Table 1.
Characteristics of included studies in the meta-analysis and systematic review
| Author | Country | Treatment | Mean age (years) | Male/female | Study design | Number of cases | Median treatment period (days) | BCLC stage (%) | Child–Pugh (%) | ECOG (%) | Viral hepatitis (%) (HBV, HCV) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hisashi Hidaka 2019 | Japan | TACE + orantinib VS TACE + placebo | 71 VS 71 |
Male: 178 VS 176 Female: 41 VS 37 |
RCT | 219 VS 213 | 298 |
0: 2.7% VS 4.2% A: 29.7% VS 25.4% B: 55.3% VS 55.9% C: 12.3% VS 14.1% |
A: 100% VS 100% |
0: 94.5% VS 91.5% 1: 5.5% VS 8.5% |
HbsAg positive:17.8% VS 14.1% HCVAb positive:59.8% VS 57.3% |
| Masatoshi Kudo 2017 | Japan | TACE + orantinib VS TACE + placebo | 66·2 VS 65·4 |
Male: 363 VS 364 Female:81 VS 80 |
RCT | 445 VS 444 | 327 |
0: 2% VS 3% A: 33% VS 27% B: 47% VS 52% C: 17% VS 16% |
A: 100% VS 100% |
0: 90% VS 91% 1: 10% VS 9% |
HbsAg positive: 38% VS 45% HbsAb positive: 24% VS 20% HbcAb positive: 70% VS 68% HCV positive:43% VS 37% |
| Yoshitaka Inaba 2013 | Japan | TACE + orantinib VS TACE-alone | NA | Male: 39 VS 43 Female: 11 VS 8 | RCT | 50 VS 51 | 122 |
0: 6.0% VS 17.6% A: 36.0% VS 25.5% B: 48.0% VS 52.9% C: 10.0% VS 10.0% |
A: 80.0% VS 88.2% B: 18.0% VS 11.8% unknown: 2.0% VS 0.0% |
0: 90.0% VS 96.1% 1: 10.0% VS 3.9% |
HbsAg positive: 4.0% VS 7.8% HbcAb positive:80.0% VS 70.6% |
| Tao Sun 2020 | China | TACE + apatinib VS TACE-alone | 55.56 ± 5.2 VS 58.65 ± 6.6 |
Male: 24 VS 21 Female:3 VS 10 |
Retrospective controlled study | 27 VS 31 | NA | C: 100% VS 100% |
A:77.8% VS 74.2% B: 22.2% VS 25.8% |
1: 77.8% VS 80.6% 2: 22.2% VS 19.4% |
B: 92.6% VS 90.3% |
| Wenzhe Fan 2019 | China | TACE + apatinib VS TACE-alone | 49 VS 50 |
Male: 68 VS 71 Female:17 VS 32 |
Retrospective controlled study | 85 VS 103 | NA | B or C: 100% VS 100% |
A: 85.9% VS 84.5% B: 14.1% VS 15.5% |
0: 78.8% VS 87.4% 1–2: 21.2% VS 12.6% |
B: 81.9% VS 75.7% |
| Xuefeng Kan 2020 | China | TACE + apatinib VS TACE-alone | 52.7 ± 9.7 VS 53.1 ± 10.1 |
Male: 77 VS 78 Female:13 VS 12 |
Retrospective controlled study | 90 VS 90 | NA | B: 88.9% VS 87.8% |
A: 87.8% VS 85.6% B: 12.2% VS 14.4% |
1: 82.2% VS 83.3% 2: 17.8% VS 16.7% |
B: 88.9% VS 87.8% |
| Juanfang Liu 2019 | China | TACE + apatinib VS TACE-alone | 53.3 ± 9.4 VS 56.5 ± 9.7 |
Male: 29 VS 39 Female:5 VS 9 |
Retrospective controlled study | 34 VS 48 | NA |
B:52.9% VS 58.3% C:47.1% VS 41.7% |
A: 58.8% VS 60.4% B: 41.2% VS 39.6% |
0–1: 47.1% VS 45.8% 2: 52.9% VS 54.2% |
