Review
Copyright ©The Author(s) 2021.
World J Gastrointest Oncol. Dec 15, 2021; 13(12): 1896-1918
Published online Dec 15, 2021. doi: 10.4251/wjgo.v13.i12.1896
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 112222.372.3%67.5%/32.5%/12.5%
Hou et al[23], 2016 51070.654.9%88.2%/66.7%/52.9%
Zhang et al[24], 2014 1140.9--34.4%/70.7%/40.7%
Huang et al[25], 2020 51---86.3%/66.6%/34.2%
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], 2013TACE + RFA (132)HCC 1-5 cm, subcapsular98.5% CRLTP (3 yr) 9.7%. OS (3, 5, 7 yr): 79.3%, 60.6%, 50.9%
Song et al[31], 2016TACE (71) vs TACE + RFA (87) vs RFA (43)HCC within Milan81.6% 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], 2018TACE (85) vs TACE + RFA (n = 82)HCC BCLC 0 or A invisible for ultrasound97.6% 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], 2019TACE (195) vs TACE + RFA (209)HCC B1N/AMedian 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], 2017TACE (32) vs TACE + RFA (32)HCC BCLC B1 + B2N/AMedian 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], 2019TACE (271) vs TACE + RFA (128)HCC BCLB A and B44.7% 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], 2019TACE (314) vs TACE + RFA (109) vs RFA (115)HCC 3.1-10 cm84.7% 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], 2020TACE (124) vs TACE + RFA (77)HCC 3-10 cmN/AMedian 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], 2016TACE (54) vs TACE + RFA (37)HCC not feasible for RFA57% 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], 2020TACE + RFA special location (n = 37) vs TACE + RFA conventional location (n = 85)HCC special locations91.9% 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], 2016TACE + RFA (14)HCC < 2 cm caudate lobe90.9% CRLTP (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], 2018TACE +RFA (69)HCC < 3 cm not feasible for RFA100% CRLTP (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], 2018TACE + RFA single session (87)HCC < 7 cm not resectable87.4% CRLTP (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], 2019TACE + RFA (67)BCLC A, non-surgicalN/APFS (1, 3, 5 yr): 86.8%, 55.9%, 29.7%. OS (1, 3, 5 yr): 100%, 93.4%, 83.5%
Duan et al[116], 2020TACE + RFA, one session (46)HCC > 8 cmN/APFS (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], 2020TACE + RFA (1) naive (40); (2) recurrent (36); and (3) hepatectomy1 tumor < 7 cm, up to 3 tumors < 3 cm, Child A or B62.5% 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], 2018TACE (13) vs TACE + RFA (13)HCC with hepatic vein thrombus0% + 92.3% vs 46.2% + 53.7% (CR + PR)Median OS: 6.5 mo vs 18 mo (P = 0.02)
Song et al[119], 2020TACE (63) vs TACE + RFA (96)Recurrent HCC < 5 cm after HRN/ADFS (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)
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 cmN/AOS (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 criteriaN/AMedian 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 MilanN/AOS (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-BN/AOS (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 HRN/ADFS (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], 2016TACE (n = 20) vs TACE + RFA (n = 20) vs TACE + MWA (n = 10)Non resectable single lesion HCC > 4 cm50% 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], 2019TACE + RFA (n = 41) vs TACE + MWA (n = 34)HCC > 3 cm. HCC 3-5 cm. HCC > 5 cm68.3 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 A80% vs 95% (NS)LTR: 30% vs 0%
Vasnani et al[67], 2016 TACE + RFA (n = 11) vs TACE + MWA (n = 31)HCC within Milan91% vs 67% (CR) 45% vs 35% (rates of complete tumor coagulation on pathology)
