Stereotactic body radiotherapy combination treatment for patients with locally advanced unresectable hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a serious global health burden. With the improvements in radiation technology and understanding of radiobiology and advances in imaging techniques, stereotactic body radiotherapy (SBRT) has emerged as a promising therapeutic option of HCC. The promising local control rate of HCC afforded by SBRT in patients with early-stage HCC has resulted in the inclusion of SBRT as a treatment option in clinical practice guidelines worldwide. However, for patients with large-sized tumours, multi-focal disease, and/or macrovascular invasion, the benefits of SBRT are less clear as out-of-field progression is common after treatment. As such, there is a growing interest in studying SBRT combination strategies to overcome this clinical challenge. In the work reported in this thesis, I first examined SBRT treatment outcomes in 156 patients with large-sized unresectable HCC. The results showed that radiation achieved an impressive anti-tumour response with an acceptable safety profile and that performing transarterial chemoembolisation (TACE) before SBRT had promising therapeutic benefits. Second, a propensity score matching analysis to compare the clinical outcomes of patients with large-sized unresectable HCC treated with combined TACE and SBRT (TACE+SBRT) versus TACE alone showed that TACE+SBRT was associated with a better tumour response, which translated into survival benefits. Pre-clinical data suggest that radiation is likely to harness the host immune system and may work synergistically with immune checkpoint inhibitors. In addition, SBRT and immunotherapy have complementary anti-tumour mechanisms as a local and systemic therapy, respectively. The subsequent chapters describe our evaluation of the efficacy and safety of the novel combination of SBRT and immunotherapy (SBRT+IO). First, we conducted a propensity score matching analysis to evaluate the outcomes of patients with locally advanced HCC treated with SBRT+IO versus TACE alone. The results demonstrated superior outcomes in the SBRT+IO group. Second, a comparative analysis of the clinical outcomes of patients with HCC treated with SBRT+IO versus SBRT alone was conducted. The results showed that performing immunotherapy after SBRT improved the in-field control, out-of-field control, tumour response, and survival of patients. These data provided a rationale for us to study the combination of locoregional therapy and immunotherapy as a conversion treatment for patients with unresectable HCC. Chapter 6 reports the results of a prospective phase II clinical trial (the START-FIT trial). Among 33 cases of locally advanced HCC, over 50% were converted to resectable disease and 42% achieved a radiological complete response after the START-FIT regimen. These results indicate the promising potential of SBRT+IO as an oncological downstaging treatment. Our study demonstrated the promising potential of SBRT+IO and START-FIT combinations in treating HCC patients. A randomised trial with a larger cohort is warranted to confirm our findings. Also, it would be of interest to gather long-term follow-up data of patients attained complete remission. Third, further studies on biomarkers are recommended to better define the candidates suitable for this combined approach. Finally, translational studies should be conducted to uncover the mechanisms underlying the host immunostimulatory effect of locoregional therapy and refine the timing, sequence, and optimal combination of SBRT and immunotherapy.