B: 64.7% VS 77.1% C:14.7% VS 10.4% |
| Yuanyuan Li 2021 | China | TACE‑apatinib VS TACE‑125I | 56.62 ± 10.1 VS 51.63 ± 9.9 |
Male: 19 VS 25 Female:2 VS 2 |
Retrospective controlled study | 21 VS 27 | NA | B or C: 100% VS 100% |
A: 81.0% VS 66.7% B: 19.0% VS 33.3% |
0:71.4% VS 74.1% 1:29.0% VS 25.9% |
NA |
| Zhiyu Qiu 2019 | China | TACE + apatinib VS TACE-alone | NA |
Male: 41 VS 73 Female:1 VS 10 |
A Propensity Score Matching Analysis | 42 VS 83 | NA |
B:21.4% VS 34.9% C:78.6% VS 65.1% |
A:85.7% VS 90.4% B:14.3% VS 9.6% |
NA | B: 92.9% VS 88.0% |
| Lujun Shen 2020 | China | TACE + apatinib VS TACE-alone | NA |
Male: 38 VS 74 Female:2 VS 6 |
Retrospective controlled study | 40 VS 80 | 111 | NA |
A: 82.5% VS 80.0% B: 17.5% VS 20.0% |
NA | B: 90.0% VS 93.8% |
| Masatoshi Kudo 2014 | Japan | TACE + Brivanib VS TACE + placebo | 57 VS 59 | Male: 206 VS 216, female: 43 VS 37 | RCT | 249 VS 253 | NA |
A: 26% VS 23% B: 52% VS 59% C: 22% VS 17% |
A: 96% VS 91% B: 4% VS 8% C: < 1% VS 1% |
0: 80% VS 84% 1: 20% VS 16% |
B: 63% VS 66% C: 20% VS 17% |
| Zhigang Fu 2021 | China | TACE + lenvatinib VS TACE-alone | 60 VS 60 | Male: 50 VS 55, Female: 10 VS 5 | Retrospective controlled study | 60 VS 60 | 246.9 |
A:3.3% VS 5.0% B:55.0% VS 43.3% C:41.7% VS 51.7% |
A:93.3% VS 95.0% B:6.7% VS 5.0% |
NA |
B:80.0% VS 80.0% C:3.3% VS 3.3% |
| Tim Meyer 2017 | UK | DEB-TACE + sorafenib VS DEB-TACE + placebo | 65 VS 68 | Male: 139 VS 138, female: 18 VS 18 | RCT | 157 VS 156 | 120 | NA | A: 100% VS 100%, (5) 68% vs 73% (6) 25% VS 22% (7) 3% VS 1% unknown: 4% VS 3% | 0: 62%: 62% 1: 37%: 37% unknown: 1%: 1% | B: 5% VS 6%, C: 12% VS 6% B + C: 2% VS 2% |
| Xuesong Yao 2016 | China | TACE + sorafenib VS TACE-alone | 56.5 VS 55.9 | Male: 44 VS 87, female: 6VS 13 | Prospective nonrandomized controlled study | 50 VS 100 | NA | B: 42% VS 40%, C: 58% VS 60% | A: 84% VS 86%, B: 16% VS 14% | 0: 42% VS 34% 1: 58% VS 66% | B: 84% VS 83% C: 4% VS 4% B + C: 4% VS 3% |
| Riccardo Lencioni 2016 | USA | DEB-TACE + sorafenib VS DEB-TACE + placebo | 64.5 VS 63.0 | Male: 135 VS 126, female: 19 VS 27 | RCT | 154 VS 153 | 147 | B: 100% VS 100% | A: (5) 63.6% VS 68.6%(6) 35.7% VS 30.7%(7) 0.6% VS 0, unknown: 0: 0.7% | 0: 100% VS 100% | B:35.7% VS 32.7% C: 25.3% VS 26.8% B + C: 1.3% VS 0 |
| Masatoshi Kudo 2019 | Japan | TACE + sorafenib VS TACE-alone | 72.0 VS 73.0 | Male: 63 VS 55, female: 17 VS 21 | RCT | 80 VS 76 | 270.9 | A:33.8% VS 43.4% B:55.0% VS 44.7% C:11.3% VS 11.8% | A: 98.8% VS 93.5% B: 1.3% VS 5.6% | 0: 88.8% VS 88.2%, 1: 11.3% VS 11.8% | B: 12.5% VS 2.6% C: 47.5% VS 69.7% |
