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Neoadjuvant therapy regimen improves outcomes in high-risk intrahepatic cholangiocarcinoma
1. In a randomized phase 2–3 trial of patients with resectable high-risk intrahepatic cholangiocarcinoma, neoadjuvant therapy with gemcitabine–oxaliplatin, lenvatinib, and an anti programmed death-1 antibody prior to curative resection significantly prolonged event-free survival compared with surgery alone.
2. The regimen demonstrated manageable toxicity and did not compromise surgical feasibility, with most adverse events being low-grade and postoperative outcomes being comparable between groups.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Intrahepatic cholangiocarcinoma is the second most common primary liver cancer and carries a poor prognosis, particularly among patients with high-risk features such as vascular invasion, multifocal disease, or elevated tumor markers. Even after curative resection, recurrence is common and long-term survival remains limited. While adjuvant chemotherapy has modest benefit, there has been no established neoadjuvant standard for patients with resectable but high-risk disease. This randomized phase 2–3 trial evaluated whether a multimodal neoadjuvant regimen combining chemotherapy, targeted therapy, and immunotherapy (the GOLP regimen) improved outcomes. Patients receiving neoadjuvant therapy followed by surgery and adjuvant capecitabine experienced substantially longer event-free survival than those undergoing immediate surgery followed by adjuvant therapy alone. Tumor regression and pathological responses were observed in a subset of treated patients, suggesting meaningful biologic activity of the combination regimen. Overall survival appeared improved as well, though longer follow-up is needed to confirm a definitive benefit. The study’s strengths include its randomized design, centralized outcome assessments, and focus on a well-defined population. However, several limitations may affect generalizability. The trial was conducted exclusively in high-volume centers within a single country and enrolled relatively fit patients, and the chemotherapy backbone may differ from regimens commonly used in other regions. Overall, neoadjuvant GOLP therapy appeared to meaningfully delay disease progression or recurrence in patients with resectable high-risk intrahepatic cholangiocarcinoma.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: This multicenter, open-label phase 2–3 randomized controlled trial evaluated whether neoadjuvant combination therapy could improve outcomes in patients with resectable high-risk intrahepatic cholangiocarcinoma. Between January 2021 and February 2025, 178 patients across 11 hospitals in China were randomized in a 1:1 ratio to receive either neoadjuvant GOLP (gemitabine-oxaliplatin, lenvatinib, toripalimab) therapy followed by surgery and adjuvant capecitabine or immediate surgery followed by adjuvant capecitabine alone. High-risk disease was defined by at least one adverse feature such as large tumor size (>5 cm), vascular invasion, multiple tumors, portal lymph node involvement, or elevated CA 19-9 levels. The primary endpoint was event-free survival, defined as time from randomization to progression precluding resection, postoperative recurrence or metastasis, second primary cancer, or death. Secondary outcomes included overall survival, response rates, pathological response, recurrence-free survival, and safety. At a median follow-up of 16.9 months, 95 events had occurred. Median event-free survival was 18.0 months in the neoadjuvant group compared with 8.7 months in the control group (P < 0.001). Restricted mean survival time was also calculated and showed a 6.6-month difference favoring neoadjuvant therapy. Event-free survival at 24 months was 37% in the neoadjuvant group versus 25% in controls. Overall survival also favored the neoadjuvant group, with 79% survival at 24 months versus 61% in the control group (hazard ratio for death, 0.43; 95% confidence interval, 0.23 to 0.79; p = 0.005), although this did not cross the prespecified statistical significance threshold. Radiologic objective response occurred in 55% of patients receiving neoadjuvant therapy, and 24% achieved major or complete pathological response. Regarding safety, 97% of patients receiving neoadjuvant therapy experienced adverse events as compared with 70% of patients in the control group. Grade ≥3 events occurred in 28% of patients during the neoadjuvant phase, most commonly neutropenia or leukopenia. Importantly, no treatment-related deaths occurred, and surgical outcomes—including operative duration, blood loss, and complication rates—were comparable between groups.
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