Transcatheter Arterial Chemoembolization Followed by Surgical Resection for Hepatocellular Carcinoma: A Focus on Its Controversies and Screening of Patients Most Likely to Benefit
Hepatocellular carcinoma (HCC) is the third most common cancer worldwide, with an increasing mortality rate. Surgical resection (SR) is often recommended as a radical procedure for HCC. However, the long-term efficacy of SR is compromised by postoperative recurrence, prompting the exploration of preoperative adjuvant therapies. Among these, transcatheter arterial chemoembolization (TACE) has been adopted by some clinicians to improve resection rates, reduce tumor recurrence, and enhance prognosis. Despite its potential benefits, the efficacy of preoperative TACE remains controversial, with some studies suggesting it may not improve long-term survival and could even negatively impact resection rates. This review aims to analyze existing clinical studies, focusing on the screening of patient subgroups most likely to benefit from preoperative TACE, the exploration of optimal TACE treatment regimens, and the determination of tumor necrosis extent as a prognostic factor.
Introduction
HCC is a significant global health concern, with SR being a primary treatment option. However, the practical effectiveness of SR is often limited by postoperative recurrence. To address this, preoperative adjuvant therapies like TACE have been introduced. TACE involves the delivery of chemotherapy drugs via the hepatic artery, targeting the tumor directly while minimizing systemic effects. Despite its potential, the impact of preoperative TACE on HCC prognosis remains debated. This review seeks to provide a comprehensive analysis of the factors influencing the efficacy of preoperative TACE combined with SR, with a focus on patient selection, treatment optimization, and prognostic indicators.
HCC Combination Therapy with TACE and SR
HCC is predominantly a locoregional disease, with distant metastasis occurring in advanced stages. The hepatic artery serves as the primary feeding vessel for most HCC tumors, making it an effective pathway for targeted therapy. TACE leverages this characteristic by delivering chemotherapy drugs and embolizing agents like lipiodol to reduce tumor blood supply, promote necrosis, and inhibit malignant changes in residual liver tissue. TACE is versatile, applicable regardless of tumor size, location, or number, and is widely used as a palliative treatment for unresectable HCC. It has also become a common postoperative adjuvant therapy after SR and is increasingly used preoperatively before liver transplantation and SR.
Improvement of Prognosis by Preoperative TACE
The primary goal of preoperative TACE is to inactivate HCC cells and shrink the tumor by embolizing its feeding artery. Studies have shown that preoperative TACE can enhance apoptosis of HCC cells, upregulate Bax protein expression, and downregulate Bcl-2 protein expression, leading to tumor shrinkage. This can transform unresectable HCC into resectable HCC, improve the R0 resection rate, increase residual liver volume, and enhance 5-year survival rates. Additionally, TACE can destroy small tumors and satellite nodules, eliminating microtumor lesions that SR might miss. It also inhibits HCC cell dissemination during surgery, reducing tumor recurrence, and can detect microtumor lesions not visible in early imaging, aiding in complete tumor removal during SR.
Detrimental Effects of Preoperative TACE
Despite its potential benefits, preoperative TACE has several drawbacks. It can cause perihepatic adhesions, making SR more challenging, and increase the risk of liver damage and failure. Delays in SR due to TACE can turn resectable tumors into unresectable ones, and repeated TACE can enhance collateral feeding artery formation, complicating future treatments. Additionally, TACE can destabilize residual tumor cells, increasing the likelihood of metastasis during SR. Other adverse effects include postembolization syndrome, ascites, liver function deterioration, tumor progression, bacteremia, and bleeding from the femoral puncture site. Severe adverse events are more likely in patients with large tumors, multiple tumors, or when TACE is not performed superselectively.
Screening of Subgroups of Patients Who Benefit from Preoperative TACE
Given the mixed outcomes of preoperative TACE, identifying patient subgroups most likely to benefit is crucial. Studies suggest that TACE is more effective in patients with advanced HCC and large tumors (≥5 cm). For patients with stage III or IV HCC, preoperative TACE can reduce the number and scope of recurrent tumors, improving the pattern of tumor recurrence. Conversely, TACE may not benefit patients with early-stage HCC or small tumors. Additionally, patients with poor liver function should avoid preoperative TACE due to the risk of further liver damage. Genetic factors, such as TP53 mutations, may also influence TACE efficacy, warranting further research into the relationship between oncogenes and TACE outcomes.
Exploration of Optimal Treatment Regimen of Preoperative TACE
The effectiveness of preoperative TACE can vary based on the number of TACE sessions and the interval between TACE and SR. While some studies recommend at least two TACE sessions before SR, others suggest that repeated TACE can increase recurrence rates and complicate surgical procedures. The optimal interval between TACE and SR should balance the safety of SR, the effectiveness of TACE, and the risk of tumor recurrence. Clinicians must consider tumor diameter, degree of embolization, liver function recovery, and preoperative evaluation results to determine the best timing for SR.
Extent of Tumor Necrosis as the Deciding Prognostic Factor
The extent of tumor necrosis induced by TACE is a critical prognostic factor. Complete tumor necrosis is associated with better disease-free survival, while incomplete necrosis increases the risk of recurrence. The deposition of lipiodol in the tumor is a key determinant of necrosis extent, with subtotal necrosis (>90%) linked to favorable outcomes. Pathological examination can predict recurrence-free and overall survival based on necrosis extent. However, complete necrosis is uncommon, occurring in only about 20% of cases. Factors influencing necrosis extent include tumor burden, biology, TACE regimen, and patient condition, highlighting the need for personalized treatment plans.
Several Issues That Deserve Further Study
Antiviral therapy may interfere with TACE efficacy, particularly in HBV-related HCC, where TACE can reactivate the virus. Antiviral therapy can reduce this risk and improve liver function post-TACE. Additionally, microparticle-TACE (mTACE) using agents like gelatin sponge microparticles (GSMs) and biocompatible polymer poly(D,L-lactide-co-glycolide) (PLGA) microparticles has shown superior efficacy compared to conventional TACE. mTACE reduces damage to normal liver tissue, enhances tumor necrosis, and may trigger a stronger antitumor immune response. Further research is needed to explore the benefits of mTACE and its combination with SR.
Conclusion
Preoperative TACE combined with SR remains a controversial topic in HCC treatment. While TACE can benefit certain patient subgroups, particularly those with large tumors and advanced HCC, its efficacy is influenced by various factors, including tumor necrosis extent, treatment regimen, and patient condition. Identifying patients most likely to benefit from preoperative TACE and optimizing treatment protocols are essential for improving outcomes. As TACE techniques continue to evolve, further research is needed to refine its application and enhance its safety and efficacy in HCC treatment.
doi.org/10.1097/CM9.0000000000001767
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