1Department of Radiation Oncology, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
2Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
3Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark
© 2024 The Korean Liver Cancer Association.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conflicts of Interest
Sun Hyun Bae is an editorial board member of Journal of Liver Cancer, and was not involved in the review process of this article. Otherwise, the authors have no conflicts of interest to disclose.
Ethics Statement
Not applicable.
Funding Statement
This work was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS) funded by the Ministry of Science and ICT (MSIT), Republic of Korea (No. 50572-2024). This work was also supported by the Soonchunhyang University Research Fund. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data Availability
Not applicable.
Author Contributions
Conceptualization: SHB, WIJ, MSK, HRM, BW, MH
Data curation: SHB, WIJ, MSK
Formal analysis: SHB
Supervision: MH
Writing - original draft: SHB, WIJ
Writing - review & editing: SHB, WIJ, MSK, HRM, BW, MH
All authors approved the final version of the manuscript.
Study | Nation | Study type | Study period | Number of patients | Age (years) |
ECOG PS (%) |
Hepatitis (%) |
CP class (%) |
BCLC stage (%) |
Tumor size (cm) | Multiplicity (%) | PVTT (%) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0 | 1 | 2 | 3 | HBV | HCV | Alcoholic | A | B | C | 0 | A | B | C | D | |||||||||
Uchinami et al., 202323 | Japan | R/SC/CT | 2015-2021 | 41 | 69 (44-88) | NR | 22 | 27 | NR | 100 | 0 | 0 | NR | 2.6 (1.9-3.6) | 27 | NR | |||||||
Lizumi et al., 202324 | Japan | R/SC/ST | 2009-2018 | 15 | 71 (58-90) | 40 | 60 | 13 | 53 | NR | 53 | 47 | NR | 4.0 (1.5-8.0) | 27 | NR | |||||||
Bush et al., 202325 | USA | P3/MC/CT | 2008-2017 | 35 | 62 (53-70)* | 3 | 65 | 32 | 0 | 0 | 69 | 34 | NR | 0 | 86 | 11 | 3 | 0 | 3.3 (2.0-4.5) | 17 | 0 | ||
Lin et al., 202126 | Taiwan | R/SC/ST | 2014-2017 | 43 | 71 (48-85) | 51 | 44 | 5 | 0 | 53 | 35 | 5 | 93 | 7 | 0 | NR | 3.1 (1.1-17.1) | 23 | 19 | ||||
Kim et al., 202118 | Korea | P3/SC/CT | 2013-2017 | 80 | 61 (40-82) | 91 | 9 | 0 | 0 | 84 | NR | NR | 96 | 4 | 0 | 6 | 54 | 35 | 5 | 0 | 1.2 (1.0-2.9) | 6 | 0 |
Iwata et al., 202127 | Japan | R/SC/ST | 2013-2019 | 71 | 82 (80-96) | 62 | 28 | 6 | 4 | 10 | 39 | 7 | 90 | 10 | 0 | 10 | 63 | 2 | 21 | 4 | 3.2 (0.8-11.1) | NR | NR |
Iwata et al., 202128 | Japan | P2/SC/ST | 2013-2016 | 45 | 68 (36-80) | 93 | 7 | 0 | 0 | 35 | 29 | 7 | 91 | 9 | 0 | 27 | 67 | 0 | 6 | 0 | 2.5 (1.0-10.0) | 0 | 0 |
Yoo et al., 202029 | Korea | R/SC/ST | 2016-2017 | 167 | 62 (35-91) | 55 | 45 | 0 | 78 | 9 | 5 | 89 | 9 | 2 | 66 | 34 | NR | NR | NR | ||||
