Hepatocellular carcinoma (HCC), often called the "king of cancers," not only has a low survival rate in advanced stages but also carries a high risk of postoperative recurrence, with a five-year recurrence rate reaching up to 80%. Reducing tumor recurrence through postoperative adjuvant therapy has long been a challenge for clinicians. With the advancement of medical technologies, China has developed unique experiences and research achievements in interventional treatments for liver cancer, which continue to evolve and optimize. At the recent 2024 CACA Liver Cancer Integrated Conference, Dr. Minshan Chen from Sun Yat-sen University Cancer Center delivered an insightful presentation on the "Clinical Application of Postoperative TACE" and further shared thoughts on the current research progress and strategic considerations in liver cancer adjuvant treatment in an interview with Hepatology Digest.Hepatology Digest: Could you discuss the evolution and clinical value of interventional therapy in postoperative adjuvant treatment for liver cancer?
Dr. Minshan Chen: Interventional therapy is one method for preventing postoperative recurrence. According to a survey of postoperative adjuvant treatment models in 27 hospitals in China, the application rate of transarterial chemoembolization (TACE) for liver cancer after surgery reached 44% (17% for TACE alone, 27% for TACE combined with systemic therapy), even though the clinical value of postoperative TACE is not widely recognized internationally.
Postoperative TACE for liver cancer in China began in the early 1990s, and it has been more than 30 years since then. At that time, imaging technology was not yet precise—MRI was not available, and CT was in its infancy. After liver cancer surgery, residual lesions were often undetected and untreated. To address this, we began using postoperative hepatic arterial angiography to detect residual lesions and treat them with embolization and chemotherapy. As research progressed and experience accumulated, we found that postoperative TACE provided little benefit to early-stage patients. Therefore, we shifted our strategy to focus on high-risk recurrence cases, such as those with high tumor burden, vascular invasion, unclear margins, P53 positivity, high PCNA index, or postoperative residual disease.
With the clinical introduction of MRI, the use of postoperative hepatic arterial infusion chemotherapy (HAIC) and TACE has decreased. However, we found that high-risk patients can still benefit from 1-2 sessions of postoperative TACE. TACE is the most commonly used treatment for intermediate and advanced liver cancer, but it often cannot shrink tumors, and its effectiveness is limited for large tumors or satellite lesions. It is also ineffective in clearing micro-metastases, and repeated treatments may increase adverse effects. Therefore, we are continuing to explore optimal postoperative interventional strategies.
Professor Rongping Guo’s team discovered that preoperative HAIC significantly reduced micro-metastases in surgical specimens, and a randomized controlled study published in JCO in 2022 confirmed that adjuvant HAIC could reduce the postoperative recurrence risk in high-risk patients (e.g., single tumors larger than 5 cm with microvascular invasion) and prolong disease-free survival. Overall, the era of HAIC replacing TACE is approaching. A phase III randomized controlled study by Professor Ming Shi, also published in JCO, showed that HAIC with FOLFOX chemotherapy as first-line treatment for large hepatocellular carcinomas (≥7 cm, without vascular invasion or extrahepatic metastasis) was more effective than TACE.
Additionally, we have explored the timing of adjuvant therapy and found that regular postoperative follow-up with treatment initiated upon recurrence is feasible and allows for more precise and effective interventions. However, this view still requires further clinical validation. Currently, for high-risk recurrence patients, 1-2 sessions of HAIC after surgery seem to be a viable strategy to clear micro-metastases and reduce recurrence risk.
Hepatology Digest: As you mentioned, the proportion of interventional therapy in China is relatively high. From a technical perspective, how should TACE or HAIC be optimized? What are the differences between the two?
Dr. Minshan Chen: As mentioned earlier, the rapid development of imaging technology, particularly MRI, allows us to detect even the smallest lesions in the liver, down to just a few millimeters, greatly reducing the risk of residual disease after surgery. TACE is primarily useful for detecting and treating residual cancer in the liver after surgery, but it may not benefit patients without residual lesions. Therefore, I believe that the application of postoperative TACE will decrease and may no longer be a routine practice in the future.
