Treatment of intermediate-to-advanced unresectable hepatocellular carcinoma is shifting toward a multidisciplinary strategy that includes multiple modalities as needed

Table 1 Ongoing prospective trials of external beam radiotherapy combined with transarterial chemoembolization and/or molecular targeted therapy and/or immunotherapy

Ref.	Clinical trial name	Countries	Start year	Design	Target diseases	Actual or estimated enrollment	Interventions	Primary endpoints
Dawson[25]	NCT01730937	United States, Australia, Canada, China, and Korea	2013	Randomized, two-arm, phase 3	HCC	193	Sorafenib vs SBRT followed by sorafenib	OS
Knox[26]	NCT03316872	Canada	2018	Single-arm, phase 2	Advanced HCC	19	Pembrolizumab (PD-1 inhibitor) and SBRT	ORR
Hong[27]	NCT03482102	United States	2018	Single-arm, phase 2	HCC or biliary tract cancer	70	Tremelimumab (CTLA-4 inhibitor), Durvalumab (PD-L1 inhibitor), and RT	Best ORR
Lock[28]	NCT03895359	Canada	2019	Randomized, two-arm, phase 3	Primary or secondary liver carcinoma	128	TACE vs TACE and SBRT	OS
Chan[29]	NCT04988945	China	2020	Single-arm, phase 2	Unresectable HCC	33	TACE, SBRT, Durvalumab, and Tremelimumab	Downstaging for liver resection
Sun[30]	NCT04387695	China	2020	Randomized, two-arm, phase 3	Unresectable HCC with PVTT	54	SBRT, TACE, and Sorafenib vs Sorafenib	PFS rate
Wo[31]	NCT04857684	United States	2021	Single-arm, early phase 1	Resectable HCC	20	Atezolizumab (PD-L1 inhibitor), Bevacizumab, and SBRT	Proportion of patients with grade 3-4 TRAE
[32]	NCT05010434	China	2021	Single-arm, phase 2	Advanced HCC	46	Sintilimab (PD-1 inhibitor), Bevacizumab, and RT	ORR
Welsh[33]	NCT04785287	United States	2021	Randomized, two-arm, phase 1/2	Advanced solid malignancies including Stage III/IV or metastatic liver cancer	13	Anti-CTLA4 monoclonal antibody BMS-986218 and SBRT with Nivolumab vs those without	Incidence of AE
Zhao[34]	NCT05185531	China	2022	Single-arm, phase 1b	Resectable HCC	20	Tislelizumab (PD-1 inhibitor) and SBRT	Delay to surgery, ORR, pathologic response rate on evaluation of the resected specimen, and TEAE
Ben-Josef[35]	NCT05488522	United States	2022	Single-arm, phase 1	Advanced HCC	18	SBRT, Atezolizumab, and Bevacizumab	Tolerability and safety
Wo[36]	NCT05096715	United States	2022	Single-arm, phase 1	Unresectable HCC	20	Atezolizumab, Bevacizumab, and SBRT	Dose limiting toxicity rate
[37]	NCT05225116	China	2023	Single-arm, phase 1	HCC with PVTT	20	Sintilimab, Lenvatinib, and RT	Safety and number of patients who complete pre-op treatment and proceed to surgery
[38]	NCT05917431	China	2023	Single-arm, phase 2	Unresectable or oligometastatic HCC	39	SBRT, Tislelizumab, and Regorafenib	PFS
Xi[39]	NCT06261125	China	2024	Two-arm, phase 2	HCC with abdominal lymph node metastases	60	SBRT, Adebrelimab (PD-L1 inhibitor), and Lenvatinib	PFS
Wei[40]	NCT06561399	China	2024	Single-arm, phase 2	Unresectable HCC	28	TACE, Lenvatinib, Sintilimab, and RT	ORR
[41]	NCT06664996	China	2024	Single-arm, phase 2	Resectable HCC with PVTT	33	SBRT and Sintilimab	1-year DFS rate
Zeng[42]	NCT06349317	China	2024	Single-arm, phase 2	Resectable HCC with PVTT	33	IMRT, Camrelizumab (PD-1 inhibitor), and Apatinib	1-year EFS rate
[43]	NCT06349044	China	2024	Randomized, two-arm, phase 2 (liver adenocarcinoma)	Advanced digestive system malignancies including liver adenocarcinoma	120 (overall)	Hypo-RT/SBRT, Sintilimab, and Bevacizumab with Probio-M9 microbial agents vs those with placebo	ORR

AE: Adverse event; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; DFS: Disease-free survival; EFS: Event-free survival; HCC: Hepatocellular carcinoma; Hypo-RT: Hypofractionated radiotherapy; IMRT: Intensity-modulated radiation therapy; ORR: Overall response rate; OS: Overall survival; PD-1: Programmed cell death 1; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; PVTT: Portal vein tumor thrombus; pre-op, preoperative; RT: Radiation therapy; SBRT: Stereotactic body radiation therapy; TACE: Transarterial chemoembolization; TEAE: Treatment-emergent adverse event; TRAE: Treatment-related adverse event.