What is the role of radiation therapy and immune checkpoint inhibitors, such as pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of Cholangiocarcinoma?

Radiation and Immune Checkpoint Inhibitors in Cholangiocarcinoma

First-Line Treatment: Immune Checkpoint Inhibitors Are Now Standard of Care

Gemcitabine plus cisplatin combined with either durvalumab or pembrolizumab should be considered standard of care for first-line systemic treatment of unresectable or metastatic cholangiocarcinoma. 1

The TOPAZ-1 trial demonstrated that durvalumab plus gemcitabine-cisplatin achieved superior overall survival compared to chemotherapy alone (HR 0.76,95% CI 0.64-0.91; median OS 12.9 vs 11.3 months), with particularly strong benefit in extrahepatic cholangiocarcinoma (HR 0.61,95% CI 0.41-0.91). 1 The Keynote-966 trial similarly showed benefit for pembrolizumab plus gemcitabine-cisplatin (HR 0.83,95% CI 0.72-0.95), though the benefit was primarily driven by intrahepatic cholangiocarcinoma patients (HR 0.76) rather than extrahepatic disease (HR 0.99). 1

Both durvalumab and pembrolizumab combinations are FDA and EMA approved for locally advanced unresectable or metastatic biliary tract cancers. 1

Patient Selection for Immunotherapy

• Performance status requirements: Patients must have WHO/ECOG performance status 0-2 with adequate organ function. 1
• Avoid treating patients with ECOG >2, as they derive no benefit and experience increased toxicity. 1
• Optimize biliary drainage before initiating chemotherapy-immunotherapy in jaundiced patients. 1

Special Populations with Enhanced Immunotherapy Benefit

For patients with MSI-high or dMMR cholangiocarcinoma who have progressed on first-line chemotherapy, immune checkpoint blockade (pembrolizumab or dostarlimab) should be strongly recommended. 1 This recommendation is reserved for patients who received only chemotherapy in first-line, as durvalumab is not universally available. 1

A case report demonstrated pathological complete response after pembrolizumab treatment in MSI-high perihilar cholangiocarcinoma, enabling successful conversion surgery. 2 Another case showed durable response lasting over 27 months with pembrolizumab plus nab-paclitaxel in metastatic extrahepatic cholangiocarcinoma, despite low TMB, MSS status, and negative PD-L1 expression. 3

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Role of Radiation Therapy in Cholangiocarcinoma

Stereotactic Body Radiation Therapy (SBRT) for Intrahepatic Disease

SBRT may be considered for unique intrahepatic cholangiocarcinoma lesions less than 5 cm if surgical resection is not possible. 1, 4 The French Association for the Study of the Liver recommends this approach with expert opinion and strong agreement, noting that SBRT provides benefits including improved local control, overall survival, and acceptable toxicity. 1, 4

SBRT dosing is typically 30-50 Gy in 3-5 fractions, depending on the ability to meet normal organ constraints and underlying liver function. 4 For hilar (perihilar) cholangiocarcinoma, SBRT demonstrates promising efficacy with 2-year local control rates of 47-78%. 4

Technical Considerations for SBRT

• Hydrodissection techniques can enable safe treatment of lesions abutting critical structures including the diaphragm, bile ducts, stomach, or bowel. 4
• Ensure sufficient uninvolved liver volume and strict adherence to liver radiation dose constraints. 4
• Most safety and efficacy data exist for Child-Pugh A liver function; limited data exist for Child-Pugh B, and SBRT should not be used for Child-Pugh C cirrhosis. 4
• Verify adequate respiratory motion management for lesions abutting the diaphragm and confirm diaphragm dose constraints can be met. 4

Conventional External Beam Radiotherapy: Not Recommended

Conventional chemoradiotherapy is probably not recommended for patients with unresectable intrahepatic or perihilar cholangiocarcinoma outside of therapeutic trial settings. 1, 4 There is currently no evidence to support adjuvant postoperative radiation therapy, as radiotherapy did not improve survival or quality of life in patients with resected perihilar cholangiocarcinoma when assessed prospectively. 1

External beam radiotherapy has no proven survival benefit in advanced disease and carries significant toxicity from current methods of delivery, with no evidence of disease sterilizing effects without significant morbidity. 1, 5, 6 Radiation alone retains important palliative value only for painful localizable metastases or uncontrolled bleeding. 1

