From July 6th to 8th, 2023, the 13th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2023) was held in Seoul, South Korea. Hepatocellular carcinoma (HCC) experts from around the world gathered to rekindle academic discussions on HCC’s basics, clinical aspects, research, and technology offline. The conference featured the latest research results from over a thousand scholars representing more than 50 countries. In this publication, Dr. Ming Zhao from Sun Yat-sen University Cancer Center, China, offers insightful interpretations of the significant clinical research emerging from APPLE 2023 for the benefit of our readers.

IMbrave050 study: atelizumab+bevacizumab as adjuvant therapy for hepatocellular carcinoma with high risk of recurrence after resection or ablation

In the IMbrave050 study (NCT04102098), for patients with hepatocellular carcinoma (HCC) at high risk of recurrence after resection or ablation, the use of atezolizumab + bevacizumab as adjuvant therapy showed statistically and clinically significant improvements in recurrence-free survival (RFS) compared to active surveillance (control group), with overall safety being manageable (Chow, AACR 2023). This study also delved into patient-reported outcomes (PRO).

Patients were randomly assigned to Group A (atezolizumab + bevacizumab) or Group B (active surveillance). Group A received atezolizumab 1200 mg + bevacizumab 15 mg/kg IV every 3 weeks for one year (17 cycles). Group B underwent active surveillance for one year, with the option to cross over to atezolizumab + bevacizumab after recurrence. Predefined exploratory analyses included changes in overall health status (GHS)/quality of life (QoL), physical function, role function, emotional function, and social function compared to baseline. Clinically significant deterioration was defined as a decrease of ≥10 points from baseline. Patients completed the IL42-EORTC QLQ-C30 (abbreviated) questionnaire at baseline and were followed up during odd-numbered cycles over the 17 cycles.

A total of 334 patients were included, with a median follow-up of 17.4 months (clinical cutoff date: October 21, 2022). Completion rates for questionnaires in both groups were ≥93% from baseline to the 17th cycle, with high and similar average baseline scores for all scales. There were no significant changes in average scores compared to baseline during the 17 cycles, and there was overlap in the 95% confidence intervals between the groups. Patients’ GHS/QoL and functional monitoring remained stable up to the 17th cycle, with no clinically significant deterioration observed.

PRO results analysis demonstrated that the atezolizumab + bevacizumab group had similar overall health-related quality of life (HRQoL) and functional status as the active surveillance group. The use of atezolizumab + bevacizumab as adjuvant therapy for high-risk HCC patients aiming for cure does not lead to clinically significant deterioration in HRQoL or functional status.

Expert’s Review

Dr. Zhao: In recent years, there have been many advancements in the treatment of liver cancer, including systemic therapies. One highlighted study at the APPLE conference was the IMbrave 050 study, which evaluated the efficacy and safety of atezolizumab + bevacizumab as adjuvant therapy for HCC patients at high risk of recurrence after surgical resection or ablation. This study reported PRO results. According to the latest data, atezolizumab + bevacizumab as adjuvant therapy resulted in higher RFS compared to the control group, with OS results yet to be disclosed. Patients’ quality of life and functional status were similar to those in the control group. These results suggest that atezolizumab + bevacizumab as adjuvant therapy can reduce the postoperative recurrence rate in high-risk patients without affecting their quality of life.

Early Single HCC (≤5 cm) Treated with Stereotactic Body Radiation Therapy vs. TACE+Stereo

The aim of this study was to compare the clinical outcomes of recurrent hepatocellular carcinoma (HCC) single lesions (≤5 cm) treated with transarterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) versus SBRT alone.

The researchers retrospectively reviewed the medical records of 1014 patients with non-vascular invasion and no extrahepatic metastases who underwent SBRT treatment at Ewha Womans University Medical Center between 2007 and 2017. Among them, 54 patients who had not received prior targeted therapy underwent SBRT for recurrent single HCC lesions (SBRT-alone group), while 423 patients with recurrent single HCC lesions received SBRT after TACE (TACE-SBRT group). The primary endpoint was local control (LC) rate, and secondary endpoints included overall survival (OS), intrahepatic recurrence-free survival (IHRFS), recurrence-free survival (RFS), and treatment-related adverse events. The researchers used propensity score matching (PSM) to compare the outcomes between the SBRT-alone and TACE-SBRT groups.

The median age of the study population was 63 years (range 56-69 years), and 89.7% of patients had Child-Pugh class A liver function. Tumor size in the SBRT-alone group (median 1.4 cm, interquartile range [IQR] 1.2-1.7 cm) was smaller than in the TACE-SBRT group (median 1.9 cm, IQR 1.5-2.5 cm). Alpha-fetoprotein levels in the SBRT-alone group (median 5.9 ng/mL, IQR 2.7-16.0 ng/mL) were lower than in the TACE-SBRT group (median 9.8 ng/mL, IQR 4.3-40.8 ng/mL). Both groups received a median total dose of 45 Gy (range 30-60 Gy) and a median dose of 15 Gy (range 10-20 Gy) per fraction, delivered over 3-4 days. The median follow-up period was 37.2 months (IQR 24.1-46.3 months).

