Neoadjuvant systemic therapy for hepatocellular carcinoma: challenges and opportunities-a narrative review

Hepatocellular carcinoma (HCC) is one of the most common cancers with high mortality rate worldwide. Surgical resection, liver transplantation (LT), and thermal ablation are primary curative methods for early-stage HCC. However, the high recurrence rate following surgical intervention is the primary factor contributing to the unfavorable prognosis. Therefore, the critical aspect in improving the overall survival of HCC lies in reducing the postoperative recurrence rate. This review is aimed at summarizing the current evidence base regarding the safety and efficacy of systemic therapy administered in the neoadjuvant context for patients with resectable HCC. Furthermore, we will offer a perspective on the potential future trajectories of systemic therapy as a neoadjuvant modality in the management of HCC.

We searched PubMed with terms: hepatocellular carcinoma, neoadjuvant, preoperative, chemotherapy, hepatic arterial infusion chemotherapy, targeted therapy, systemic therapy, immunotherapy. Relevant ongoing clinical trials registered at ClinicalTrials.gov are included.

In the context of resectable solid organ cancers, neoadjuvant therapy is frequently administered to delay disease progression, ensure appropriate patient selection, reduce tumor burden and potentially eradicate micrometastases prior to surgical procedures. In recent years, the advancements in systemic therapy for advanced HCC, especially with anti-vascular endothelial growth factor antibodies, tyrosine-kinase inhibitors and immunotherapy combination, have significantly contributed to notable improvements in overall survival. These breakthroughs have prompted the exploration and implementation of systemic therapy in the setting of neoadjuvant and adjuvant therapy for HCC. In this review, we aim to briefly summarize the current available evidence on the safety and efficacy of systemic therapy in neoadjuvant settings designed to improve the outcome of curative-intent liver resection or LT for patients with resectable HCC. Additionally, we discuss the challenges and issues that need to be further clarified before widespread adoption of neoadjuvant therapies, providing an outlook on future directions of systemic therapy as neoadjuvant treatment in HCC.

Neoadjuvant therapy involving immunotherapy, particularly immune checkpoint inhibitors, seems to exhibit the most promising characteristics of preventing recurrence and improving long-term survival of HCC patients following curative hepatectomy or LT, especially when combined with anti-angiogenic therapies and locoregional therapy. Further research is needed to identify suitable candidates, predictive biomarkers, optimal regimens for neoadjuvant therapy, and ideal timing for surgery.