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

Table 1 Morbidity, mortality, recurrence and survival after hepatic resection plus intraoperative ablation

Ref.	Patients, n (%)	MO, n (%)	Mo, n (%)	Recurrence	Survival rates (1 yr/3 yr/5 yr)
Qiu et al[6], 2014	112	2	22.3	72.3%	67.5%/32.5%/12.5%
Hou et al[23], 2016	51	0	70.6	54.9%	88.2%/66.7%/52.9%
Zhang et al[24], 2014	114	0.9	-	-	34.4%/70.7%/40.7%
Huang et al[25], 2020	51	-	-	-	86.3%/66.6%/34.2%

MO: Mortality; Mo: Morbidity.

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.

Table 3 Comparison transarterial chemoembolization + radiofrequency ablation to other curative therapies

Ref.	Treatment type, n (%)	Clinical scenario	Response rate mRECIST	Outcome
Saviano et al[49], 2017	TACE + RFA (n = 25) vs HR (n = 29)	HCC 3.0-8.8 cm, solitary HCC 3-5 cm	N/A	OS (1, 3 yr): 89.4%, 48.2% vs 91.8%, 79.3% (P = 0.117). TR (1, 3 yr): 42.4%, 76.0% vs 29.5%, 45.0% (P = 0.034); LTP (3 yr): 58.1% vs 21.8% (P = 0.005). TR: 75.1% vs 35.4% (P = 0.016); LTP: 55.7% vs 16.0% P = 0.013)
Pan et al[50], 2017	TACE + RFA (n = 154) vs HR (n = 176)	Within Up-To Seven criteria	N/A	Median OS: 56 mo vs 58 mo (NS). OS (1, 3, 5 yr): 96.1%, 76.7%, 41.3% vs 96.1%, 86.4%, 46.2% (P = 0.138). Median OS (beyond Milan): 52 mo vs 45 mo (P = 0.023)
Liu et al[51], 2016	TACE + RFA (n = 100) vs HR (n = 100)	Within Milan	N/A	OS (1, 3, 5 yr): 96%, 67.2%, 45.7% vs 97%, 83.7%, 61.9% (P = 0.007). RFS (1, 3, 5 yr): 83%, 44.9%, 35.5% vs 94%, 68.2%, 48.4% (P = 0.026). Complications rate: 11% vs 23%, P = 0.024)
Lin et al[52], 2020	TACE (n = 231) vs TACE + RFA (n = 57) vs HR (n = 140)	BCLC-B	N/A	OS (1, 3, 5 yr): 69.5%, 37.0%, 15.2% vs 86.0%, 57.9%, 38.2% vs 89.2%, 69.4%, 61.2%. OS higher HR vs TACE + RFA (P = 0.009), HR vs TACE (P < 0.001) and TACE + RFA vs TACE (P = 0.004)
Wei et al[63], 2020	TACE + RFA (n = 107) vs HR (n = 79)	Recurrent HCC < 5 cm after HR	N/A	DFS (1, 3, 5 yr): 58.2%, 35.2%, 29.6% vs 64.8%, 41.6%, 38.3% (P = 0.258). OS (1, 3, 5 yr): 84.6%, 66.9%, 49.1% vs 84.8%, 60.2%, 51.9% (P = 0.871). Lower major complication rates (P = 0.009) and shorter hospital stay (P < 0.001) for TACE + RFA
Sheta et al[64], 2016	TACE (n = 20) vs TACE + RFA (n = 20) vs TACE + MWA (n = 10)	Non resectable single lesion HCC > 4 cm	50% vs 70% vs 80% (CR at 6 mo)	LTR (1, 3, 6 mo): 30% vs 5% vs 0% (P = 0.027); 14.3% vs 15.8% vs 10% (NS); 16.7% vs 12.5% vs 11.1% (NS). Complications rate: 40% vs 10% vs 10%
Yuan et al[65], 2019	TACE + RFA (n = 41) vs TACE + MWA (n = 34)	HCC > 3 cm. HCC 3-5 cm. HCC > 5 cm	68.3 vs 85.3% (NS). 73.5 vs 88.5% (NS). 42.9 vs 75% (P = 0.041)	DFS (1, 2, 3 yr): 53%, 29%, 12% vs 58%, 38%, 29% (P = 0.07). OS (1, 2, 3 yr): 68%, 36%, 14% vs 79%, 53%, 38% (P = 0.393)
Thornton et al[120], 2017	TAE/TACE + RFA (n = 15) vs TAE/TACE + MWA (n = 20)	BCLC 0 and A	80% vs 95% (NS)	LTR: 30% vs 0%
Vasnani et al[67], 2016	TACE + RFA (n = 11) vs TACE + MWA (n = 31)	HCC within Milan	91% vs 67% (CR) 45% vs 35% (rates of complete tumor coagulation on pathology)