Tamura et al., 202030 | Japan | R/SC/CT | 2003-2017 | 31 | 72 (51-84) | 65 | 32 | 3 | 0 | 13 | 58 | NR | 94 | 6 | 0 | NR | 3.5 (1.0-9.0) | 0 | 0 | ||||
Hojo et al., 202031 | Japan | R/SC/ST | 2008-2015 | 110 | 74 (48-90) | 65 | 35 | 0 | 25 | 45 | NR | 86 | 14 | 0 | NR | 4.3 (0.8-15.0) | 23 | NR | |||||
Sanford et al., 201932 | USA | R/SC/CT | 2008-2017 | 49 | 65 (60-74)† | 47 | 49 | 4 | 12 | 49 | NR | 83 | 17 | 0 | NR | NR | 49 | NR | |||||
Kim et al., 201933 | Korea | R/SC/ST | 2012-2017 | 243 | 61 (24-92) | 98 | 2 | 0 | 0 | 77 | 8 | 7 | 94 | 6 | 0 | 0 | 40 | 35 | 25 | 0 | 2.2 (1.0-17.0) | NR | NR |
Chadha et al., 201934 | USA | R/SC/ST | 2007-2016 | 46 | 72 (52-90) | 44 | 54 | 2 | 0 | 4 | 28 | 52 | 83 | 17 | 0 | NR | 6.0 (1.5-21.0) | 22 | 20 | ||||
Mizuhata et al., 201835 | Japan | R/SC/ST | 2011-2015 | 40 | 72 (38-87) | 95 | 5 | 0 | 12 | 38 | 25 | 70 | 30 | 0 | NR | 3.7 (1.1-12.4) | 75 | 30 | |||||
Kimura et al., 201736 | Japan | R/SC/ST | 2008-2015 | 24 | 73 (49-89) | 67 | 33 | 0 | 0 | 29 | 25 | 17 | 100 | 0 | 0 | NR | 9.0 (5.0-18.0) | 0 | 83 | ||||
Kim et al., 201537 | Korea | P1/SC/ST | 2007-2010 | 27 | NR (51-78) | 78 | 22 | 0 | 0 | 56 | 30 | 7 | 89 | 11 | 0 | 0 | 48 | 37 | 15 | 0 | NR (1.3-7.0) | NR | NR |
Lee et al., 201438 | Korea | R/SC/ST | 2008-2011 | 27 | 55 (42-70) | 67 | 33 | 0 | 0 | 74 | 15 | NR | 67 | 33 | 0 | 0 | 0 | 0 | 100 | 0 | 7.0 (3.0-16.0) | NR | 100 |
Mizumoto et al., 201139 | Japan | R/SC/ST | 2001-2007 | 266 | 70 (26-88) | 60 | 38 | 2 | 0 | 12 | 75 | NR | 76 | 23 | 1 | NR | 3.4 (0.6-13.0) | 53 | NR | ||||
Komatsu et al., 201140 | Japan | R/SC/CT | 2001-2009 | 242 | NR | 71 | 24 | 4 | 1 | 12 | 67 | NR | 76 | 23 | 1 | 4 | 34 | 13 | 47 | 2 | NR | 12 | NR |
Kawashima et al., 201141 | Japan | R/SC/ST | 1999-2007 | 60 | 70 (48-92) | 95 | 5 | 0 | 7 | 83 | NR | 78 | 22 | 0 | NR | 4.5 (2.0-9.0) | 15 | 2 | |||||
Chiba et al., 200542 | Japan | R/SC/ST | 1985-1998 | 162 | 63 (41-84) | 37 | 49 | 13 | 1 | 11 | 81 | 1 | 56 | 38 | 6 | NR | 3.8 (1.5-14.5) | 51 | NR | ||||
Bush et al., 200443 | USA | P2/SC/ST | 1998-2003 | 34 | 65‡ (47-86) | NR | NR | 41 | 41 | NR | 5.6 (1.5-10.0) | 6 | NR |
ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCV, hepatitis C virus; CP, Child-Pugh; BCLC, Barcelona Clinic Liver Cancer Stage; PVTT, portal vein tumor thrombosis; R, retrospective study; SC, single center; CT, comparative trial; NR, not reported; ST, single-arm trial; P3, prospective phase 3 study; MC, multicenter; P2, prospective phase 2 study; P1, prospective phase 1 study.
* Mean value (standard deviation);
† Median (interquartile range);
‡ Mean value.
