Efficacy of Local Treatments for Hepatocellular Carcinoma Involving the Inferior Vena Cava and/or Right Atrium

Figures & data

Table 1 Selected Studies of External Radiotherapy for Hepatocellular Carcinoma with Inferior Vena Cava and/or Right Atrium Thrombosis

First Author, Year of Publication	Patient Who Underwent EBRT (n)	Patient Recruitment Period	Affiliation	EBRT (Dose in EQD2)	Response Rate	Survival			Complications of Grade ≥3	Pulmonary Embolism	Sorafenib
						Median (Months)	1-Year (%)	2-Year (%)
Zeng, 2005^Citation14	14	1998–2003	Fudan University, China	3DCRT, median 50 Gy (36–60 Gy)	CR: 64.3% PR: 14.3%	22			None	None	Pre-sorafenib era
Koo, 2010^Citation15	42	2004–2006	Asan Medical Center, Korea	3DCRT, median 48.75 Gy	CR: 14.3% PR: 28.6% SD: 28.6%	11.7	47.7	42.8	None	None
Rim, 2018 (meta-analysis)^Citation6	164	2018	8 studies with 9 cohorts, mostly China and Japan	3DCRT (6 of 8 studies), median dose range: 48–60 Gy in EQD2	Pooled RR: 59.2% Pooled LC: 91.7%	Ranged 5.6–25.4	Pooled rate: 53.6%	Pooled rate: 36.9	1.2%	1 case among 164 patients
Rim, 2020^Citation11	49	2003–2017	6 centers, Korea	3DCRT (65.3%) IMRT (34.7%)median 46.7 Gy (35.4–71.5)	1 and 2-year LC: 88.7%	10.1 (7.5–12.7)	43.5%	30.1%	GI 0%; ascites 2%; varices 2%; LFT 30.6%; blood count 26.5%	None	28.6%
Lou, 2019^Citation17	75	2008–2016	3 centers, China	Hypofractionated RTMedian 38 Gy in 3–4 Gy per fraction	CR 22.7% PR: 73.3% LC: 100%	10	38.7%	13.3%	None	None	NA
Pao, 2019^Citation37	42	2007–2018	National Cheng Kung University Hospital, Taiwan	IMRT 83.3%Median 48.75 Gy (3.25–67.1)	RR: 47.6%	6.6	30.0%		None	None	40.5%

Note: HCC patients with IVC and/or RA thrombosis who underwent EBRT.

Abbreviations: IVC, inferior vena cava; RA, right atrium; EQD2, equivalent dose in 2 Gy per fraction scheme; EBRT, external beam radiotherapy; 3DCRT, 3-dimensional conformal radiotherapy; CR, complete remission; PR, partial remission; SD, stable disease; RR, response rate; LC, local control; IMRT, intensity modulated radiotherapy; GI, gastrointestinal; LFT, liver function test.