| Zhexuan Wang 2020 | China | TACE + sorafenib VS TACE-alone | 53.7 ± 12.0 VS 56.7 ± 12.1 | Male: 267 VS 1183, female: 46 VS 223 | Retrospective controlled study | 1,406 VS 313 | 309 | A:11.5% VS 13.7% B:53.3% VS 53.8% C:35.1% VS 32.6% | A: 95.6% VS 93.8% B: 4.5% VS 6.2% | 0: 64.9% VS 67.4%, 1: 35.1% VS 32.6% | B: 83.1% VS 83.0% C: 5.1% VS 2.6% |
| Kangshun Zhu 2014 | China | TACE + sorafenib VS TACE-alone | 48.4 ± 8.1 VS 51.9 ± 12.2 | Male: 39 VS 38, female: 7 VS 7 | Retrospective controlled study | 46 VS 45 | 330 | NA | A: 84.7% VS 86.7% B: 15.2% VS 13.3% | 0: 47.8% VS 44.4%, 1–2: 52.1% VS 55.6% | B: 82.3% VS 88.9% C: 10.9% VS 2.2% |
| Masatoshi Kudo 2011 | Japan and Korean | TACE + sorafenib VS TACE + placebo | 69 VS 70 | Male: 174VS 168, female: 55 VS 61 | RCT | 229 VS 229 | 513 | NA | NA | 0: 87.8% VS 87.8% 1: 12.2% VS 12.2% | B: 20.5% VS 22.7% C: 60.7% VS 64.6% |
| Yan Zhao 2016 | China | TACE + sorafenib VS TACE-alone | 53 VS 54 | Male: 159 VS 159, female: 24 VS 24 | Multicenter retrospective controlled study | 183 VS 183 | 489 | NA | A: 97.3% VS 3.8% B: 97.3% VS 2.7% | 0: 85.8% VS 14.2%, 1: 88.5% VS 11.5% | B/C: 88.0% VS 88.0% |
| Katrin Hoffmann 2015 | Germany | TACE + sorafenib VS TACE + placebo | 58.5 VS 58.0 | 45\5 | RCT | 24 VS 26 | 125 | NA | A: 58.3% VS 83.3% B: 37.5% VS 23.1% C: 4.2% vs 0% | NA |
B: 12.5% VS 11.5% C: 45.8% VS 26.9% |
| Jianbing Wu 2017 | China | TACE + sorafenib VS TACE-alone | NA | Male: 25 VS 28, female: 2 VS 3 | Retrospective controlled study | 30 VS 31 | NA | C: 100% VS 100% | A: 93.3% VS 80.6% B: 6.6% VS 6.5% | 0: 80% VS 77.4%, 1: 20% VS 22.6% | B/C: 90% VS 96.8% |
| Hao Hu 2014 | china | TACE + sorafenib VS TACE-alone | 61 ± 11 VS 60 ± 11 | Male: 69 VS 140, female: 13 VS 24 | retrospective cohort study | 82 VS 164 | NA | NA | A: 70.7% VS 62.8% B: 29.3% VS 37.2% | NA | B: 82.9% VS 84.8% C: 7.3% VS 6.1% |
| Wei Bai 2013 | China | TACE + sorafenib vs TACE-alone | 54 ± 13 VS 52 ± 12 | Male: 73 VS 146 female: 9 VS 18 | Prospective nonrandomized controlled study | 82 VS 222 | NA |
B: 23.2% VS 27.4% C: 76.8% VS 72.6% |
A:76.8% VS 70.1% B:23.2% VS 29.9% |
0: 36.6% VS 29.3% 1: 46.4% VS 61.6% 2: 14.6% VS 9.1% 3: 1.2% VS 0% 4: 1.2% VS 0% |
B: 87.8% VS 89.6% C: 4.9% VS 4.3% |
| Zhenwei Peng 2019 | China | TACE + sorafenib VS TACE-alone | 55 ± 7.6 VS 56 ± 8.3 | Male: 107 VS 110 female: 21VS 22 | Retrospective cohort study | 128 VS 132 | NA | A: 80.4% VS 72.0%, B: 19.5% VS 28.0% | NA | NA | B: 82.0% VS 85.6% C: 4.7% VS 5.3% |