mRECIST: Modified RECIST; n: Number of patients; BCLC: Barcelona Clinic Liver Cancer; TACE: Transarterial chemoembolization; RFA: Radiofrequency ablation; MWA: Microwave ablation; HR: Hepatic resection; OS: Overall survival; PFS: Progression free survival; TTP: Time to progression; LTP: Local tumor progression; DFS: Disease free survival; TR: Tumor recurrence; CR: Complete response; NS: Not significative; N/A: Not applicable.

Table 4 Available studies on the transarterial chemoembolization plus microwave ablation

Ref.	Treatment type, n (%)	Clinical scenario	Response rate (CR + PR) mRECIST	Outcome
Ni et al[59], 2020	TACE + MWA (546)	BCLC B	N/A	Median PFS: 6.5 mo. Median OS: 35 mo
Ni et al[121], 2019	TACE + MWA (349)	Up to 3 nodules, 5-8 cm diameter	77.1%	Median PFS: 4.8 mo. Median OS: 28 mo
Chen et al[47], 2017	TACE (96) vs TACE + MWA (48)	HCC ≤ 5 cm	46.3% vs 92.1%	2-yr PFS: 57.3% vs 10.4%; 2-yr OS: NS
Smolock et al[56], 2018	TACE (16) vs TACE + MWA (22)	HCC 3-5 cm	76% vs 95% (NS)	Median PFS: 4.2 mo vs 22.3 mo. Median OS: 14.8 mo vs 18.5 mo. 3-yr OS: 42.1% vs 79%
Zheng et al[57], 2018	TACE (166) vs TACE + MWA (92)	Solitary HCC > 5 cm; 2-3 nodules > 3 cm; 4-10 nodules regardless of size	55.4% vs 81.5%	Median PFS: 12.5 mo vs 26.6 mo. Median OS: 6.7 mo vs 17.1 mo. 3-yr OS: 11.4% vs 32.6%
Zhang et al[60], 2018	TACE (100) vs TACE + MWA (50)	BCLC-B	55% vs 74%. At 6-mo, including stable disease	Median PFS: 6.1 mo vs 10.1 mo. Median OS: 14.4 mo vs 18.5 mo. 3-yr OS: 42.1% vs 79%. 5-yr OS: 21% vs 67.7%
Wang et al[61], 2020	TACE (111) vs TACE + MWA (72)	Recurrent (post-surgery) BCLC-B	N/A	Median PFS: N/A. Median OS: 14.4 mo vs 26.7 mo. 5-yr PFS: 13.0% vs 21.7%. 5-yr OS: 27.9% vs 43.3%
Li et al[29], 2020	MWA (88) vs TACE + MWA (62)	BCLC-B	N/A	3-yr PFS: 34.5% vs 32.5% (NS). 3-yr OS: 47.6% vs 49.2% (NS)
Biederman et al[55], 2017	TACE + MWA (80) vs Radiation segmentectomy (41)	Unresectable, solitary, ≤ 3 cm	CR 82.5% vs 82.9% (NS)	Median PFS: 12.1 mo vs 11.1 mo (NS). 90-d mortality: 0% all groups. Median OS: N/A
Ni et al[59], 2020	TACE + Sorafenib (n = 75) vs TACE + Sorafenib + MWA (77)	BCLC C	12% vs 46.7%	Median PFS: 3 mo vs 6 mo. Median OS: 13 mo vs 19 mo
Sheta et al[64], 2016	TACE (20) vs TACE + RFA (20) vs TACE + MWA (10)	Unrsesectable, solitary	6-mo CR–50% vs 70% vs 80%	Median PFS: N/A. Median OS: N/A
Wei et al[63], 2020	TACE + MWA (48) vs TACE + Cryoablation (60)	BCLC B	73.3% vs 33.4%	Median PFS: 8.8 mo vs 9.3 mo (NS). Median OS: 20.9 vs 13 mo (NS)