Study | Previous treatment (%) | Median total dose (GyE) | Number of fx | Median BED (GyE10) | Median fu (months) |
LPFS (%) |
PFS (%) |
OS (%) |
||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1-yr | 3-yr | 5-yr | 1-yr | 3-yr | 5-yr | 1-yr | 3-yr | 5-yr | ||||||
Uchinami et al., 202323 | - | 72.6 (66.0-76.0) | 10-22 | 99.0 | - | - | - | - | - | - | - | - | - | - |
Iizumi et al., 202324 | 53 | - | - | - | 23 (8-54) | 93 | 75 | - | 73 | 0 | - | 80 | 40 | - |
Bush et al., 202325 | 0 | 70.2 | 15 | 103.1 | 30 | 89 | 62 | - | 76 | 63 | - | 81 | 49 | 42 |
Lin et al., 202126 | 84 | 72.6 (66.0-72.6) | 10-22 | 96.6 | 40 (9-62) | - | - | 93 | 74 | - | 56 | 88 | 76 | 63 |
Kim et al., 202118 | 95 | 66.0 | 10 | 109.6 | 52 (46-60) | 95 | 88 | 75 | 54 | 21 | 11 | 98 | 79 | 65 |
Iwata et al., 202127 | 35 | 66.0 (66.0 or 72.6) | 10 or 22 | 109.6 | 33 (9-68) | 97 | 86 | 70 | 72 | 38 | 25 | 93 | 68 | 38 |
Iwata et al., 202128 | - | 66.0 (66.0 or 72.6) | 10 or 22 | 109.6 | 53 (10-75) | 99 | 95 | 92 | 83 | 55 | 40 | 98 | 79 | 70 |
Yoo et al., 202029 | - | - | - | - | 14 (1-29) | 93 | - | - | - | - | - | 95 | - | - |
Tamura et al., 202030 | - | 73.5 (47.6-78.4) | 10-38 | 99.2 | 56 (22-82) | - | - | - | 69 | 39 | 31 | 92 | 69 | 51 |
Hojo et al., 202031 | - | 76.0 | 20 | 104.9 | 37 (1-100) | 97 | 92 | 89 | 70 | 40 | 28 | 94 | 74 | 69 |
Sanford et al., 201932 | 24 | 58.1 (30.0-67.5) | 5-16 | 80.5 | 14 | - | 93 | 93 | - | - | - | 69 | 44 | - |
Kim et al., 201933 | 79 | 66.0 (50.0, 60.0, or 66.0) | 10 | 109.6 | 32 (2-68) | - | 89 | 88 | - | 19 | 12 | - | 62 | 48 |
Chadha et al., 201934 | 54 | 67.5 (24.0-91.0) | 6-25 | 97.9 | 15 (1-60) | 95 | - | - | 74 | - | - | 73 | 47 | - |
Mizuhata et al., 201835 | 90 | 76.0 | 20-38 | 104.9 | 20 (1-72) | 100 | 94 | 94 | 70 | - | - | 86 | 51 | 23 |
Kimura et al., 201736 | - | 72.6 (60.8-85.8) | 10-35 | 96.6 | 18 (3-64) | 95 | 66 | - | - | - | - | 70 | 52 | - |
Kim et al., 201537 | 96 | 66.0 (60.0, 66.0, or 72.0) | 20-24 | 85.8 | 31 (5-63) | - | 80 | 64 | - | 17 | 0 | - | 56 | 42 |
Lee et al., 201438 | 78 | 55.0 (50.0-66.0) | 20-22 | 68.8 | 13 (2-52) | 71 | - | - | 11 | - | - | 56 | - | - |
Mizumoto et al., 201139 | 63 | 72.6 (66.0, 72.6, or 77.0) | 10-35 | 96.6 | - | 98 | 87 | 81 | 56 | 21 | 12 | 87 | 61 | 48 |
Komatsu et al., 201140 | 47 | 66.0 (52.8-84.0) | 4-38 | 109.6 | 31 | - | 90 | 90 | - - | - | - | - | 38 | |
Kawashima et al., 201141 | 60 | 76.0 (60.0, 65.0, or 76.0) | 10-26 | 104.9 | - | 97 | 90 | 86 | -18 | 4 | 83 | 56 | 25 | |
Chiba et al., 200542 | 72 | 72.0 (50.0-84.0) | 10-24 | 104.4 | 32 (3-133) | 97 | 91 | 87 | - - | - | 81 | 44 | 24 | |
Bush et al., 200443 | - | 63.0 | 15 | 89.5 | 20 | - | - | - | - | - | - | - | - | - |
Group | Cohorts | Patients | heterogeneity* | I2 (%) | Egger’s test* | Fixed event rate | Random event rate |
---|---|---|---|---|---|---|---|
LPFS | |||||||
1-year LPFS | 14 | 1,148 | 0.0031 | 58.34 | 0.0993 | 0.97 (0.95-0.98) | 0.96 (0.94-0.98) |
3-year LPFS | 15 | 1,469 | 0.0019 | 59.15 | 0.1683 | 0.89 (0.87-0.91) | 0.88 (0.85-0.91) |
5-year LPFS | 13 | 1,438 | <0.0001 | 73.78 | 0.8187 | 0.86 (0.84-0.88) | 0.86 (0.82-0.90) |