| Baosheng Ren 2019 | China | TACE + sorafenib VS TACE-alone | NA | Male: 48 VS 102 female: 13 VS 20 | Retrospective controlled study | 61 VS 122 | 351 | B: 49.2% VS 59.0%, C: 50.8% VS 41.0% | A: 90.1% VS 91.0%, B: 9.8% VS 9.0% | 0: 59.0% VS 56.6%, 1–2: 41.0% VS 43.4% | B: 82.0% VS 76.2% C: 8.2% VS 7.3% |
| Xinhua Zou 2021 | China | TACE + sorafenib VS TACE-alone | 58.31 ± 7.83 VS 58.53 ± 8.11 | Male: 32 VS 31 female: 10 VS 12 | Retrospective controlled study | 42 VS 43 | NA | B: 54,8% VS 58.1%, C: 45.2% VS 41.9% | A: 69.0% VS 67.4%, B: 26.2% VS 30.2%, C: 4.8% VS 2.3% | 0: 21.4% VS 23.3% 1: 69.0% VS 69.8, 2: 9.5% VS 7.0% | B: 54.8% VS 58.1% C: 45.2% VS 41.9% |
| Xue-Fen Lei 2018 | China | TACE + sorafenib vs TACE-alone | 52 ± 5 VS 51 ± 6 | Male: 24 VS 18 female: 14 VS 11 | Retrospective controlled study | 38 VS 29 | NA | B: 100% VS 100% |
A:65.8% VS 65.5% B:34.2% VS 34.5% |
0: 100% VS 100% | NA |
| Takamasa Ohki 2015 | Japan | TACE + sorafenib vs TACE-alone | 70.0 VS 72.9 | Male: 20 VS 54 female: 4 VS 17 | Retrospective controlled study | 24 VS 71 | 412 | NA |
A:70.8% VS 29.2% B:56.3% VS 43.7% |
NA | C: 75.0% VS 67.6% |
| Xuying Wan 2016 | China | TACE + sorafenib vs TACE-alone | NA | Male: 218 VS 218 female: 27 VS 27 | Retrospective controlled study | 245 VS 245 | 324 ± 315.3 | NA |
A:86.6% VS 93.7% B:13.4% VS 6.3% |
0/1: 90.6% VS 82.7% 2: 9.4% VS 17.3% |
NA |
| Author | Alcohol hepatitis(%) | Viral hepatitis + alcohol hepatitis | Dose(mg) | ORR | DCR | CR | PR | SD | PD | TTP (days) | OS (days) |
| Hisashi Hidaka 2019 | NA | NA | 200, twice daily | NA | NA | NA | NA | NA | NA | 141 VS 93, HR 0.76 (0.619, 0.940) | 975 VS 990, HR 0.981 (0.717, 1.343) |
| Masatoshi Kudo 2017 | NA | NA | 200, twice daily | NA | NA | NA | NA | NA | NA | 87 VS 75, HR 0.858 (0.744, 0.990) | 933 VS 969, HR 1.09 ( 0.878, 1.352) |
| Yoshitaka Inaba 2013 | NA | NA | 200, twice daily | NA | NA | NA | NA | NA | NA | 157 VS 122, HR 0.699 (0.450, 1.088) | 780: unknown, HR 1.06 (0.578, 1.492) |
| Tao Sun 2020 | NA | NA | 500, twice daily | mRECIST: 37.0% VS 16.1% | 62.9% VS 29.0% | 0% VS 0% | 37.0% VS 16.1% | 25.9% VS 12.9% | 37.0% VS 71.0% | 270 VS 150, HR 0.56 (0.310, 1.022) | 360 VS 270, HR 0.343 ( 0.185, 0.636) |
| Wenzhe Fan 2019 | NA | NA | 500, twice daily | mRECIST:24% VS 4% | 59% VS 14% | 0% VS 0% | 24% VS 4% | 26% VS 10% | 35% VS 89% | 183 VS 111, HR 0.61( 0.48, 0.77) | 360 VS 210, HR 0.443 (0.306, 0.641) |
| Xuefeng Kan 2020 | NA | NA | 500, twice daily | mRECIST:51% VS 10% | 59% VS 33% | 4% VS 0% | 47% VS 10% | 8% VS 23% | 41% VS 67% | 210 VS 90 | 390 VS 240, HR 0.35 ( 0.26, 0.49) |