TACE: Transarterial chemoembolization; MWA: Microwave ablation; RFA: Radiofrequency ablation; HCC: Hepatocellular carcinoma; BCLC: Barcelona Clinic Liver Cancer classification system; CR: Complete response; PR: Partial response according to the mRECIST criteria; PFS: Progression-free survival; OS: Overall survival; NS: Non-significant; N/A: Not available.

Table 5 Chemoembolization plus systemic therapies

Trial	Experimental arms, n (%)	Outcomes
TACE + sorafenib
SPACE trial (Lencioni et al[80], 2016)	DEB-TACE plus sorafenib (154) vs DEB-TACE plus placebo (153)	5.6 mo vs 5.5 mo; HR: 0.797 (95%CI: 0.588–1.080); P = 0.072
TACE 2 trial (Meyer et al[81], 2017)	DEB-TACE plus sorafenib (157) vs DEB-TACE plus placebo (156)	7.8 mo vs 7.7 mo; HR: 1.03 (95%CI: 0.75–1.42); P = 0.85
STAH trial (Park et al[82], 2019)	cTACE plus sorafenib (170) vs sorafenib (169)	12.8 mo vs 10.8 mo; HR: 0.91 (95%CI: 0.69–1.21); P = 0.290
TACTICS trial (Kudo et al[83], 2020)	cTACE plus sorafenib (80) vs cTACE (76)	25.2 mo vs 13.5 mo; HR: 0.59 (95%CI: 0.41–0.87); P = 0.006
TACE + other therapies
BRISK-TA trial (Kudo et al[85], 2014)	cTACE or DEB-TACE plus brivanib (249) vs cTACE plus placebo (253)	26.4 mo vs 26.1 mo; HR: 0.90 (95%CI: 0.66-1.23); P = 0.53
ORIENTAL trial (Kudo et al[86], 2018)	cTACE plus orantinib (445) vs cTACE plus placebo (444)	31.1 mo vs 32.3 mo; HR: 1.090 (95%CI: 0.878–1.352); P = 0.435
TACE combined with celecoxib and lanreotide (Tong et al[89], 2017)	TACE (n = 35) vs TACE + C + L (36)	7.5 mo vs 15.0 mo; HR: 0.534 (95%CI: 0.321-0.888); P = 0.016
TACE combined with thalidomide (Wu et al[87], 2014)	TACE + thalidomide (56)	21 mo (95%CI: 16–28 mo)
TACE plus bevacizumab (Pinter et al[88], 2015)	TACE + bevacizumab (20) vs TACE + placebo (20)	5.3 mo vs 13.7 mo; HR: 1.7 (95%CI: 0.8-3.6); P = 0.195

HR: Hepatic resection; TACE: Transarterial chemoembolization.

