Editor's Note: In recent years, with the continuous improvement of radiotherapy technology, not only has the effectiveness of tumor reduction been optimized compared to the past, but it has also further improved the overall survival of liver cancer patients. The combination of radiotherapy and immunotherapy has gradually become a new exploration in the treatment of primary liver cancer. On December 9, 2023, the "Beijing Tsinghua Chang Gung Hospital Hepatobiliary Tumor Multidisciplinary Academic Conference," hosted by the Precision Medicine and Oncology MDT Special Committee of the China Research Hospital Association, was successfully held online and offline. During the conference, Dr. Guangxin Li from Tsinghua University Affiliated Chang Gung Hospital gave a fascinating special report on the recent advances in radiotherapy combined with immunotherapy for liver cancer, attracting wide attention from the participants. This publication summarizes the content of the report for the learning and exchange of fellow professionals.As early as 2017, when immunotherapy was just introduced for the treatment of liver cancer, Korean scholars began clinical trials of combining radiotherapy with immunotherapy. In a clinical study published in 2019, researchers observed a total of 76 liver cancer patients treated with the immunotherapy drug nivolumab (Opdivo). Among them, 54 patients received a combination therapy of external radiotherapy and immunotherapy. After long-term follow-up, the final results of the study showed that this subset of patients who received radiotherapy had a significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those who did not receive radiotherapy (Figure 1). This confirmed the synergistic effect of the combination of radiotherapy and immunotherapy in the field of liver cancer treatment[1].
Figure 1: Comparison of Patients Undergoing External Radiotherapy Combined with Immunotherapy with Those Not Receiving Radiotherapy in Terms of Progression-Free Survival (PFS) and Overall Survival (OS).
In the same year that Korean scholars published the above research results, scholars from Hong Kong, China, also released a clinical research article on the combination of stereotactic body radiation therapy (SBRT), intervention, and immunotherapy for patients with unresectable hepatocellular carcinoma. This article disclosed the clinical data of five liver cancer patients, all of whom were in the advanced stage of the disease. The median diameter of liver tumors in these five patients was 9.6 cm (with the largest reaching 16.1 cm), and one patient also had lung metastasis, as shown in Table 1 for baseline clinical characteristics. After receiving combined treatment, all tumors in these patients shrank, with three patients experiencing complete tumor inactivation. All five patients survived for over 1 year (1-year survival rate of 100%), and the median progression-free survival was as long as 14.9 months (Table 2). This clinical outcome further confirms the potential synergistic effect of radiotherapy combined with immunotherapy in the treatment of liver cancer[2].
Table 1: Baseline Clinical Characteristics of Patients
Table 2: Outcomes and Adverse Reactions of Patients with Unresectable Hepatocellular Carcinoma Treated with SBRT, Intervention, and Immunotherapy
At the 2022 ASCO Annual Meeting, Hong Kong scholar Chi from China reported for the first time a single-arm phase II clinical study, the Sequential Transarterial Chemoembolization (TACE) Combined with Stereotactic Body Radiation Therapy (SBRT) and Immunotherapy for Advanced Hepatocellular Carcinoma (START-FIT study). The data on downstaging and conversion therapy were disclosed, initiating a new exploration of local treatment combined with immunotherapy in the conversion therapy of liver cancer. Among the 67 patients screened, a total of 33 patients were included. The median sum of intrahepatic lesion diameters was 15.1 cm (range 5.3-31.1 cm), and 21 patients (63.6%) had involvement of major vessels (13 with pure hepatic vein involvement, 3 with pure portal vein branch involvement, and 5 with both). The median follow-up time in the study was 17.2 months (range 3.5-31.6 months), during which 3 patients successfully downstaged and underwent curative surgery, achieving a surgical conversion rate of 9.1%. According to mRECIST 1.1 criteria, the objective response rate (ORR) was 62.5% (95% CI: 45.3%-77.1%), with 15 cases of complete response (CR) (43.8%) and 6 cases of partial response (18.7%). The median overall survival (OS) and progression-free survival (PFS) were 30.3 months (95% CI: 22.7-37.8 months) and 20.7 months (95% CI: 14.6-26.8 months), respectively, as shown in Figure 2. The three patients who underwent successful surgery had a survival time exceeding 2 years. Among the 15 CR patients, the 2-year OS rate was 92.9%[3].
