Neoadjuvant GOLP Doubles Event-Free Survival in Cholangiocarcinoma

The Challenge of Recurrence in Resectable Biliary Tract Cancers

Intrahepatic cholangiocarcinoma is an aggressive biliary tract malignancy characterized by poor long-term outcomes and high rates of disease recurrence, even following curative-intent surgical resection [1, 2]. While surgery remains the only definitive curative modality, a significant proportion of patients harbor micrometastatic disease at the time of operation, underscoring the urgent need for effective perioperative systemic therapies [3]. Adjuvant regimens, such as capecitabine, have become standard practice to help reduce postoperative recurrence, yet the role of neoadjuvant treatment remains largely investigational [2]. Recent efforts have explored various combinations of chemotherapy, targeted agents, and immunotherapy to downsize tumors and control early micrometastases before patients reach the operating room [4, 1]. A recent phase 2-3 trial evaluates how a specific multi-agent neoadjuvant approach, the GOLP regimen (intravenous gemcitabine and oxaliplatin, oral lenvatinib, and the programmed cell death protein-1 inhibitor toripalimab), affects survival outcomes for patients with high-risk, resectable disease [5].

Trial Design and the GOLP Regimen

Currently, no neoadjuvant treatment is considered standard therapy for patients with resectable intrahepatic cholangiocarcinoma who have high-risk factors for recurrence. To address this clinical gap, researchers conducted a phase 2-3 trial (registry number NCT04669496) enrolling 178 patients with resectable, high-risk disease. Participants underwent randomization in a 1:1 ratio, with 88 patients assigned to the neoadjuvant group and 90 to the control group. The experimental arm utilized the GOLP regimen, a combination therapy consisting of cytotoxic chemotherapy (gemcitabine and oxaliplatin), a targeted tyrosine kinase inhibitor (lenvatinib), and an immune checkpoint inhibitor (the anti-programmed death 1 antibody toripalimab). Patients in the neoadjuvant group received intravenous gemcitabine-oxaliplatin plus toripalimab every three weeks for three cycles, alongside oral lenvatinib once daily for nine weeks, followed by curative resection. The control group underwent immediate curative resection with no preoperative therapy. To maintain a standardized postoperative approach and isolate the effect of the neoadjuvant intervention, all patients in both groups received standard adjuvant capecitabine for eight cycles after surgery.

Event-Free and Overall Survival Outcomes

The primary end point of the trial was event-free survival, a critical metric for evaluating how long patients remain free from disease recurrence or progression after surgery. At the interim analysis, conducted at a median follow-up of 16.9 months, the researchers found that neoadjuvant GOLP led to significantly longer event-free survival than control therapy. Specifically, the median event-free survival was 18.0 months (95% confidence interval [CI], 13.8 to 27.6) in the neoadjuvant group, compared to 8.7 months (95% CI, 7.2 to 12.4) in the control group (P<0.001). This doubling of event-free survival suggests that aggressive preoperative systemic therapy can effectively clear micrometastatic disease, offering patients a substantially longer period without debilitating recurrence. The study also evaluated overall survival to determine if this delay in recurrence translated to a longer lifespan. Overall survival at 24 months was 79% (95% CI, 70 to 90) in the neoadjuvant group and 61% (95% CI, 50 to 75) in the control group. The calculated hazard ratio for death was 0.43 (95% CI, 0.23 to 0.79; P=0.005). However, clinicians should note that this overall survival difference did not meet the prespecified significance criterion of a two-sided alpha of 0.0019. Because the statistical threshold for this secondary endpoint was set exceptionally high to account for multiple testing, the overall survival benefit remains formally non-significant at this interim stage, though the hazard ratio points toward a meaningful reduction in mortality risk.

Safety Profile and Adverse Events

When evaluating the tolerability of the preoperative regimen, the researchers noted that the adverse events associated with neoadjuvant GOLP were primarily low-grade. However, the addition of multi-agent systemic therapy predictably increased the overall side effect burden. Across all treatment phases, adverse events occurred in 97% of patients in the neoadjuvant group, compared to 70% of patients in the control group. Looking specifically at the preoperative period, the study quantified the rates of severe toxicity to determine if the regimen might compromise surgical candidacy. During the neoadjuvant phase, adverse events of grade 3 or higher occurred in 28% of the patients, with treatment-related adverse events of grade 3 or higher occurring in 26%. Despite this expected incidence of severe side effects, the regimen demonstrated a manageable safety profile for surgical candidates. Crucially for practicing oncologists and surgeons, no treatment-related adverse event led to death, indicating that the GOLP protocol can be safely administered without precluding patients from undergoing their planned curative resections.

References

1. Fruscione M, Pickens RC, Baker EH, et al. Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review.. Current problems in cancer. 2021. doi:10.1016/j.currproblcancer.2020.100614

2. Nara S, Esaki M, Ban D, et al. Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials. Japanese Journal of Clinical Oncology. 2020. doi:10.1093/jjco/hyaa170

3. Medin C, Maithel S. Neoadjuvant therapy trials in biliary tract malignancies. Journal of Surgical Oncology. 2021. doi:10.1002/jso.26714

4. Cheng Y, Xia J, Chi Y, Rao J, Cheng F. Neoadjuvant hepatic arterial infusion chemotherapy (HAIC) with GEMOX and lenvatinib in combination with adebrelimab for resectable high-risk recurrent intrahepatic cholangiocarcinoma (ICC): study protocol of the NEO-ERA-01 feasibility trial.. BMJ open. 2026. doi:10.1136/bmjopen-2025-101101

5. Shi G, Huang X, Liang F, et al. Neoadjuvant GOLP in Resectable High-Risk Intrahepatic Cholangiocarcinoma.. New England Journal of Medicine. 2026. doi:10.1056/NEJMoa2513918