Table 6 Summary of ongoing clinical trials evaluating combination therapy of immune checkpoint inhibitors with locoregional therapies

BCLC stage	Estimated/included patients	Clinical trial identifier	Phase	Arm
0	530	NCT03383458	III	Arm 1: RFA/MWA/curative resection + nivolumab (neoadjuvant) vs Arm 2: RFA/MWA/curative resection
B	26	NCT03397654 (PETAL)	Ib	Single arm: TACE followed by pembrolizumab
B	950	NCT04246177 LEAP-012	III	Arm 1: TACE + lenvatinib + pembrolizumab vs Arm 2: TACE
B	49	NCT03572582 (IMMUTACE)	II	Single arm: TACE + Nivolumab
B	522	NCT04268888 TACE-3	II/III	Arm 1: DEB-TACE + Nivolumab vs Arm 2: DEB-TACE
B	765	NCT04340193, CheckMate 74W	III	Arm 1: TACE + nivolumab + ipilimumab vs Arm 2: TACE + nivolumab + placebo
A	50	NCT03939975	II	Single arm: Pembrolizumab or nivolumab or toripalimab. For participants with stable disease or atypical progression to immunotherapy therapy, RFA or MWA is performed additionally
B	130	NCT03864211	I/II	Single arm: RFA or MWA followed by Toripalimab
B	61	NCT01853618	I/II	Single arm: Tremelimumab + RFA or TACE
B	30	NCT03638141	II	Single arm: Initial DEB-TACE followed by Durvalumab + tremelimumab
B	22	NCT03937830	II	Single arm: Durvalumab and bevacizumab + TACE
B/C	600	NCT03778957 EMERALD-1	III	Arm 1: TACE + durvalumab vs Arm 2: TACE +bevacizumab + durvalumab
A/B	662	NCT04102098 IMbrave050	III	Atezolizumab plus bevacizumab in HCC patients at high risk of recurrence after surgical resection or ablation vs Active surveillance in HCC patients at high risk of recurrence after surgical resection or ablation

BCLC: Barcelona Clinic Liver Cancer Classification; RFA: Radiofrequency ablation; MWA: Microwave ablation; HCC: Hepatocellular carcinoma.

Table 7 Radiofrequency ablation combined with immunotherapy

Ref.	BCLC, n (%)	Treatment, n (%)	Results	Level of evidence
Cui et al[100], 2014	A (10); B (10); C (10)	RFA and cellular immunotherapy 8-11 d after RFA vs RFA alone	Higher PFS (P < 0.001). Six courses had better survival prognosis than three courses	III
Ma et al[99], 2010	A (7)	RFA and autologous RAK cells 14 d after RFA	No severe adverse events, recurrences or deaths during a seven month follow-up	IV
Duffy et al[98], 2017	C (21)	Tremelimumab every 4 wk and subtotal RFA on day 36	Median OS-12.3 mo. Median time to progression–7.4 mo. A significant increase of CD3+ and CD8+ immune cells infiltrates in lesions not treated by RFA	III
Lee et al[102], 2015	A (114)	PEI (13); RFA (69); Surgery (32) and adjuvant CIK cells vs PEI, RFA or Surgery alone	OS was significantly longer in the immunotherapy group than in control group (P = 0.006). CSS was significantly longer in the immunotherapy group (P = 0.02)	II
Tu et al[103], 2014	A and B	RFA and monoclonal antibody (131I-chTNT) injection during ablation vs RFA alone	Increased OS. Improved progression-free survival. Increased circulating white blood cells	IV
Bian et al[104], 2014	0 + A (94); B (33)	RFA and adjuvant 131I metuximab vs RFA alone	Prevention of tumor recurrence	II
Lee et al[101], 2019	0 and A (239)	RFA or PEI or Surgery plus CIK vs RFA or PEI or surgery alone	Increased recurrence-free survival and OS	I

BCLC: Barcelona Clinic Liver Cancer Classification; RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; CIK: Cytokine-induced Killer; OS: Overall survival; CSS: Cyberchondria severity scale; PFS: Progression-free survival.