What are the next treatment options for cholangiocarcinoma after cisplatin, gemcitabine, FOLFOX, and FOLFIRI?

Next Treatment Options for Cholangiocarcinoma After Multiple Chemotherapy Regimens

For patients with cholangiocarcinoma who have progressed after cisplatin/gemcitabine, FOLFOX, and FOLFIRI, enrollment in a clinical trial is strongly recommended as the best next option, particularly trials targeting specific molecular alterations if present. 1

Molecular Profiling-Guided Approach

Molecular profiling should be performed immediately if not already done, as nearly 40% of patients with biliary tract cancer harbor potentially targetable genetic alterations:

1. IDH1/2 mutations (10-20% of iCCA):

   • Ivosidenib for IDH1 R132 mutations - significantly improved progression-free survival in the ClarIDHy study 1, 2
   • Response rate ~2%, disease stability rate ~51%
   • Median PFS: 2.7 months, median OS: 10.8 months 2

2. FGFR2 fusions/alterations:

   • FGFR inhibitors have shown response rates of 20.7-35.5%
   • Disease stability rates: 76-82%
   • Median PFS: 5.7-6.9 months, median OS: 12.5-21.1 months 2

3. BRAF mutations:

   • Dabrafenib plus trametinib combination
   • Overall response rate: 51%, disease stability: 40%
   • Median PFS: 9 months, median OS: 14 months 2

Non-Targeted Approaches (If Molecular Profiling Negative or Unavailable)

If no targetable alterations are found or molecular profiling is not available, consider:

1. Clinical trial participation (highest priority) 1

2. Palliative options:

   • Single-agent chemotherapy with capecitabine or 5-FU if not previously used 1
   • 5-FU with nano-liposomal irinotecan (nal-iri) - showed improved PFS in a Korean phase IIb study, though the NALIRICC phase II study in Western patients did not confirm benefit 1
   • Consider local therapies for symptom control:
     • Radiation for painful metastases 1
     • Intraluminal brachytherapy for biliary obstruction 1
     • SBRT for liver-limited disease 1

Important Considerations

• Performance status is the most important prognostic factor - patients with Karnofsky status ≥50 who are not rapidly deteriorating are suitable for further therapy 1

• Quality of life should be the primary focus rather than survival alone 1

• Stable disease (lack of progression) has value that translates into both length and quality of life 1

• Symptom control is paramount and requires multidisciplinary team input 1

Prognostic Factors to Consider

When deciding on further treatment, consider these poor prognostic indicators:

• Elevated pretreatment serum lactate dehydrogenase
• Elevated C-reactive protein
• Elevated carcinoembryonic antigen 3

Pitfalls to Avoid

1. Delaying molecular profiling - should be done before or during first-line therapy to evaluate options for subsequent lines 1

2. Continuing toxic therapy in patients with poor performance status - quality of life should be prioritized 1

3. Missing opportunities for clinical trials - all patients with inoperable tumors should be actively encouraged to participate in clinical trials 1

4. Overlooking local therapies for symptom control - radiation still has important palliative value for painful metastases 1