Hepatocellular carcinoma (HCC) represents a significant portion of primary liver cancer cases and is a leading cause of cancer-related deaths globally. In China, a majority of HCC patients are diagnosed at intermediate or advanced stages, limiting their treatment options. Transarterial chemoembolization (TACE) has been a cornerstone in the local treatment of unresectable HCC, especially for those in the intermediate stage. However, the limitations of TACE, such as the activation of hypoxia-inducible factor-1α (HIF-1α), have led to the exploration of combination therapies involving TACE, molecularly targeted agents, and immune checkpoint inhibitors (ICIs).
Recent advancements have introduced atezolizumab plus bevacizumab (T+A) and tremelimumab plus durvalumab as first-line treatments for advanced HCC, marking the beginning of the immunotherapy era for HCC. Despite the initial lack of significant clinical response to ICIs monotherapy, combination therapies have shown positive outcomes. A systemic review suggests that the triple therapy of TACE, tyrosine kinase inhibitors (TKIs), and ICIs offers clinical benefits for unresectable HCC (uHCC) without increasing severe adverse events (AEs).
Key Findings:
- Median OS and PFS were significantly prolonged in patients receiving TACE combined with molecularly targeted agents and ICIs (TACE+T+I) compared to those receiving TACE combined with molecularly targeted agents alone (TACE+T).
- The objective response rate (ORR) was significantly higher in the TACE+T+I group, with a complete response (CR) rate of 9.5% and a disease control rate (DCR) of 83.3%.
- The study also highlighted the role of anti-angiogenic agents in vascular normalization and positive immune regulation, enhancing the efficacy of immunotherapy.
Discussion:
The combination of TACE with targeted and immune therapies has shown to transform the immunosuppressive tumor microenvironment into an immunosupportive one, facilitating better efficacy of immune agents. Despite the promising results, the study acknowledges the need for further research to determine the optimal intervals for initiating targeted and immune therapies, their sequence relative to TACE, and the criteria for terminating combination therapy.
Limitations:
- The retrospective nature of the study and limited follow-up time may affect the robustness of the evidence.
- The diversity in anti-angiogenic agents and immune agents used introduces potential confounding effects.
In conclusion, the triple combination therapy of TACE, molecularly targeted agents, and ICIs represents a significant advancement in the treatment of intermediate and advanced HCC, offering improved prognosis over traditional therapies. However, addressing the identified issues and limitations is crucial for optimizing this treatment approach.