| Juanfang Liu 2019 | 11.8% VS 8.3% | NA | 500, twice daily | mRECIST: 55.9% vs 31.3% | 70.6% vs 43.8% | 0% VS 0% | 55.9% VS 31.2% | 14.7% VS 12.5% | 29.4% VS 56.3% | NA | 210 VS 167, HR 0.346 (0.203, 0.591) |
| Yuanyuan Li 2021 | NA | NA | 500, twice daily | mRECIST:4.76% VS 40.74% | 23.81% VS 77.78% | 0%VS 0% | 4.8% VS 40.7% | 19% VS 37.0% | 76.2% VS 22,2% | NA | 324 VS 399, HR 0.455 (0.245, 0.848) |
| Zhiyu Qiu 2019 | NA | NA | 500, twice daily | RECIST: 16.7% VS 8.4% | 81.0% VS 53.0% | 4.8% VS 3.6% | 11.9% VS 4.8% | 64.3% VS 44.6% | 19.0% VS 47.0% | NA | 510 VS 321, HR 0.28 (0.158, 0.499) |
| Lujun Shen 2020 | NA | NA | 500, twice daily | NA | NA | NA | NA | NA | NA | NA | 546 VS 255, HR 0.38 ( 0.22, 0.66) |
| Masatoshi Kudo 2014 | 16% VS 15% | NA | 800, once-daily | mRECIST:48% VS 42% | 79% VS 79% | 22% VS 11% | 26% VS 31% | 31% VS 37% | 9% VS 18% | NA | 792 VS 783, HR 0.9 (0.66, 1.23) |
| Zhigang Fu 2021 | NA | NA | 12 mg (≥ 60 kg) or 8 mg (< 60 kg) once daily based on body weight/0, once-daily | mRECIST: 68.3% VS 31.7% | 93.3% VS 86.7% | 10.0% VS 5.0% | 58.3% VS 26.7% | 25.0% VS 55.0% | 6.7% VS 13.3% | NA | NA, HR 0.466 (0.226, 0.886) |
| Tim Meyer 2017 | 34% VS 33% | B + C + alcohol: 2% VS 2% B + alcohol: 2% VS 2% | 400, twice daily | mRECIST: 54% VS 52% | mRECIST: 75% VS 77% | mRECIST: 29% VS 23% | mRECIST: 25% VS 29% | mRECIST: 21% VS 25% | mRECIST: 8% VS 10% | 326 VS 320, HR 0.88 (0.67,1.17) | 631 VS 598, HR 0.91 (0.67, 1.24) |
| Xuesong Yao 2016 | NA | NA | 400, twice daily | mRECIST: 8% VS 1% | 32% VS 24% | 0% VS 0% | 8% VS 1% | 24% VS 23% | 68% VS 76% | 306 VS 201 | 651 VS 345, HR 0.481 (0.297, 0.778) |
| Riccardo Lencioni 2016 | 17.5% VS 19.6% | B + alcohol: 1.9% VS 0.7% C + alcohol: 1.9% VS 2% | 400, twice daily | mRECIST: 42.9% VS 34.6% | 80.5% VS 71.9% | 13.6% VS 13.1% | 29.2% VS 21.6% | 37.7% VS 37.3% | 10.4% VS 19.6% | 169 VS 166, HR 0.797 (0.588, 1.08) | 270 VS 272, HR 0.898 (0.606, 1.330) |
| Masatoshi Kudo 2019 | NA | NA | 400, twice daily | RECICL: 71.3% VS 61.8% | 83.8% VS 77.6% | 28.8% VS 27.6% | 42.5% VS 34.2% | 12.5% VS 15.8% | 2.5% VS 3.9% | 801 VS 492, HR 0.54 (0.35, 0.83) | NA |
| Zhexuan Wang 2020 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | 219 VS 189, HR 0.75 (0.60, 0.93) | 672 VS 666, HR 0.87 (0.74,1.02) |
| Kangshun Zhu 2014 | NA | NA | 400, twice daily | mRECIST: 28.3% VS 4.4% | 57% VS 13% | 0% VS 0% | 28.3% VS 4.4% | 28.3% VS 8.9% | 43.5% VS 86.7% | 180 VS 90 | 330 VS 180, HR 0.429 (0.268, 0.690) |
