Combined treatments in hepatocellular carcinoma: Time to put them in the guidelines?

Table 2 Comparison of transarterial chemoembolization plus radiofrequency ablation to transarterial chemoembolization

Ref.	Treatment type, n (%)	Clinical scenario	Response rate mRECIST	Outcome
Morimoto et al[111], 2013	TACE + RFA (132)	HCC 1-5 cm, subcapsular	98.5% CR	LTP (3 yr) 9.7%. OS (3, 5, 7 yr): 79.3%, 60.6%, 50.9%
Song et al[31], 2016	TACE (71) vs TACE + RFA (87) vs RFA (43)	HCC within Milan	81.6% vs 96.5% vs 97.6% (TACE vs TACE + RFA P = 0.019)	LTR (1, 3, 5 yr): 17%, 58%, 78% vs 6%, 33%, 54% vs 10%, 31%, 48% (TACE + RFA vs TACE P = 0.015; RFA vs TACE P = 0.005). OS (1, 3, 5 yr): 98%, 90%, 83% vs 98%, 95%, 90% vs 94%, 84%, 71% OS significantly higher (P = 0.019) for TACE + RFA vs TACE or RFA for lesions < 3 cm but not for lesions > 3 cm
Lee et al[32], 2018	TACE (85) vs TACE + RFA (n = 82)	HCC BCLC 0 or A invisible for ultrasound	97.6% vs 100% (CR)	LTP (1, 3, 5, 7 yr): 12.5%, 31%, 37% vs 7.3%, 16.5%, 16.5% (P = 0.013). Median TTP: 18 mo vs 24 mo (P = 0.037). OS (1, 3, 5 yr): 100%, 93.2%, 87.7% vs 100%, 96.6%, 87.4% (P = 0.686)
Liu et al[33], 2019	TACE (195) vs TACE + RFA (209)	HCC B1	N/A	Median PFS: 14 mo vs 20 mo. PFS (1, 3, 5 yr): 59.1%, 11.0%, 2.2% vs 71.8%, 26.6%, 13.0% (P < 0.001). OS (1, 3, 5 yr): 80.7%, 26.4%, 6.7% vs 83.7%, 45.8%, 24.8% (P = 0.003)
Hiraoka et al[73], 2017	TACE (32) vs TACE + RFA (32)	HCC BCLC B1 + B2	N/A	Median OS: 840 d vs 2466 d. OS (1, 3, 5 yr): 86.3%, 43.5%, 15.8% vs 100%, 78.6%, 62.3% (P < 0.001). Median TTP: 140 d vs 1148 d (P < 0.0001)
Ren et al[35], 2019	TACE (271) vs TACE + RFA (128)	HCC BCLB A and B	44.7% vs 85.9% (CR)	Median OS: 16 mo vs 59 mo (P < 0.001). Median PFS: 4 mo vs 45 mo. OS (1, 3, 5, 8 yr): 64.5%, 15.1%, 10.8%, 10.8% vs 90.6%, 76.6%, 68.0%, 68.0%
Chu et al[36], 2019	TACE (314) vs TACE + RFA (109) vs RFA (115)	HCC 3.1-10 cm	84.7% vs 95.4% vs 94.8% (CR)	RFS (5, 10, 15 yr): 59.1%, 11.0%, 2.2% vs 25.5%, 13.3%, 7.9% vs 9.2%, 2.9%, and 2.9% (P = 0.002). OS (5, 10, 15 yr): 16.2%, 10.9%, 7.7% vs 57.8%, 41.8%, 30.9% vs 35.2%, 11.9%, 11.9% (P = 0.022)
Liu et al[37], 2020	TACE (124) vs TACE + RFA (77)	HCC 3-10 cm	N/A	Median PFS: 4 mo vs 9.13 mo (P < 0.001). PFS (1, 3, 5 yr): 11.9%, 0%, 0% vs 43%, 18%, 9.5%. Median OS: 12 mo vs 27.57 mo (P < 0.001). OS (1, 3, 5 yr): 48%, 6.5%, 0% vs 76.2%, 37.1%, 16.4%
