Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials

by Selleckchem | Dec 04 2023

Background: Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results.

Methods: In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome.

Results: A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE.

Conclusions: TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.

Comments:

This systematic review and meta-analysis provide valuable insights into the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) for patients with unresectable hepatocellular carcinoma (HCC). Here's a breakdown of the key findings:

### Positive Outcomes:

1. **Time to Progression (TTP):**
- **Positive Result:** TACE+MKI significantly prolonged TTP compared to TACE monotherapy. This suggests that the combination therapy delays disease progression, indicating a potential benefit for patients in terms of disease control.

2. **Objective Response Rate (ORR):**
- **Positive Result:** TACE+MKI increased the objective response rate. Patients on this combination therapy were more likely to exhibit a positive response to the treatment, indicating a reduction in tumor size or extent.

### Neutral Outcomes:

1. **Overall Survival (OS):**
- **Neutral Result:** There was no significant difference in overall survival between the TACE+MKI group and the TACE monotherapy group. While TTP was improved, it did not translate into a significant increase in overall survival, suggesting that the combination therapy might not impact patients' long-term survival.

2. **Progression-Free Survival (PFS):**
- **Neutral Result:** The combination therapy did not significantly improve progression-free survival. This indicates that, although the disease progression was delayed (as indicated by the improved TTP), it did not result in a significant extension of the time before the disease worsened.

### Adverse Events (AEs):

1. **Overall Adverse Events:**
- **Neutral Result:** The overall incidence of any adverse events did not significantly differ between the TACE+MKI and TACE groups. This suggests that the combination therapy did not increase the overall risk of adverse events compared to TACE monotherapy.

2. **Serious Adverse Events:**
- **Negative Result:** There was a significant increase in serious adverse events in the TACE+MKI group. However, these events were primarily associated with MKI toxicities rather than TACE. This indicates that while the combination therapy might be associated with more serious adverse events, these are related to the MKI component of the treatment.

### Implications and Recommendations:

- **Clinical Benefits:** The study suggests that TACE+MKI combination therapy could be beneficial in delaying disease progression and improving objective response rates in unresectable HCC patients.
- **Long-term Survival:** While TTP was improved, there was no significant impact on overall survival or progression-free survival. This suggests that while the combination therapy controls the disease temporarily, it might not provide a long-term survival advantage.
- **Adverse Events:** Careful consideration of MKI-related toxicities is crucial when deciding on this combination therapy. Serious adverse events associated with MKIs need to be managed effectively.

### Future Directions:

- **Further Trials:** The study emphasizes the need for additional high-quality trials to validate these findings. It's essential to conduct more research to understand the long-term effects and benefits of TACE+MKI combination therapy fully.
- **Trial Design:** The findings of this study can inform the design of future clinical trials, ensuring that they account for the observed benefits and risks associated with this combination therapy.

In summary, while the combination therapy shows promise in controlling the disease and eliciting positive responses, especially in terms of delaying disease progression, careful monitoring and management of MKI-related adverse events are necessary. Additionally, ongoing research and well-designed trials will be instrumental in fully understanding the clinical benefits and risks associated with TACE+MKI combination therapy for unresectable HCC.