Looking back at past TACE procedures, we found that some doctors may not have followed standardized protocols. Traditionally, 3 ml of ultra-liquid lipiodol was mixed with doxorubicin and slowly injected into the liver in the form of tiny particles. However, some doctors may opt for drug-loaded microspheres, gelatin sponges, or even direct injection of chemotherapy drugs, which deviates from the fundamental principle of TACE. TACE relies on lipiodol’s tumor affinity to deliver chemotherapy drugs for embolization and cytotoxic treatment of residual liver lesions.
In the HAIC era, we have transitioned from traditional lipiodol embolization to continuous infusion of chemotherapy drugs over 12-48 hours, with the infusion rate controlled by a pump. This method is more effective than TACE, killing more tumors, shrinking tumors, treating satellite lesions, and most importantly, clearing micro-metastases.
Hepatology Digest: Besides interventional therapy, systemic therapy is also a potential option for postoperative adjuvant treatment in liver cancer. How do you view the current research on systemic therapy and its reasonable application in adjuvant treatment for liver cancer?
Dr. Minshan Chen: Regarding adjuvant systemic therapy after liver cancer surgery, I maintain a cautious attitude. This is mainly because liver cancer has a unique pathological background, including hepatitis and cirrhosis. Over-treatment may further damage liver function, even leading to liver failure or exacerbation of hepatitis and cirrhosis. Additionally, the side effects of drugs, particularly targeted and immunotherapy drugs, should not be overlooked, as they can cause significant health issues.
I have summarized my views on drug adjuvant therapy into 11 points:
- Adjuvant therapy is preventive, unknown, and blind, requiring higher safety standards, similar to vaccines.
- The recurrence mechanism of hepatocellular carcinoma involves two pathways of intrahepatic recurrence, and only one can be targeted.
- Most liver cancer patients also have hepatitis and cirrhosis (80%), and exacerbating cirrhosis is not worth the risk.
- There is no conclusive, high-level evidence (due to company interests), and most patients (80-90%) do not benefit.
- Patients bear the cost, endure side effects, and face risks to their liver function and drug toxicity.
- Recurrence in liver cancer is often multiple and repetitive, raising the question of how many rounds of adjuvant therapy can be justified.
- Recurrence is not the end of life. Patients can still achieve long-term survival through curative treatments after recurrence.
- Postoperative regular follow-ups with recurrence treatments like resection or ablation are far superior to drug therapies.
- Drugs cannot completely prevent recurrence; they may only delay it in some cases (ORR <36%).
- Even post-recurrence, starting drug treatment does not necessarily delay therapeutic outcomes.
- If adjuvant drug therapy is administered and recurrence still occurs, subsequent second-line drug options become more challenging.
These views were summarized in July 2023. Overall, we still lack large-scale phase III clinical evidence supporting the benefits of postoperative adjuvant systemic therapy. Recently, at the 2024 ESMO conference, updated results from the IMbrave050 study showed that one year of adjuvant therapy with “T+A” (atezolizumab + bevacizumab) compared to active surveillance resulted in a progression-free survival (RFS) hazard ratio adjustment from 0.72 to 0.90. The Kaplan-Meier curves for the treatment and observation groups are converging, and overall survival (OS) data for the two groups are still immature (HR=1.12). The incidence of grade 3-4 adverse events in the treatment group was 41%, three times higher than in the control group (13%), posing significant challenges for postoperative adjuvant treatment management.
Regarding the management of postoperative adjuvant treatment, I believe that the principle of “if it can be avoided, it should be avoided” should still be followed unless the patient is at high risk of recurrence. Even in such cases, we need to proceed with caution and avoid over-treatment. This approach balances the benefits and risks for the patient and reflects my personal view.