PFS | |||||||
1-year PFS | 12 | 809 | <0.0001 | 82.91 | 0.5067 | 0.64 (0.60-0.67) | 0.65 (0.56-0.74) |
3-year PFS | 11 | 983 | <0.0001 | 87.22 | 0.3211 | 0.26 (0.23-0.29) | 0.29 (0.21-0.38) |
5-year PFS | 10 | 976 | <0.0001 | 90.22 | 0.3193 | 0.16 (0.14-0.18) | 0.19 (0.11-0.28) |
OS | |||||||
1-year OS | 17 | 1,271 | <0.0001 | 81.02 | 0.1802 | 0.88 (0.87-0.90) | 0.86 (0.81-0.91) |
3-year OS | 17 | 1,347 | <0.0001 | 76.74 | 0.8238 | 0.61 (0.58-0.63) | 0.60 (0.54-0.66) |
5-year OS | 14 | 1,455 | <0.0001 | 89.09 | 0.7089 | 0.45 (0.42-0.47) | 0.46 (0.38-0.54) |
Group | Cohorts | Patients | heterogeneity* | I2 (%) | Egger’s test* | Fixed event rate | Random event rate | P-value between groups |
---|---|---|---|---|---|---|---|---|
1-year | ||||||||
CP_A >80%† | 10 | 666 | <0.0001 | 81.49 | 0.0694 | 0.92 (0.90-0.94) | 0.90 (0.83-0.95) | 0.0536 |
CP_A ≤80% | 6 | 570 | 0.0152 | 64.45 | 0.1765 | 0.84 (0.81-0.87) | 0.81 (0.74-0.87) | |
mSize <3.5 cm | 6 | 540 | 0.0037 | 71.35 | 0.5529 | 0.91 (0.88-0.93) | 0.92 (0.86-0.96) | 0.0264 |
mSize ≥3.5 cm | 9 | 515 | <0.0001 | 75.82 | 0.2988 | 0.84 (0.81-0.87) | 0.82 (0.74-0.89) | |
Median BED ≥100 GyE10 | 8 | 603 | <0.0001 | 78.26 | 0.7585 | 0.90 (0.87-0.92) | 0.90 (0.84-0.95) | 0.0279 |
Median BED <100 GyE10 | 7 | 486 | 0.0002 | 77.45 | 0.1681 | 0.83 (0.79-0.86) | 0.79 (0.69-0.87) | |
PVTT <20%‡ | 6 | 294 | 0.0054 | 69.80 | 0.4145 | 0.92 (0.89-0.95) | 0.91 (0.84-0.97) | 0.0039 |
PVTT ≥20% | 4 | 137 | 0.0740 | 56.73 | 0.3961 | 0.74 (0.66-0.81) | 0.73 (0.60-0.84) | |
3-year | ||||||||
CP_A >80% | 11 | 769 | 0.0001 | 71.44 | 0.7695 | 0.66 (0.63-0.69) | 0.65 (0.58-0.72) | 0.0216 |
CP_A ≤80% | 5 | 543 | 0.0095 | 70.12 | 0.4854 | 0.54 (0.50-0.58) | 0.52 (0.43-0.61) | |
mSize <3.5 cm | 7 | 783 | 0.0024 | 70.55 | 0.2785 | 0.65 (0.62-0.69) | 0.67 (0.60-0.74) | 0.0488 |
mSize ≥3.5 cm | 8 | 488 | <0.0001 | 77.54 | 0.9648 | 0.55 (0.51-0.60) | 0.55 (0.45-0.65) | |
Median BED ≥100 GyE10 | 9 | 846 | <0.0001 | 84.51 | 0.7053 | 0.62 (0.59-0.65) | 0.63 (0.54-0.71) | 0.4894 |
Median BED <100 GyE10 | 7 | 486 | 0.0314 | 56.67 | 0.7397 | 0.60 (0.55-0.64) | 0.59 (0.51-0.67) | |
PVTT <20% | 6 | 294 | 0.0052 | 69.95 | 0.4491 | 0.70 (0.64-0.75) | 0.69 (0.58-0.78) | 0.0095 |
PVTT ≥20% | 3 | 110 | 0.8862 | 0.00 | 0.1256 | 0.50 (0.40-0.59) | 0.50 (0.40-0.59) | |
5-year | ||||||||
CP_A >80% | 8 | 650 | <0.0001 | 78.98 | 0.6883 | 0.55 (0.51-0.59) | 0.56 (0.47-0.65) | 0.0009 |
CP_A ≤80% | 5 | 770 | <0.0001 | 88.58 | 0.2195 | 0.36 (0.33-0.40) | 0.32 (0.22-0.43) | |
mSize <3.5 cm | 7 | 783 | 0.0006 | 74.51 | 0.3558 | 0.51 (0.47-0.54) | 0.53 (0.45-0.61) | 0.1924 |
mSize ≥3.5 cm | 5 | 403 | <0.0001 | 94.36 | 0.9484 | 0.38 (0.33-0.42) | 0.38 (0.18-0.60) | |
Median BED ≥100 GyE10 | 10 | 1,088 | <0.0001 | 91.87 | 0.7846 | 0.43 (0.40-0.46) | 0.44 (0.33-0.55) | 0.3464 |
Median BED <100 GyE10 | 4 | 367 | 0.2563 | 25.89 | 0.7088 | 0.50 (0.44-0.55) | 0.50 (0.43-0.58) | |
PVTT <20% | 6 | 294 | <0.0001 | 85.19 | 0.8998 | 0.53 (0.48-0.59) | 0.53 (0.38-0.68) | 0.0043 |
PVTT ≥20% | 1 | 40 | 1.0000 | - | - | 0.22 (0.11-0.37) | 0.22 (0.11-0.37) |
Values are presented as number (95% confidence interval).
