Neoadjuvant Therapy as a Selection Strategy for Curative Resection in High-Risk Intrahepatic Cholangiocarcinoma.

BACKGROUND

High-risk features (e.g., vascular invasion, lymph node involvement, multifocality, elevated carbohydrate antigen 19-9 [CA19-9], tumor size >5 cm) in intrahepatic cholangiocarcinoma (iCCA) are associated with poor prognosis, leading to increased use of neoadjuvant therapy (NAT).

METHODS

Patients (n = 425) treated in 2000-2024 at Mayo Clinic Rochester were categorized into four groups: (1) high-risk iCCA with NAT (chemotherapy- or chemoimmunotherapy-based regimens) followed by surgery, (2) high-risk iCCA with upfront resection, (3) low-risk iCCA with upfront resection, and (4) high-risk iCCA receiving NAT without surgery ("dropouts"). Outcomes included overall (OS) and recurrence-free survival (RFS). An external cohort of 203 iCCA patients from MD Anderson Cancer Center also was analyzed using identical criteria.

RESULTS

Of 425 patients, 342 (80.5%) were at high risk and 83 (19.5%) were at low risk (all upfront resection). Among the high-risk patients, 172 (50.3%) received NAT and 96 (55.8%) underwent upfront resection, whereas 76 (44.2%) dropped out. The NAT regimens included doublet gemcitabine-cisplatin (GC, n = 56) and triplet chemo(immuno)therapy with gemcitabine-cisplatin-nab-paclitaxel (GAP, n = 30) or gemcitabine-cisplatin-durvalumab (GCD, n = 10). The NAT patients who proceeded to resection showed significantly longer OS than those who had upfront resection (68.6 vs. 34.9 months; p = 0.007), with no significant difference from low-risk patients (106.2 months, p = 0.132). Intensified regimens (GAP/GCD) yielded superior OS, whereas RFS did not significantly differ across groups. Comparable survival trends were observed in the external cohort.

CONCLUSION

Neoadjuvant therapy followed by curative-intent resection was associated with improved OS, reflecting selection of systemic therapy-responsive high-risk patients with more favorable tumor biology, achieving outcomes similar to those of low-risk groups. Conversely, 45% failed to proceed to surgery due to progression or clinical deterioration, experiencing OS comparable with palliative care.