Table 2 Selected Studies of Surgery and Comparison with Other Modalities

First Author, Year of Publication	Patient (n)	Study Design	Patient Recruitment Period	Affiliation	Complete Resection	Overall Survival			≥G3 Complication	Perioperative Mortality	Post-Surgery or Radiotherapy Treatments
						Median, Months	1-Year	2-Year
Matsukuma, 2020^Citation21	37	Single arm analysis of surgical cases	1997–2017	Yamaguchi University, Osaka Cancer Institute, Osaka Univ. Hospital, Japan	67.6% (R0 or R1)	13.8	59.5%	35.1%	17.9%	5.4% (90 days)	CTx. (10.8%); HAIC (8.1%); RT (2.7%)
Kasai, 2017^Citation22	39		1996–2015	Kyoto University, Japan	79% (R0 or R1)	15.2	64.0%	38.5%	67%	5% (30 days)	CTx. (17.9%); sorafenib (10.3%); HAIC (10.3%)
Li, 2019^Citation23	51 (surgery) 57 (EBRT)	Comparative study with matched cohorts	2004–2016	Eastern Hepatobiliary Surgery Hospital, China		Surgery: 14.5	58.8%	21.6%	3.9%	None
						EBRT: 14.5	57.9%	24.6%	0	NA
						p=0.466
Komatsu, 2017^Citation24	19 (surgery) 19 (EBRT)	Comparative study with matched cohorts	2001–2016	Kobe University, Japan		Surgery:	34.0%	10.5%	26% (1 grade 5 case)
						EBRT:	68.0%	36.8%	0.0%
						p=0.106
Lee, 2020^Citation25	366 (surgery) 389 (EBRT)	Comparative meta-analysis		18 studies 22 cohorts (China, Japan, Korea, Taiwan)		Surgery:	62.4% (95% CI: 53.8–70.3)	26.9% (95% CI: 20.7–34.2)	3.9–67%	0–7.6%
						EBRT:	48.8% (95% CI: 40.9–56.8)	27.5% (95% CI: 19.7–37.1)	None except 1 study	NA
						p=0.023 (1-year); p=0.913 (2-year)
Wang, 2013^Citation12	25 (surgery) 20 (TACE) 11 (no Tx.)	Comparative study with matched cohorts	2000–2010	Eastern Hepatobiliary Surgery Hospital, China		Surgery: 19	68.0%	28.0%	8%	none	TACE (72%); EBRT (60%); RFA (8%); re-resection (4%)
						TACE: 4.5	15%		5%		EBRT (25%)
						No Tx.: 5	0%
						p<0.001, favoring surgery

Abbreviations: CTx, chemotherapy; HAIC, hepatic arterial infusion chemotherapy; RT, radiotherapy; EBRT, external beam radiotherapy; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; Tx, treatment.

Table 3 Clinical Trials of Systemic Agents in the Adjuvant Setting After Locoregional Treatment of Advanced-Stage HCC

Setting	Trial Identifier	Design	Agents (Generic Name)	Agents (Type)	Number of Patients	Eligibility	Estimated Completion Date	Sponsor
Randomized phase III	NCT01730937	SBRT vs SBRT+sorafenib	Sorafenib	Multikinase inhibitor	368	BCLC stage B or C	June 2025	Radiation Therapy Oncology Group
Randomized phase II	NCT03971201	Surgery+sorafenib vs sorafenib	Sorafenib	Multikinase inhibitor	200	HCC with portal vein invasion	June 2022	White Plains Hospital
Randomized phase III	NCT04227808	Surgery+lenvatinib	Lenvatinib	Multikinase inhibitor	50	BCLC stage B or C	February 2022	Shanghai Zhongshan Hospital
Phase II	NCT03316872	SBRT+pembrolizumab	Pembrolizumab	Anti-PD-1 antibody	30	BCLC stage C	April 2022	University Health Network, Toronto
Randomized phase I	NCT03203304	SBRT+nivolumab vs SBRT+nivolumab+ipilimumab	Nivolumab Ipilimumab	Anti-PD-1 antibody Anti-CTLA-4 antibody	50	Unresectable HCC	August 2022	University of Chicago
Randomized phase III	NCT03383458 (CheckMate 9DX)	Hepatic resection+placebo vs Hepatic resection+nivolumab	Nivolumab	Anti-PD-1 antibody	530	First diagnosis	June 2025	Bristol-Myers Squibb
Randomized phase III	NCT04102098 (IMbrave050)	Hepatic resection vs hepatic resection+atezolizumab+bevacizumab	Atezolizuma Bevacizumab	Anti-PD-L1 antibody Anti-VEGFR2 antibody	662	First diagnosis	August 2027	Hoffmann-La Roche
Randomized phase III	NCT03867084 (KEYNOTE-937)	Hepatic resection+placebo vs Hepatic resection +pembrolizumab	Pembrolizumab	Anti-PD-1 antibody	950	Diagnosis of HCC	June 2025	Merck Sharp & Dohme Corp

Abbreviations: SBRT, stereotactic body radiotherapy; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PD, programmed death; CTLA, cytotoxic T-lymphocyte antigen; VEGFR, vascular endothelial growth factor receptor.

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