CP, Child-Pugh; mSize, median tumor size; median BED, median total dose of biologically effective dose using a linear quadratic model with alpha/beta ratios of 10 for tumor; PVTT, portal vein tumor thrombosis.
* P-value;
† The proportion of patients with CP class of A was >80% among the whole patients;
‡ The proportion of patients with PVTT was <20% among the whole patients.
Study | Toxicity criteria | Hepatic toxicity ≥Gr 3 (%) | Classic RILD (%) | Non-classic RILD (%) | GI toxicity ≥Gr 3 (%) | Skin toxicity ≥Gr 3 (%) | |
---|---|---|---|---|---|---|---|
Uchinami et al., 202323 | CTCAE | - | 0 | 5 | - | - | |
Iizumi et al., 202324 | CTCAE 4.0 | 7 | - | - | 7 | 0 | |
Bush et al., 202325 | CTCAE 5.0 | 11 | - | - | 6 | 0 | |
Lin et al., 202126 | CTCAE 4.0 | 0 | - | 0 | 0 | 2 | |
Kim et al., 202118 | CTCAE 3.0 | 0 | 0 | 0 | 0 | 0 | |
Iwata et al., 202127 | CTCAE 4.0 | 0 | 0 | 0 | 0 | 1 | |
Iwata et al., 202128 | CTCAE v4.0 | 0 | 2 | 0 | 0 | 0 | |
Yoo et al., 202029 | CTCAE 5.0 | 4 | 6 | 1 | 1 | 0 | |
Tamura et al., 202030 | CTCAE 5.0 | 0 | - | - | 3 | - | |
Hojo et al., 202031 | CTCAE 4.0 | 2 | - | 4 | - | - | |
Sanford et al., 201932 | Not specify | - | - | 8 | - | - | |
Kim et al., 201933 | CTCAE v4.0 | 0 | - | 0 | 0 | - | |
Chadha et al., 201934 | CTCAE v4.03 | 13 | 0 | 9 | 2 | 2 | |
Mizuhata et al., 201835 | CTCAE v4.0 | 3 | - | - | 3 | 0 | |
Kimura et al., 201736 | CTCAE v4.0 | 0 | - | 13 | 0 | 8 | |
Kim et al., 201537 | CTCAE v3.0 | 0 | 0 | 0 | 0 | 0 | |
Lee et al., 201438 | CTCAE v3.0 | 0 | 0 | 0 | 0 | - | |
Mizumoto et al., 201139 | CTCAE v3.0 + RTOG/EORTC | 0 | - | - | 1 | 1 | |
Komatsu et al., 201140 | CTCAE v2.0 | 1 | 2 | - | 0 | 2 | |
Kawashima et al., 201141 | CTCAE v3.0 | - | 18 | - | 3 | - | |
Chiba et al., 200542 | RTOG/EORTC | - | 11 | - | 1 | - | |
Bush et al., 200443 | CTCAE v2.0 | - | 0 | - | 0 | 0 | |
Pooled rates |
|||||||
Group | Cohorts | Patients | I2 (%) | I2 (%) | Egger’s test* | Fixed event rate (95% CI) | Random event rate (95% CI) |
Hepatic toxicity ≥Gr 3 | 17 | 1,512 | <0.0001 | 67.12 | 0.0898 | 0.00 (0.00-0.01) | 0.01 (0.00-0.02) |
Classic RILD | 12 | 999 | <0.0001 | 80.22 | 0.3300 | 0.03 (0.02-0.04) | 0.02 (0.00-0.05) |
Non-classic RILD | 13 | 970 | 0.0002 | 67.62 | 0.0709 | 0.01 (0.00-0.01) | 0.01 (0.00-0.03) |
GI toxicity ≥Gr 3 | 19 | 1,658 | 0.6106 | 0.00 | 0.0477 | 0.00 (0.00-0.01) | 0.00 (0.00-0.01) |
Skin toxicity ≥Gr 3 | 14 | 1,135 | 0.4488 | 0.00 | 0.6103 | 0.00 (0.00-0.01) | 0.00 (0.00-0.01) |
Study | Nation | Study type | Study period | Number of patients | Age (years) | ECOG PS (%) |
Hepatitis (%) |
CP class (%) |
BCLC stage (%) |