The 3-year LC rate (88.6% vs. 89.6%, p=0.92), 3-year OS rate (64.8% vs. 69.2%, p=0.48), 3-year IHRFS rate (41.3% vs. 31.8%, p=0.29), and 3-year RFS rate (34.9% vs. 28.6%, p=0.27) did not significantly differ between the SBRT-alone and TACE-SBRT groups. Even after PSM, the 3-year LC rate (91.0% vs. 93.9%, p=0.90), OS rate (67.9% vs. 73.2%, p=0.62), IHRFS rate (36.1% vs. 41.2%, p=0.50), and RFS rate (33.7% vs. 38.2%, p=0.58) still did not significantly differ.

Further analysis showed that no patients in the SBRT-alone group experienced a deterioration of Child-Pugh score ≥2, while 18 patients (4.3%) in the TACE-SBRT group had a decrease in Child-Pugh score ≥2. Both groups did not experience complications such as gastrointestinal bleeding or perforation.

This study did not find statistically significant differences in terms of local control and survival rates between the SBRT-alone and TACE-SBRT groups. This result suggests that SBRT without prior treatment can be considered an alternative treatment option for recurrent HCC with a single lesion ≤5 cm, especially when local treatment is not feasible.

Expert’s Review

Dr. Zhao: This retrospective study included 1014 patients with non-vascular invasion and no extrahepatic metastases. It compared the outcomes of SBRT-alone treatment and SBRT after TACE for single lesions of HCC ≤5 cm. Looking at the baseline characteristics of patients, the median tumor size in the SBRT-alone group was 1.4 cm, while in the TACE-SBRT group, it was 1.9 cm, with both groups having tumors averaging around 2 cm in size. Therefore, this study at least confirms that in patients with single hepatocellular carcinoma lesions ≤2 cm, SBRT treatment alone is sufficient, and there is no need for TACE treatment. However, the study did not include patients with lesions above 2 cm, so further validation is needed for this patient population in the future.

Efficacy of Liver-Directed Combined Radiotherapy in Locally Advanced HCC with Portal Vein Tumor Thrombosis

While systemic treatment is the primary approach for advanced hepatocellular carcinoma (HCC), several studies emphasize the value of local treatments. Sorafenib is currently widely recommended for treating portal vein tumor thrombosis (PVTT) in locally advanced HCC. This study aimed to analyze clinical efficacy by comparing liver-directed combined therapy with radiotherapy (LD-CRT) against sorafenib in a multi-country patient cohort.

This study included HCC patients with PVTT who received sorafenib or LD-CRT treatment at ten tertiary hospitals in Asia from 2005 to 2014. Propensity score matching (PSM) was used to minimize imbalances in patient and tumor characteristics. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS) and treatment-related toxicity.

The study included 1035 patients (LD-CRT group: 675 patients, sorafenib group: 360 patients). After PSM, 305 patients were included in each group, with all characteristics well-matched. The median follow-up was 22.5 months. LD-CRT group vs. sorafenib group had a median OS of 10.6 months vs. 4.2 months (p<0.001), and the LD-CRT group showed a significantly higher rate of curative surgery conversion (8.5% vs. 1.0%, p<0.001) and fewer Grade 3 or higher toxicities (9.2% vs. 16.1%, p<0.001).

This multi-country patient cohort analysis demonstrated that LD-CRT improved survival outcomes by increasing the rate of curative surgery conversion in locally advanced HCC patients with PVTT. Therefore, despite the need for further prospective research, it is recommended to actively explore various local treatment modalities, including radiotherapy, for locally advanced HCC patients with PVTT.

Expert’s Review

Dr. Zhao: For locally advanced HCC patients with PVTT, the current standard treatment options are combined therapy using atezolizumab + bevacizumab or the dual immunotherapy of camrelizumab + apatinib. This international multicenter clinical study had a substantial sample size. The study explored whether local control for PVTT is necessary in the context of targeted therapy or monotherapy. The results of this study indicate that, among patients with PVTT, combining local therapy with systemic treatment yields better efficacy. Interestingly, the use of radiotherapy in combination with targeted drugs resulted in fewer Grade 3 or higher adverse reactions compared to using targeted drugs alone. Therefore, this study suggests that local therapy plays a significant role in the treatment of patients with PVTT.

In this field, there are still various approaches, including domestically used methods like drug-eluting bead transarterial chemoembolization (DEB-TACE) and transarterial radioembolization (TARE), as well as hepatic artery infusion chemotherapy (HAIC). These local treatments are highly effective in controlling tumors. Overall, for unresectable intermediate to advanced HCC, the combination of local therapy with systemic treatment can achieve better efficacy.

Reference :

1. Han Chu Lee , Ann-Lii Cheng, Pierce Chow, et al. IMbrave050: Adjuvant Atezolizumab+Bevacizumab VS Active Surveillance in Hepatocellular Carcinoma Patients at High Risk of Disease Recurrence Following Resection or Ablation. APPLE 2023 Abstract OP-03

2. Youngju Song , Jinhong Jung , Jin-hong Park , et al. Clinical Outcomes of Stereotactic Body Radiation Therapy Alone versus Stereotactic Body Radiation Therapy after Incomplete Transarterial Chemoembolization for a Single Small (≤ 5 cm) Recurrent Hepatocellular Carcinoma. APPLE 2023 Abstract PE-90

3. Jina Kim, Jason Chia-Hsien Cheng, Taek-Keun Nam, et al. Efficacy of Liver-Directed Combined Radiotherapy in Locally Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis. APPLE 2023 Abstract PE-101