Hyun et al[38], 2016	TACE (54) vs TACE + RFA (37)	HCC not feasible for RFA	57% vs 100% P < 0.01 (CR)	Median TTP: 29.7 mo vs 34.9 mo (P = 0.014). OS (1, 2, 3 yr): 91%, 79%, 71% vs 100%, 97%, 93%
Yang et al[39], 2020	TACE + RFA special location (n = 37) vs TACE + RFA conventional location (n = 85)	HCC special locations	91.9% vs 85.9% (CR) (NS)	Median PFS: 14 mo vs 17 mo (NS). Median OS: 32 mo vs 28 mo (NS). OS (1, 2 yr): 96.3%, 65% vs 89.9%, 63.3% (NS)
Hyun et al[112], 2016	TACE + RFA (14)	HCC < 2 cm caudate lobe	90.9% CR	LTP (1, 3, 5 yr): 0%, 12.5%, 12.5%. PFS (1, 3, 5 yr): 81.8%, 51.9%, 26%. OS (1, 3, 5 yr): 100%, 80.8%, 80.8%
Hyun et al[113], 2018	TACE +RFA (69)	HCC < 3 cm not feasible for RFA	100% CR	LTP (1, 3, 5, 7 yr): 4.4%, 6.8%, 8.2%, 9.5%, 9.5%. OS (1, 3, 5, 7 yr): 100%, 95%, 89%, 80%, 80%
Yan et al[114], 2018	TACE + RFA single session (87)	HCC < 7 cm not resectable	87.4% CR	LTP (1, 3, 5 yr): 0%, 29.9%, 55.2%. Median OS: 39 mo. OS (1, 3, 5 yr): 100%, 65.5%, 47.5%
Kim et al[115], 2019	TACE + RFA (67)	BCLC A, non-surgical	N/A	PFS (1, 3, 5 yr): 86.8%, 55.9%, 29.7%. OS (1, 3, 5 yr): 100%, 93.4%, 83.5%
Duan et al[116], 2020	TACE + RFA, one session (46)	HCC > 8 cm	N/A	PFS (2, 3 yr): 9.4 mo and 10.2 mo. OS (2, 3 yr): 18.4 mo and 26.4 mo
Zhang et al[117], 2020	TACE + RFA (1) naive (40); (2) recurrent (36); and (3) hepatectomy	1 tumor < 7 cm, up to 3 tumors < 3 cm, Child A or B	62.5% vs 70% (CR + PR)	OS (1, 2, 3 yr): 97.5%, 84%, 66% (A) vs 90%, 82%, 66% (B) vs 90%, 79%, 63% (C) (A vs B vs C NS). DFS: 75%, 51%, 35% (A) vs 50%, 31%, 17% (B) vs 80%, 59%, 40% (C) (A vs B P = 0.013)
Wang et al[118], 2018	TACE (13) vs TACE + RFA (13)	HCC with hepatic vein thrombus	0% + 92.3% vs 46.2% + 53.7% (CR + PR)	Median OS: 6.5 mo vs 18 mo (P = 0.02)
Song et al[119], 2020	TACE (63) vs TACE + RFA (96)	Recurrent HCC < 5 cm after HR	N/A	DFS (1, 3, 5 yr): 41.1%, 9.9%, 4.9% vs 55.1%, 22.5%, 9.7%. OS (1, 3, 5 yr): 75.9%, 30.7%, 11.3% vs 82.3%, 42.7%, 16.5% (NS)

P value less than 0.05 (typically ≤ 0.05) is statistically significant. HCC: Hepatocellular carcinoma; RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization; OS: Overall survival; PFS: Progression free survival; RFS: Recurrence free survival; TTP: Time to progression; LTP: Local tumor progression; LTR: Local tumor recurrence; DFS: Disease free survival; TR: Tumor recurrence; CR: Complete response.