Tumor size (cm) | Multiplicity (%) | PVTT (%) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0 | 1 | 2 | 3 | HBV | HCV | Alcoholic | A | B | C | 0 | A | B | C | D | |||||||||
Uchinami et al., 202323 | Japan | R/SC/CT | 2015-2021 | 41 | 69 (44-88) | NR | 22 | 27 | NR | 100 | 0 | 0 | NR | 2.6 (1.9-3.6) | 27 | NR | |||||||
Lizumi et al., 202324 | Japan | R/SC/ST | 2009-2018 | 15 | 71 (58-90) | 40 | 60 | 13 | 53 | NR | 53 | 47 | NR | 4.0 (1.5-8.0) | 27 | NR | |||||||
Bush et al., 202325 | USA | P3/MC/CT | 2008-2017 | 35 | 62 (53-70) |
3 | 65 | 32 | 0 | 0 | 69 | 34 | NR | 0 | 86 | 11 | 3 | 0 | 3.3 (2.0-4.5) | 17 | 0 | ||
Lin et al., 202126 | Taiwan | R/SC/ST | 2014-2017 | 43 | 71 (48-85) | 51 | 44 | 5 | 0 | 53 | 35 | 5 | 93 | 7 | 0 | NR | 3.1 (1.1-17.1) | 23 | 19 | ||||
Kim et al., 202118 | Korea | P3/SC/CT | 2013-2017 | 80 | 61 (40-82) | 91 | 9 | 0 | 0 | 84 | NR | NR | 96 | 4 | 0 | 6 | 54 | 35 | 5 | 0 | 1.2 (1.0-2.9) | 6 | 0 |
Iwata et al., 202127 | Japan | R/SC/ST | 2013-2019 | 71 | 82 (80-96) | 62 | 28 | 6 | 4 | 10 | 39 | 7 | 90 | 10 | 0 | 10 | 63 | 2 | 21 | 4 | 3.2 (0.8-11.1) | NR | NR |
Iwata et al., 202128 | Japan | P2/SC/ST | 2013-2016 | 45 | 68 (36-80) | 93 | 7 | 0 | 0 | 35 | 29 | 7 | 91 | 9 | 0 | 27 | 67 | 0 | 6 | 0 | 2.5 (1.0-10.0) | 0 | 0 |
Yoo et al., 202029 | Korea | R/SC/ST | 2016-2017 | 167 | 62 (35-91) | 55 | 45 | 0 | 78 | 9 | 5 | 89 | 9 | 2 | 66 | 34 | NR | NR | NR | ||||
Tamura et al., 202030 | Japan | R/SC/CT | 2003-2017 | 31 | 72 (51-84) | 65 | 32 | 3 | 0 | 13 | 58 | NR | 94 | 6 | 0 | NR | 3.5 (1.0-9.0) | 0 | 0 | ||||
Hojo et al., 202031 | Japan | R/SC/ST | 2008-2015 | 110 | 74 (48-90) | 65 | 35 | 0 | 25 | 45 | NR | 86 | 14 | 0 | NR | 4.3 (0.8-15.0) | 23 | NR | |||||
Sanford et al., 201932 | USA | R/SC/CT | 2008-2017 | 49 | 65 (60-74) |
47 | 49 | 4 | 12 | 49 | NR | 83 | 17 | 0 | NR | NR | 49 | NR | |||||
Kim et al., 201933 | Korea | R/SC/ST | 2012-2017 | 243 | 61 (24-92) | 98 | 2 | 0 | 0 | 77 | 8 | 7 | 94 | 6 | 0 | 0 | 40 | 35 | 25 | 0 | 2.2 (1.0-17.0) | NR | NR |
Chadha et al., 201934 | USA | R/SC/ST | 2007-2016 | 46 | 72 (52-90) | 44 | 54 | 2 | 0 | 4 | 28 | 52 | 83 | 17 | 0 | NR | 6.0 (1.5-21.0) | 22 | 20 | ||||
Mizuhata et al., 201835 | Japan | R/SC/ST | 2011-2015 | 40 | 72 (38-87) | 95 | 5 | 0 | 12 | 38 | 25 | 70 | 30 | 0 | NR | 3.7 (1.1-12.4) | 75 | 30 | |||||
Kimura et al., 201736 | Japan | R/SC/ST | 2008-2015 | 24 | 73 (49-89) | 67 | 33 | 0 | 0 | 29 | 25 | 17 | 100 | 0 | 0 | NR | 9.0 (5.0-18.0) | 0 | 83 | ||||
Kim et al., 201537 | Korea | P1/SC/ST | 2007-2010 | 27 | NR (51-78) | 78 | 22 | 0 | 0 | 56 | 30 | 7 | 89 | 11 | 0 | 0 | 48 | 37 | 15 | 0 | NR (1.3-7.0) | NR | NR |
Lee et al., 201438 | Korea | R/SC/ST | 2008-2011 | 27 | 55 (42-70) | 67 | 33 | 0 | 0 | 74 | 15 | NR | 67 | 33 | 0 | 0 | 0 | 0 | 100 | 0 | 7.0 (3.0-16.0) | NR | 100 |