| Masatoshi Kudo 2011 | 8.2% VS 5.2% | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | 162 VS 111, HR 0.87( 0.7, 1.09) | NA, HR 1.06 (0.69, 1.64) |
| Yan Zhao 2016 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | 393 VS 150 | 669 VS 537, HR 0.4(0.4, 0.83) |
| Katrin Hoffmann 2015 | 29.1% VS 42.3% | NA | 400, twice daily | mRECIST: 20.8%: 26.9% | 66.7% VS 73.1% | 4.3% VS 0% | 17.4% VS 26.9% | 47.8% VS 46.2% | 30.4% VS 26.9% | 71 VS 85, HR 1.106 (0.387, 3.162) | NA |
| Jianbing Wu 2017 | NA | NA | 400, twice daily | mRECIST:NA | 73.4% VS 51.6% | NA | 16.7% VS 6.5% | 56.7% VS 45.1% | 26.6% VS 48.4% | 279 VS 102, | 537 VS 213, HR 0.151 (0.071, 0.322) |
| Hao Hu 2014 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | 78 VS 57 HR 0.62 (0.47,0.82) | 210 VS147, HR 0.63 (0.48, 0.84) |
| Wei Bai 2013 | NA | NA | 400, twice daily | RECIST: 9.7% VS 3.4% | 58.5% VS 44.5% | 0% VS 0% | 9.7% VS 3.4% | 48.8% VS 41.1% | 41.5% VS 55.5% | 189 vs 129, HR 0.6 (0.422, 0.853) | 225 vs 153, HR 0.61(0.42, 0.884) |
| Zhenwei Peng 2019 | 3.9% VS 3.8% | NA | 400, twice daily | mRECIST: 72.3% VS 50.0% | 87.3% VS 80.6% | 34.5% VS 20.8% | 38.1% VS 29.2% | 14.5% VS 30.6% | NA | NA | 516 VS 363, HR 0.62(0.44, 0.89) |
| Baosheng Ren 2019 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | NA | 870 ± 216 VS 447 ± 45, HR 0.684 (0.470,0.997) |
| Xinhua Zou 2021 | NA | NA | 400, twice daily | mRECIST: 23.81% VS 16.28% | 80.95% VS 55.81% | 4.76% VS 0.00% | 19.05% VS 16.28% | 57.14% VS 39.53% | 19.05% VS 44.19% | NA | 960 VS 630, HR 0.6155 (0.3978, 0.9524) |
| Xue-Fen Lei 2018 | NA | NA | 400, twice daily | mRECIST: 60.5% VS 41.4% | 86.8% VS 65.5% | 31.6% VS 13.8% | 28.9% VS 27.6% | 26.3% VS 24.1% | 13.2% VS 34.5% | NA | 1056 VS 660, HR 0.113 (0.036, 0.350) |
| Takamasa Ohki 2015 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | NA | 861 VS 467, HR 0.43 (0.24, 0.76) |
| Xuying Wan 2016 | NA | NA | 400, twice daily | NA | NA | NA | NA | NA | NA | NA | 607 VS 419, HR 0.76 (0.61, 0.94) |
RECIST Response Evaluation Criteria In Solid Tumors, mRECIST modified RECIST, TACE transarterial chemoembolization, DEB-TACE drug-eluting bead transarterial chemoembolization, BCLC The Barcelona Clinic Liver Cancer, ECOG Eastern Cooperative Oncology Group, NA not available, RCT randomized controlled trial, Child–Pugh Child–Turcotte–Pugh, ORR objective response rate, DCR disease control rate, CR complete response, PR partial response, SD stable disease, PD progressive disease