What is the recommended treatment for advanced gallbladder cancer?

Treatment of Advanced Gallbladder Cancer

For advanced gallbladder cancer, gemcitabine plus cisplatin plus durvalumab is the standard first-line treatment for patients with ECOG performance status 0-1, providing superior survival compared to chemotherapy alone. 1, 2

First-Line Treatment: Chemoimmunotherapy

The current standard regimen consists of: 1, 2

• Gemcitabine 1000 mg/m² IV on days 1 and 8
• Cisplatin 25 mg/m² IV on days 1 and 8
• Durvalumab 1500 mg IV on day 1
• Repeated every 21 days for up to 8 cycles, followed by durvalumab maintenance until progression

This combination achieves a median overall survival of 12.9 months versus 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91). 2 Pembrolizumab can be substituted for durvalumab as an alternative immunotherapy option, though the benefit was primarily driven by intrahepatic cholangiocarcinoma rather than extrahepatic disease. 2

Critical pitfall: Using gemcitabine-cisplatin alone without immunotherapy is now suboptimal care given the proven survival benefit of adding durvalumab or pembrolizumab. 2

Alternative First-Line Regimens (When Cisplatin Contraindicated)

For patients unable to tolerate cisplatin due to renal dysfunction, neuropathy, or ototoxicity: 3

Gemcitabine-based combinations:

• Gemcitabine/oxaliplatin 3, 1
• Gemcitabine/capecitabine 3, 1

Fluoropyrimidine-based combinations:

• Capecitabine/oxaliplatin 3, 1
• 5-FU/cisplatin 3
• 5-FU/oxaliplatin 3

Gemcitabine-oxaliplatin shows comparable efficacy to gemcitabine-cisplatin with lower hematologic toxicity (anemia 6.7% vs 22.1%, thrombocytopenia 3.7% vs 9.8%) but higher peripheral neuropathy (9.2% vs 3.1%) and transaminitis (14.7% vs 6.1%). 4 This makes gemcitabine-oxaliplatin preferable for patients with borderline renal or cardiac function. 4

Single-agent options (gemcitabine, capecitabine, or 5-FU) are inferior to combination therapy but acceptable for patients who cannot tolerate any platinum agent. 3, 1

Avoid gemcitabine/5-FU combination due to increased toxicity and decreased efficacy compared to gemcitabine/capecitabine. 3, 1

Performance Status Considerations

For ECOG performance status 4: Best supportive care only—chemotherapy provides no survival benefit and increases toxicity. 1

For ECOG performance status 2-3: Address reversible factors first before considering chemotherapy. 1

The most critical reversible factor is biliary obstruction. 1 Biliary drainage optimization through ERCP or percutaneous transhepatic cholangiography (PTC) with plastic or covered self-expanding metal stents should be the immediate priority if obstructive jaundice is present. 1 If performance status improves to ECOG 0-1 through supportive interventions, then gemcitabine plus cisplatin with durvalumab becomes appropriate. 1

Second-Line Treatment

Upon progression on first-line therapy, FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) is the recommended second-line regimen. 2 This achieves median overall survival of 6.2 months versus 5.3 months with active symptom control alone (HR 0.69,95% CI 0.50-0.97). 2

Alternative second-line options include irinotecan-based regimens and liposomal irinotecan plus 5-fluorouracil. 2

Role of Radiation Therapy

Chemoradiation is NOT recommended for stage 4 metastatic disease. 1, 2

Radiation therapy with concurrent 5-FU or capecitabine should only be considered for: 3, 1

• Patients with locally advanced disease without distant metastases
• Symptom control from local tumor effects in highly selected cases

In non-metastatic locally advanced disease, chemoradiation can provide actuarial overall survival of 59% at 1 year and 22% at 2 years, with effective local control rates of 90% at 1 year and 61% at 2 years. 3

Concurrent chemoradiation with gemcitabine is specifically contraindicated due to excessive toxicity. 3, 1, 2 Only 5-FU or capecitabine should be used as radiosensitizers. 3, 1

Response Evaluation and Monitoring

Efficacy should be evaluated every 8-12 weeks based on: 1

• Clinical status assessment
• CA 19-9 trajectory
• Repeat imaging (CT or MRI)

Treatment should be discontinued if performance status deteriorates to ECOG >2. 1

Emerging Data on Triplet Chemotherapy

A phase 2 trial of gemcitabine-cisplatin-nab-paclitaxel showed promising results with median progression-free survival of 11.8 months and overall survival of 19.2 months, with a 45% partial response rate. 5 However, this regimen is not yet standard of care and should be reserved for clinical trials or highly selected patients, as it carries higher toxicity (58% grade 3+ adverse events, 33% grade 3+ neutropenia). 5

Similarly, the MITSUBA trial demonstrated that adding S-1 to gemcitabine-cisplatin improved median overall survival to 13.5 months versus 12.6 months (HR 0.79, P=0.046) with a notably higher response rate (41.5% vs 15.0%). 6 This regimen may become a future standard but requires validation in Western populations.

Palliative Care Integration

Regardless of treatment approach, the following should be implemented from diagnosis: 1

• Biliary stenting for obstructive jaundice to address pruritus and organ dysfunction
• Endoscopic interventions for bleeding or obstruction
• Psychosocial and spiritual support
• Multidisciplinary palliative care team involvement