Mizumoto et al., 201139 | Japan | R/SC/ST | 2001-2007 | 266 | 70 (26-88) | 60 | 38 | 2 | 0 | 12 | 75 | NR | 76 | 23 | 1 | NR | 3.4 (0.6-13.0) | 53 | NR | ||||
Komatsu et al., 201140 | Japan | R/SC/CT | 2001-2009 | 242 | NR | 71 | 24 | 4 | 1 | 12 | 67 | NR | 76 | 23 | 1 | 4 | 34 | 13 | 47 | 2 | NR | 12 | NR |
Kawashima et al., 201141 | Japan | R/SC/ST | 1999-2007 | 60 | 70 (48-92) | 95 | 5 | 0 | 7 | 83 | NR | 78 | 22 | 0 | NR | 4.5 (2.0-9.0) | 15 | 2 | |||||
Chiba et al., 200542 | Japan | R/SC/ST | 1985-1998 | 162 | 63 (41-84) | 37 | 49 | 13 | 1 | 11 | 81 | 1 | 56 | 38 | 6 | NR | 3.8 (1.5-14.5) | 51 | NR | ||||
Bush et al., 200443 | USA | P2/SC/ST | 1998-2003 | 34 | 65 |
NR | NR | 41 | 41 | NR | 5.6 (1.5-10.0) | 6 | NR |
Study | Previous treatment (%) | Median total dose (GyE) | Number of fx | Median BED (GyE10) | Median fu (months) | LPFS (%) |
PFS (%) |
OS (%) |
||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1-yr | 3-yr | 5-yr | 1-yr | 3-yr | 5-yr | 1-yr | 3-yr | 5-yr | ||||||
Uchinami et al., 202323 | - | 72.6 (66.0-76.0) | 10-22 | 99.0 | - | - | - | - | - | - | - | - | - | - |
Iizumi et al., 202324 | 53 | - | - | - | 23 (8-54) | 93 | 75 | - | 73 | 0 | - | 80 | 40 | - |
Bush et al., 202325 | 0 | 70.2 | 15 | 103.1 | 30 | 89 | 62 | - | 76 | 63 | - | 81 | 49 | 42 |
Lin et al., 202126 | 84 | 72.6 (66.0-72.6) | 10-22 | 96.6 | 40 (9-62) | - | - | 93 | 74 | - | 56 | 88 | 76 | 63 |
Kim et al., 202118 | 95 | 66.0 | 10 | 109.6 | 52 (46-60) | 95 | 88 | 75 | 54 | 21 | 11 | 98 | 79 | 65 |
Iwata et al., 202127 | 35 | 66.0 (66.0 or 72.6) | 10 or 22 | 109.6 | 33 (9-68) | 97 | 86 | 70 | 72 | 38 | 25 | 93 | 68 | 38 |
Iwata et al., 202128 | - | 66.0 (66.0 or 72.6) | 10 or 22 | 109.6 | 53 (10-75) | 99 | 95 | 92 | 83 | 55 | 40 | 98 | 79 | 70 |
Yoo et al., 202029 | - | - | - | - | 14 (1-29) | 93 | - | - | - | - | - | 95 | - | - |
Tamura et al., 202030 | - | 73.5 (47.6-78.4) | 10-38 | 99.2 | 56 (22-82) | - | - | - | 69 | 39 | 31 | 92 | 69 | 51 |
Hojo et al., 202031 | - | 76.0 | 20 | 104.9 | 37 (1-100) | 97 | 92 | 89 | 70 | 40 | 28 | 94 | 74 | 69 |
Sanford et al., 201932 | 24 | 58.1 (30.0-67.5) | 5-16 | 80.5 | 14 | - | 93 | 93 | - | - | - | 69 | 44 | - |
Kim et al., 201933 | 79 | 66.0 (50.0, 60.0, or 66.0) | 10 | 109.6 | 32 (2-68) | - | 89 | 88 | - | 19 | 12 | - | 62 | 48 |
Chadha et al., 201934 | 54 | 67.5 (24.0-91.0) | 6-25 | 97.9 | 15 (1-60) | 95 | - | - | 74 | - | - | 73 | 47 | - |
Mizuhata et al., 201835 | 90 | 76.0 | 20-38 | 104.9 | 20 (1-72) | 100 | 94 | 94 | 70 | - | - | 86 | 51 | 23 |
Kimura et al., 201736 | - | 72.6 (60.8-85.8) | 10-35 | 96.6 | 18 (3-64) | 95 | 66 | - | - | - | - | 70 | 52 | - |
