What is the role of combined Stereotactic Body Radiation Therapy (SBRT) and immunotherapy in the treatment of Cholangiocarcinoma?

Combined SBRT and Immunotherapy in Cholangiocarcinoma

Yes, there is a definitive role for combined SBRT and immunotherapy in cholangiocarcinoma, particularly when integrated with first-line chemotherapy-immunotherapy regimens for oligometastatic disease or as a strategy to enhance local control during systemic treatment. 1, 2

Standard First-Line Treatment Framework

The foundation of treatment for unresectable or metastatic cholangiocarcinoma is gemcitabine plus cisplatin combined with either durvalumab or pembrolizumab, which achieves a median overall survival of 12.9 months (HR 0.76,95% CI 0.64-0.91). 1 This chemotherapy-immunotherapy combination represents the current standard of care and provides the context within which SBRT should be considered. 1, 2

When to Integrate SBRT with Immunotherapy

Oligometastatic Disease During First-Line Treatment

Start with cisplatin-gemcitabine plus durvalumab or pembrolizumab as standard first-line therapy, then add SBRT to oligometastatic sites during ongoing immunotherapy-chemotherapy. 2 This approach targets limited disease burden while maintaining systemic control. 2

Unresectable Localized Intrahepatic Disease

For unique intrahepatic cholangiocarcinoma lesions less than 5 cm where surgical resection is not possible, SBRT should be combined with systemic chemotherapy-immunotherapy. 1, 2 The recommended SBRT dosing is 30-50 Gy in 3-5 fractions, depending on normal organ constraints and underlying liver function. 1, 2

Perihilar/Hilar Cholangiocarcinoma

SBRT demonstrates promising efficacy for hilar cholangiocarcinoma with 2-year local control rates of 47-78%, and should be combined with systemic chemotherapy-immunotherapy rather than used as monotherapy. 2

Patient Selection Criteria

Eligible patients must meet the following requirements:

• WHO/ECOG performance status 0-2 with adequate organ function 1
• Avoid treatment in patients with ECOG >2, as they derive no benefit and experience increased toxicity 1
• Child-Pugh A liver function (most safety and efficacy data available; limited data for Child-Pugh B) 2
• Never use SBRT in Child-Pugh C cirrhosis, as safety has not been established in this population 2

Treatment Sequencing Algorithm

1. Confirm unresectability through multidisciplinary tumor board evaluation 2

2. Initiate first-line systemic therapy: Cisplatin-gemcitabine plus durvalumab or pembrolizumab 1, 2

3. Add SBRT during first-line treatment for:

   • Oligometastatic sites (limited disease burden) 2
   • Solitary intrahepatic lesions <5 cm 2
   • Perihilar disease requiring local control 2

4. Alternative consideration: SBRT plus immunotherapy can be examined post-progression on immunotherapy, as these modalities act synergistically to enhance anti-tumor activity 3

Evidence Supporting the Combination

The combination of SBRT and immunotherapy demonstrates acceptable safety profiles, with concurrent treatment not significantly increasing toxicity compared to SBRT alone. 2 Case series have shown successful control of refractory advanced intrahepatic or hilar cholangiocarcinoma with anti-PD-1 antibody following or concurrent with SBRT, with one case becoming operable after initially being unresectable. 4

Special Populations

MSI-High or dMMR Cholangiocarcinoma

Patients with MSI-high or dMMR cholangiocarcinoma who have progressed on first-line chemotherapy should receive immune checkpoint blockade (pembrolizumab or dostarlimab), and SBRT can be added for oligometastatic control. 1

FGFR2 Fusions or IDH1 Mutations

After progression on first-line therapy, patients with FGFR2 fusions should receive FGFR inhibitors (objective response rates 23-42%), and those with IDH1 mutations should receive ivosidenib. 1 SBRT can be integrated for local control of specific lesions during targeted therapy.

Critical Pitfalls to Avoid

• Never use conventional low-dose palliative radiation (8 Gy in 1 fraction) for cholangiocarcinoma, as this achieves suboptimal local control 1, 2
• Do not delay chemotherapy-immunotherapy waiting for further disease progression, as early treatment correlates with improved outcomes 1
• Avoid radiotherapy alone without systemic therapy, as external beam radiotherapy alone has no proven survival benefit and carries significant toxicity 5
• Do not use SBRT for lesions abutting critical structures (bile ducts, stomach, bowel) without appropriate planning, though hydrodissection techniques can enable safe treatment in some cases 2
• Ensure sufficient uninvolved liver volume and strict adherence to liver radiation dose constraints 2
• Verify respiratory motion management is adequate for lesions abutting the diaphragm and that dose constraints can be met 2

Quality of Life Considerations

Quality of life should be the primary focus with survival as a secondary endpoint, as achieving stable disease correlates with improved length and quality of life. 1 Good symptom control is paramount and requires multidisciplinary input. 1