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) |