The Era of Neoadjuvant Chemotherapy for Cholangiocarcinoma: Has It Already Begun?

Until only a few years ago, systemic chemotherapy provided only limited survival benefits for patients with cholangiocarcinoma. However, the introduction of triplet cytotoxic chemotherapy demonstrated a meaningful improvement in overall survival and, more importantly, enabled conversion surgery by downstaging tumors previously considered unresectable. Although triplet cytotoxic chemotherapy has not been adopted as the standard first-line treatment in the National Comprehensive Cancer Network (NCCN) Guidelines, the increasing recognition of locally advanced cholangiocarcinoma as a distinct clinical entity has stimulated continued investigation in this field. Subsequent studies have consistently demonstrated not only improved survival and higher rates of conversion surgery in patients with initially unresectable disease but also superior survival outcomes with neoadjuvant chemotherapy for patients with locally advanced or even technically resectable cholangiocarcinoma compared with upfront surgery alone. More recently, a novel quadruplet regimen comprising an immune checkpoint inhibitor, a targeted agent, and two cytotoxic chemotherapeutic agents has been introduced. A randomized controlled trial demonstrated the superiority of neoadjuvant therapy using this regimen in patients with locally advanced cholangiocarcinoma, providing the strongest evidence to date in support of this treatment strategy. Looking ahead, neoadjuvant chemotherapy is expected to play an increasingly important role not only in patients with locally advanced disease but also in those with resectable tumors at diagnosis. Furthermore, treatment strategies are likely to evolve beyond conventional triplet regimens toward more intensive quadruplet or even quintuplet combination therapies designed to maximize tumor response and improve long-term survival.