival include: 4

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

These factors should inform prognosis discussions but should not exclude patients from receiving standard chemoimmunotherapy, as even poor-risk patients derive benefit. 1

Treatment Algorithm

1. Confirm advanced/unresectable/metastatic disease with appropriate staging (CT chest/abdomen/pelvis, consider MRI) 8
2. Assess performance status: ECOG 0-1 or Karnofsky ≥50 and not rapidly deteriorating 3
3. Exclude contraindications to immunotherapy: active autoimmune disease requiring systemic therapy, medical conditions requiring immunosuppression 2
4. Initiate gemcitabine-cisplatin-durvalumab (or pembrolizumab) as first-line therapy 1
5. Continue for 8 cycles of chemotherapy, then durvalumab maintenance until progression or toxicity 1
6. At progression, switch to FOLFOX as second-line therapy 1
7. Maintain focus on quality of life and symptom control throughout 3