With advancements in local treatment techniques and the emergence of new therapeutic agents, combined local and systemic therapies have demonstrated synergistic effects greater than the sum of their parts in liver cancer management. For patients with intermediate and advanced liver cancer, this approach has improved conversion therapy success rates and even achieved curative outcomes. At the 2024 Chinese Congress of Holistic Integrative Oncology (CCHIO), during the "Interventional Oncology" session, Dr. Ming Zhao from the Sun Yat-sen University Cancer Center shared his insights on the combined treatment approach. Oncology Frontier interviewed Professor Zhao to discuss the theoretical foundations, current developments, and future directions of combined local and systemic therapies.

Oncology Frontier: Could you provide an overview of the treatment models for combined local and systemic therapies in intermediate and advanced liver cancer, and what are the key principles of their application?

Dr. Ming Zhao: The field of liver cancer treatment has seen the rapid development of new methods and technologies. This year’s CCHIO dedicated a session to interventional oncology to explore the advancements in local and systemic treatments for liver cancer. Currently, local treatments include hepatic artery infusion chemotherapy (HAIC), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), ablation, radiotherapy, and surgical interventions.

Various combinations have been developed between local treatments and systemic therapies, including targeted and immunotherapy drugs, as well as between different local treatments such as TACE combined with radiotherapy or TACE combined with ablation. The most common combinations for intermediate and advanced liver cancer include TACE with ablation or radiotherapy, and TACE or HAIC with systemic therapies. The guiding principle for these combined approaches is to achieve better clinical outcomes through synergistic methods. Numerous clinical details require thorough analysis and implementation to optimize these strategies.

Oncology Frontier: Targeted or immunotherapy combined with local treatments often yields synergistic effects greater than either treatment alone. Could you elaborate on the theoretical basis for this synergy?

Dr. Ming Zhao: The concept of achieving a 1+1>2 effect through combined local and systemic therapies is supported by theoretical foundations and has been observed in clinical practice.

Firstly, local treatments like TACE and TARE induce tumor necrosis, releasing tumor antigens that can activate immune cells. These immune cells infiltrate tumors to eliminate residual cancer cells or target micrometastases outside the primary tumor.

Secondly, local treatments have inherent limitations. For instance, TACE creates a hypoxic microenvironment that upregulates PD-L1 expression in macrophages or T cells. Combining immunotherapy in such scenarios enhances the anti-tumor immune response. Additionally, local treatments are often limited in scope, while systemic therapies address tumors comprehensively. Furthermore, repeated local treatments can significantly impair liver function, negatively affecting overall survival (OS). Combining systemic therapies can mitigate or prevent these adverse effects.

Thirdly, systemic therapies have their own limitations. Not all tumors are sensitive to systemic drugs. Combining local therapies allows for the elimination of resistant lesions, enhancing treatment efficacy.

Finally, frequent hospitalizations for local treatments can be taxing for patients. Combined therapies reduce the number of hospital visits, improving the patient’s treatment experience and quality of life.

These mechanisms highlight how combined local and systemic therapies can improve treatment outcomes, survival rates, and quality of life, solidifying their role as a recommended clinical strategy.

Oncology Frontier: Conversion therapy offers a potential cure for intermediate and advanced liver cancer patients. What breakthroughs have been achieved in this area with combined local and systemic therapies?

Dr. Ming Zhao: Only 15–20% of liver cancer patients in China are diagnosed at an early stage and are eligible for direct surgical interventions, including resection, transplantation, or local treatments. For others, particularly those with inoperable tumors, local and systemic therapies are necessary.

Recent advancements in local treatments and pharmacological approaches have enabled many patients with potentially resectable tumors to undergo downstaging or conversion therapy, achieving surgical eligibility and long-term survival. Conversion therapy has thus become a focal point of research.

The primary model for conversion therapy combines local and systemic treatments. Studies indicate that single-agent or multi-agent systemic therapy alone achieves suboptimal results, with less than 5% of patients successfully undergoing surgery. However, local therapies such as HAIC, TACE, and TARE have shown efficacy in reducing tumor size and number as per RECIST or mRECIST standards. When combined with systemic therapies, these approaches significantly improve conversion success rates, as evidenced by domestic and international studies.

For liver cancer with portal vein tumor thrombus, single-agent TACE is often inadequate. Combining TACE with radiotherapy has proven effective in reducing tumor burden, and some patients achieve complete response (CR) or pathological complete response (pCR) based on mRECIST criteria. Overall, these breakthroughs have provided intermediate and advanced liver cancer patients with improved survival outcomes and the possibility of long-term remission.

Oncology Frontier: What future developments and research directions do you foresee for combined local and systemic therapies?

Dr. Ming Zhao: To identify the most promising avenues for combined therapies, we must address current challenges. Key questions include:

1. Which local therapy is best suited for combination with systemic treatments?
2. What is the optimal sequencing of local and systemic therapies?
3. How many cycles of local therapy are necessary?
4. How should we prioritize local versus systemic therapies?

These questions represent critical areas for future exploration.

Advancements in both local and systemic therapies continue to enhance their efficacy. In local treatments, improvements in vascular interventional techniques, ablative technologies, and imaging guidance allow for more precise tumor targeting. On the systemic side, combination immunotherapy, including VEGF/PD-1 bispecific antibodies, TGF-β inhibitors, CTLA-4/PD-1 inhibitors, and TCR-T or CAR-T therapies, holds great promise.

Furthermore, advancements in molecular diagnostics and pathological analysis will facilitate personalized treatments, optimizing therapeutic outcomes. The integration of these innovations will undoubtedly expand the horizons of combined local and systemic therapies for liver cancer.

About Dr. Ming Zhao

• Chief Physician and Doctoral Supervisor, Sun Yat-sen University Cancer Center
• Member, National Health Commission’s Oncology Expert Committee
• Committee Member, National Cancer Center Liver Cancer Quality Control Committee
• Executive Member, CSCO Liver Cancer Expert Committee and Interventional Medicine Committee
• Director, CACA Interventional Oncology Immunotherapy and Chemotherapy Subcommittee
• Recognized as a leading clinical scientist and recipient of the Eighth Yangcheng Outstanding Physician Award (2022)

Professor Zhao continues to spearhead innovations in the treatment of intermediate and advanced liver cancer, aiming to enhance outcomes through multidisciplinary approaches.