What is the management of advanced gallbladder (biliary) cancer?

Management of Advanced Gallbladder Cancer

For patients with advanced gallbladder cancer and good performance status (ECOG 0-1), the standard of care is gemcitabine plus cisplatin plus durvalumab (or pembrolizumab) as first-line therapy, which provides superior survival compared to chemotherapy alone. 1, 2

First-Line Treatment: Chemoimmunotherapy

The addition of immunotherapy to chemotherapy is now mandatory for eligible patients, as the TOPAZ-1 study demonstrated significant improvements in overall survival (median OS 12.9 vs 11.3 months, HR 0.76,95% CI 0.64-0.91) when durvalumab was added to cisplatin-gemcitabine. 1, 2

Standard Regimen

• Gemcitabine 1000 mg/m² IV on days 1 and 8 1, 2
• Cisplatin 25 mg/m² IV on days 1 and 8 1, 2
• Durvalumab 1500 mg IV on day 1 2
• Cycle repeated every 21 days for up to 8 cycles, followed by durvalumab maintenance until progression 2

Alternative Immunotherapy Option

• 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. 2

Critical Pitfall

Do not use gemcitabine-cisplatin alone without immunotherapy in eligible patients, as this represents suboptimal care given the proven survival benefit of adding durvalumab or pembrolizumab. 2, 3

Patient Selection and Performance Status Considerations

For ECOG PS 0-1

• Standard chemoimmunotherapy as outlined above is appropriate 1, 2
• Median OS with cisplatin-gemcitabine was 13.0 months when limited to patients with PS 0-1 in international RCT settings 1

For ECOG PS 2

• Gemcitabine monotherapy may be preferred due to concerns about tolerability of combination therapy 1
• Oxaliplatin may be substituted for cisplatin when there is concern about renal function 1

For ECOG PS >2 (PS 3-4)

• Best supportive care without chemotherapy is the only appropriate approach, as chemotherapy provides no survival benefit and increases toxicity in patients with poor performance status 4

Reversible Factors to Address First

Biliary obstruction is the most critical reversible factor that can dramatically improve performance status. 4

• Biliary drainage optimization through ERCP or percutaneous transhepatic cholangiography (PTC) should be the immediate priority if obstructive jaundice is present 4
• Non-surgical stenting with plastic or covered self-expanding metal stents (SEMS) is the first-choice approach for biliary decompression 4
• If performance status improves to ECOG 1 through supportive interventions, then standard chemoimmunotherapy becomes appropriate 4

Molecular Profiling

Comprehensive molecular profiling using next-generation sequencing (NGS) should be performed for all patients with advanced gallbladder cancer suitable for systemic treatment, as approximately 35-50% harbor clinically actionable alterations. 3

Timing and Tissue Requirements

• Molecular analysis should be initiated at the time of diagnosis with advanced disease 3
• Core biopsy (not fine needle aspiration alone) should be obtained to ensure sufficient tumor content for molecular testing 3
• Do not delay treatment initiation waiting for molecular results, as median survival without chemotherapy is only 2.5-6 months 3

Testing Panel Must Include

• Hotspot mutations: IDH1, ERBB2, BRAF, PIK3CA, KRAS 3
• Copy number alterations: ERBB2 amplification, CDKN2A biallelic inactivation 3
• Gene fusions: FGFR2 and NTRK fusion transcripts 3

Targetable Alterations for Later-Line Therapy

• IDH1 mutations (19.1% of patients) can be treated with ivosidenib in previously treated patients 1, 3
• FGFR2 fusions/rearrangements (10.1% of patients) can be treated with pemigatinib, futibatinib, or infigratinib 1, 3

Duration of First-Line Therapy

There is currently insufficient evidence to recommend continuous treatment beyond 6 months, and decisions should be based upon individual patient toxicity, tolerability and tumor response. 1

Treatment should be continued for up to 8 cycles of combination therapy, followed by durvalumab maintenance until disease progression or unacceptable toxicity. 2

Second-Line Treatment

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) is the recommended second-line therapy upon progression on first-line therapy, 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, 2

Alternative Second-Line Options

• 5-FU combined with nano-liposomal irinotecan (nal-iri) demonstrated improved PFS in a randomized phase IIb Korean study 1
• However, the NALIRICC phase II study with Caucasian patients did not report a survival benefit for 5-FU-nal-iri versus 5-FU alone in Western patients, and the doublet regimen was associated with more toxicity 1
• Evidence for irinotecan-based therapies is currently limited 1

Targeted Therapy Based on Molecular Profiling

For patients with targetable genomic alterations identified during first-line therapy, precision medicine approaches should be considered in second and higher lines of treatment. 1, 3

Role of Radiation Therapy

For Metastatic Disease (Stage 4B)

Chemoradiation is NOT recommended for stage 4 metastatic disease 4

For Locally Advanced Disease Without Distant Metastases

Radiation therapy with concurrent 5-FU or capecitabine may be considered for patients with locally advanced disease without distant metastases or for symptom control from local tumor effects in highly selected cases. 1, 4

• Chemoradiation can provide control of symptoms caused by local tumor effects and may prolong overall survival 1
• Chemotherapy administered concurrently with radiation should be limited to either 5-FU or capecitabine 1

Critical Contraindication

Concurrent chemoradiation with gemcitabine is specifically contraindicated due to limited experience and excessive toxicity. 1, 2, 4

Monitoring and Response Assessment

Efficacy should be evaluated every 8-12 weeks based on clinical status, CA 19-9 trajectory, and imaging. 4

Treatment should be discontinued if performance status deteriorates to ECOG >2 4

Alternative Chemotherapy Regimens (Historical Context)

While chemoimmunotherapy is now standard, the following chemotherapy combinations remain relevant for cisplatin-ineligible patients or when immunotherapy is contraindicated:

Gemcitabine-Based Combinations

• Gemcitabine/oxaliplatin 1, 4
• Gemcitabine/capecitabine 1, 4

Fluoropyrimidine-Based Combinations

• Capecitabine/oxaliplatin 1, 4
• Capecitabine/cisplatin 1, 4
• 5-FU/cisplatin 1, 4
• 5-FU/oxaliplatin 1, 4

Single-Agent Options

Single-agent gemcitabine, capecitabine, or 5-FU are inferior to combination therapy but acceptable for patients who cannot tolerate platinum agents. 4

Regimen to Avoid

The combination of gemcitabine/5-FU is not recommended due to increased toxicity and decreased efficacy compared with gemcitabine/capecitabine. 1, 4

Emerging Triplet Chemotherapy Regimens

Intensification of chemotherapy with triplet regimens is under evaluation, though current evidence shows mixed results:

• In Japan, preliminary results showed improved survival with cisplatin-gemcitabine-S-1 (GCS) 1, 5
• Modified FOLFIRINOX is not superior to cisplatin-gemcitabine 1
• Cisplatin-gemcitabine-nab-paclitaxel is being compared with cisplatin-gemcitabine in the phase III SWOG-1815 study based on promising phase II results 1, 6

Palliative Care Integration

Multidisciplinary palliative care team involvement should begin from diagnosis regardless of performance status. 4

Key Palliative Interventions

• Biliary stenting for obstructive jaundice to address pruritus and organ dysfunction 4
• Endoscopic interventions for bleeding or obstruction 4
• Psychosocial and spiritual support 4