Table 3: Efficacy of Sequential Transarterial Chemoembolization (TACE) Combined with Stereotactic Body Radiation Therapy (SBRT) and Immunotherapy for the Treatment of Advanced Hepatocellular Carcinoma
Figure 2: Progression-Free Survival (PFS), Overall Survival (OS), and Objective Response Rate (LCR) of Sequential Transarterial Chemoembolization (TACE) Combined with Stereotactic Body Radiation Therapy (SBRT) and Immunotherapy for the Treatment of Advanced Hepatocellular Carcinoma.
In October 2023, the Radiotherapy Team at Beijing Tsinghua Chang Gung Hospital published clinical data on liver cancer patients with combined portal vein trunk tumor thrombus treated with radiotherapy combined with targeted and immune therapy. Among the 50 screened patients, a total of 39 were included. After receiving radiotherapy combined with lenvatinib and PD-1 inhibitor treatment, the 2-year survival rate for all patients was 15.4%. The median overall survival time and progression-free survival time were 9.4 months and 4.9 months, respectively (Figure 3). The objective response rate for portal vein tumor thrombus was 61.5%. This study fills the gap in clinical data on non-targeted immunotherapy combined with radiotherapy for portal vein trunk tumor thrombus, providing a basis for further prospective research[4].
Figure 3: Overall Survival (OS) and Progression-Free Survival (PFS) of Liver Cancer Patients with Combined Portal Vein Trunk Tumor Thrombus Treated with Radiotherapy Combined with Targeted and Immune Therapy.
With the continuous release of data on the combination of radiotherapy and immunotherapy for liver cancer, this combined treatment modality has gradually gained clinical recognition and has spurred the initiation of more research explorations. As of now, a total of 26 clinical studies on the combination of radiotherapy and liver cancer treatment are registered on ClinicalTrials.gov[5], including 6 studies on the combination of radiotherapy with targeted therapy and immunotherapy, and 3 studies on the combination of radiotherapy with dual immunotherapy. As more research results are disclosed, the evidence for the combination of radiotherapy and immunotherapy for liver cancer will become more substantial. This combined treatment approach is expected to become an important therapeutic option in the treatment of liver cancer.
Reference :
[1] Yu JI, Lee SJ, Lee JY, et al. Clinical significance of radiotherapy before and/or during nivolumab treatment in hepatocellular carcinoma. Cancer Med. 2019;8(6):6986–6994.
[2] Chiang CL, Chan ACY, Chiu KWH, et al. Combined Stereotactic Body Radiotherapy and Checkpoint Inhibition in Unresectable Hepatocellular Carcinoma: A Potential Synergistic Treatment Strategy. Front Oncol. 2019:12:9:1157.
[3] Chiang CL, Chiu KWH, Chan ACY, et al. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2023,8(2): 169-178.
[4] Li GX, Zhao Y, Li KR, et al. Effectiveness and Safety of the PD-1 Inhibitor Lenvatinib Plus Radiotherapy in Patients with HCC with Main PVTT: Real-World Data from a Tertiary Centre. J Hepatocell Carcinoma. 2023 9:10:2037-2048.
[5] Yang YH, Xiong LT, Li MY, et al. Advances in radiotherapy and immunity in hepatocellular carcinoma. J Transl Med. 2023,21(1):526.
Expert Profile
Dr. Guangxin Li
Physician-in-Charge, Department of Radiotherapy
Tsinghua University Affiliated Beijing Tsinghua Chang Gung Hospital