A National Cancer Database analysis of 1,636 patients with unresectable intrahepatic cholangiocarcinoma showed that combined modality therapy (chemotherapy plus radiation) was associated with improved overall survival compared to chemotherapy alone (2-year OS 26% vs 20%), though three-quarters of inoperable patients in the United States do not receive radiation. 7

Intraluminal Brachytherapy: Insufficient Evidence

Intraluminal brachytherapy combined with external beam irradiation has shown median survival of 10-13 months in uncontrolled studies, but these studies do not support its use in isolation, and there are no controlled data confirming value compared to standard chemotherapy or stenting alone. 1

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Integration of Radiation and Immunotherapy

Combining SBRT with Immune Checkpoint Inhibitors

SBRT should be combined with systemic chemotherapy, particularly gemcitabine plus cisplatin with durvalumab or pembrolizumab, which remains the standard first-line systemic therapy. 4 The combination of SBRT and immunotherapy demonstrates acceptable safety profiles, with concurrent SBRT and immunotherapy not significantly increasing radiation necrosis rates compared to SBRT alone. 4

Treatment Sequencing Algorithm

1. Start with cisplatin-gemcitabine plus durvalumab or pembrolizumab as standard first-line therapy. 4
2. Consider adding SBRT to oligometastatic sites during first-line immunotherapy-chemotherapy for patients with limited disease burden. 4
3. Confirm unresectability through multidisciplinary tumor board evaluation before proceeding with SBRT. 4

Evidence from Other Malignancies Supporting Combination Approach

Data from lung cancer demonstrate that radiotherapy may have positive immune effects including tumor antigen release followed by presentation to dendritic cells that activate the immune system and modulate the tumor microenvironment. 1 The PACIFIC trial in stage III NSCLC showed that durvalumab consolidation after concurrent chemoradiation significantly improved both PFS (17.3 vs 5.6 months; HR 0.51) and OS (HR 0.68). 1

Phase II trials of pembrolizumab after local ablative therapy in oligometastatic NSCLC resulted in encouraging PFS of 19.1 months with acceptable toxicities. 1 However, randomized phase III trials of immune checkpoint inhibitors with or without radiotherapy are warranted to determine optimal treatment sequence, field, volume, dose, and fractionation. 1

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Second-Line Treatment Options

Targeted Therapy for Molecular Alterations

FGFR inhibitors should be recommended for patients with intrahepatic cholangiocarcinoma and FGFR2 fusions or other rearrangements after progression on standard first-line chemotherapy. 1 Pemigatinib, infigratinib, and futibatinib have demonstrated objective response rates of 23-42% in this population. 1

Ivosidenib should be offered for patients with IDH1 mutations who progress on first-line therapy. 1

Second-Line Chemotherapy

In the absence of targetable alterations, FOLFOX should be offered as subsequent-line systemic therapy for patients with advanced cholangiocarcinoma who have tumor progression on first-line therapy. 1 The ABC-06 trial showed modest benefit with FOLFOX over active symptom control alone (median OS 6.2 vs 5.3 months; HR 0.69). 1

Alternatives include irinotecan-based options such as liposomal irinotecan plus 5-fluorouracil, based on phase II trial data from the NIFTY study. 1

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Critical Pitfalls to Avoid

• Do not use conventional low-dose palliative radiation (8 Gy in 1 fraction) for cholangiocarcinoma, as this achieves suboptimal local control. 4
• Do not delay chemotherapy-immunotherapy in eligible patients waiting for further disease progression, as early treatment correlates with improved outcomes. 1, 6
• Do not proceed with SBRT or systemic therapy before optimizing biliary drainage in jaundiced patients. 1, 4
• Avoid treating patients with ECOG >2 with aggressive interventions, as they derive no benefit and experience increased toxicity. 1, 6
• Do not use SBRT for patients with Child-Pugh C cirrhosis, as safety has not been established in this population with very poor prognosis. 4
• When using BRAF and/or MEK inhibitors with radiation (not applicable to cholangiocarcinoma but relevant for other malignancies), consider holding these agents 3 days before and after fractionated radiotherapy and 1 day before and after stereotactic radiosurgery due to potential increased toxicity. 1

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Quality of Life and Palliative 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, particularly in responders. 1, 5, 6 Good symptom control is paramount and requires multidisciplinary input. 5, 6

All patients with inoperable tumors or recurrences should be actively encouraged to participate in chemotherapy and/or radiotherapy clinical trials, as there are many newer promising agents and combinations with potential improved efficacy and tolerability. 1, 5, 6