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 BN/AMedian PFS: 6.5 mo. Median OS: 35 mo
Ni et al[121], 2019TACE + MWA (349)Up to 3 nodules, 5-8 cm diameter77.1%Median PFS: 4.8 mo. Median OS: 28 mo
Chen et al[47], 2017TACE (96) vs TACE + MWA (48)HCC ≤ 5 cm46.3% 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 cm76% 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 size55.4% 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-B55% vs 74%. At 6-mo, including stable diseaseMedian 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-BN/AMedian 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-BN/A3-yr PFS: 34.5% vs 32.5% (NS). 3-yr OS: 47.6% vs 49.2% (NS)
Biederman et al[55], 2017TACE + MWA (80) vs Radiation segmentectomy (41)Unresectable, solitary, ≤ 3 cmCR 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 C12% 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, solitary6-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 B73.3% vs 33.4%Median PFS: 8.8 mo vs 9.3 mo (NS). Median OS: 20.9 vs 13 mo (NS)
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
Table 6 Summary of ongoing clinical trials evaluating combination therapy of immune checkpoint inhibitors with locoregional therapies
BCLC stageEstimated/included patientsClinical trial identifierPhaseArm
0530NCT03383458IIIArm 1: RFA/MWA/curative resection + nivolumab (neoadjuvant) vs Arm 2: RFA/MWA/curative resection
B26NCT03397654 (PETAL)IbSingle arm: TACE followed by pembrolizumab
B950NCT04246177 LEAP-012IIIArm 1: TACE + lenvatinib + pembrolizumab vs Arm 2: TACE
B49NCT03572582 (IMMUTACE)IISingle arm: TACE + Nivolumab
B522NCT04268888 TACE-3II/IIIArm 1: DEB-TACE + Nivolumab vs Arm 2: DEB-TACE
B765NCT04340193, CheckMate 74WIIIArm 1: TACE + nivolumab + ipilimumab vs Arm 2: TACE + nivolumab + placebo
A50NCT03939975IISingle arm: Pembrolizumab or nivolumab or toripalimab. For participants with stable disease or atypical progression to immunotherapy therapy, RFA or MWA is performed additionally
B130NCT03864211I/IISingle arm: RFA or MWA followed by Toripalimab
B61NCT01853618I/IISingle arm: Tremelimumab + RFA or TACE
B30NCT03638141IISingle arm: Initial DEB-TACE followed by Durvalumab + tremelimumab
B22NCT03937830IISingle arm: Durvalumab and bevacizumab + TACE
B/C600NCT03778957 EMERALD-1IIIArm 1: TACE + durvalumab vs Arm 2: TACE +bevacizumab + durvalumab
A/B662NCT04102098 IMbrave050IIIAtezolizumab 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
Table 7 Radiofrequency ablation combined with immunotherapy
Ref.
BCLC, n (%)
Treatment, n (%)
Results
Level of evidence
Cui et al[100], 2014A (10); B (10); C (10)RFA and cellular immunotherapy 8-11 d after RFA vs RFA aloneHigher PFS (P < 0.001). Six courses had better survival prognosis than three coursesIII
Ma et al[99], 2010A (7)RFA and autologous RAK cells 14 d after RFANo severe adverse events, recurrences or deaths during a seven month follow-upIV
Duffy et al[98], 2017C (21)Tremelimumab every 4 wk and subtotal RFA on day 36Median 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 RFAIII
Lee et al[102], 2015A (114)PEI (13); RFA (69); Surgery (32) and adjuvant CIK cells vs PEI, RFA or Surgery aloneOS 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], 2014A and BRFA and monoclonal antibody (131I-chTNT) injection during ablation vs RFA aloneIncreased OS. Improved progression-free survival. Increased circulating white blood cellsIV
Bian et al[104], 20140 + A (94); B (33)RFA and adjuvant 131I metuximab vs RFA alonePrevention of tumor recurrenceII
Lee et al[101], 20190 and A (239)RFA or PEI or Surgery plus CIK vs RFA or PEI or surgery aloneIncreased recurrence-free survival and OSI