Kim et al., 201537 | 96 | 66.0 (60.0, 66.0, or 72.0) | 20-24 | 85.8 | 31 (5-63) | - | 80 | 64 | - | 17 | 0 | - | 56 | 42 |
Lee et al., 201438 | 78 | 55.0 (50.0-66.0) | 20-22 | 68.8 | 13 (2-52) | 71 | - | - | 11 | - | - | 56 | - | - |
Mizumoto et al., 201139 | 63 | 72.6 (66.0, 72.6, or 77.0) | 10-35 | 96.6 | - | 98 | 87 | 81 | 56 | 21 | 12 | 87 | 61 | 48 |
Komatsu et al., 201140 | 47 | 66.0 (52.8-84.0) | 4-38 | 109.6 | 31 | - | 90 | 90 | - - | - | - | - | 38 | |
Kawashima et al., 201141 | 60 | 76.0 (60.0, 65.0, or 76.0) | 10-26 | 104.9 | - | 97 | 90 | 86 | -18 | 4 | 83 | 56 | 25 | |
Chiba et al., 200542 | 72 | 72.0 (50.0-84.0) | 10-24 | 104.4 | 32 (3-133) | 97 | 91 | 87 | - - | - | 81 | 44 | 24 | |
Bush et al., 200443 | - | 63.0 | 15 | 89.5 | 20 | - | - | - | - | - | - | - | - | - |
Group | Cohorts | Patients | heterogeneity |
I2 (%) | Egger’s test |
Fixed event rate | Random event rate |
---|---|---|---|---|---|---|---|
LPFS | |||||||
1-year LPFS | 14 | 1,148 | 0.0031 | 58.34 | 0.0993 | 0.97 (0.95-0.98) | 0.96 (0.94-0.98) |
3-year LPFS | 15 | 1,469 | 0.0019 | 59.15 | 0.1683 | 0.89 (0.87-0.91) | 0.88 (0.85-0.91) |
5-year LPFS | 13 | 1,438 | <0.0001 | 73.78 | 0.8187 | 0.86 (0.84-0.88) | 0.86 (0.82-0.90) |
PFS | |||||||
1-year PFS | 12 | 809 | <0.0001 | 82.91 | 0.5067 | 0.64 (0.60-0.67) | 0.65 (0.56-0.74) |
3-year PFS | 11 | 983 | <0.0001 | 87.22 | 0.3211 | 0.26 (0.23-0.29) | 0.29 (0.21-0.38) |
5-year PFS | 10 | 976 | <0.0001 | 90.22 | 0.3193 | 0.16 (0.14-0.18) | 0.19 (0.11-0.28) |
OS | |||||||
1-year OS | 17 | 1,271 | <0.0001 | 81.02 | 0.1802 | 0.88 (0.87-0.90) | 0.86 (0.81-0.91) |
3-year OS | 17 | 1,347 | <0.0001 | 76.74 | 0.8238 | 0.61 (0.58-0.63) | 0.60 (0.54-0.66) |
5-year OS | 14 | 1,455 | <0.0001 | 89.09 | 0.7089 | 0.45 (0.42-0.47) | 0.46 (0.38-0.54) |
Group | Cohorts | Patients | heterogeneity |
I2 (%) | Egger’s test |
Fixed event rate | Random event rate | P-value between groups |
---|---|---|---|---|---|---|---|---|
1-year | ||||||||
CP_A >80% |
10 | 666 | <0.0001 | 81.49 | 0.0694 | 0.92 (0.90-0.94) | 0.90 (0.83-0.95) | 0.0536 |
CP_A ≤80% | 6 | 570 | 0.0152 | 64.45 | 0.1765 | 0.84 (0.81-0.87) | 0.81 (0.74-0.87) | |
mSize <3.5 cm | 6 | 540 | 0.0037 | 71.35 | 0.5529 | 0.91 (0.88-0.93) | 0.92 (0.86-0.96) | 0.0264 |
mSize ≥3.5 cm | 9 | 515 | <0.0001 | 75.82 | 0.2988 | 0.84 (0.81-0.87) | 0.82 (0.74-0.89) | |
Median BED ≥100 GyE10 | 8 | 603 | <0.0001 | 78.26 | 0.7585 | 0.90 (0.87-0.92) | 0.90 (0.84-0.95) | 0.0279 |
Median BED <100 GyE10 | 7 | 486 | 0.0002 | 77.45 | 0.1681 | 0.83 (0.79-0.86) | 0.79 (0.69-0.87) | |
PVTT <20% |
6 | 294 | 0.0054 | 69.80 | 0.4145 | 0.92 (0.89-0.95) | 0.91 (0.84-0.97) | 0.0039 |
PVTT ≥20% | 4 | 137 | 0.0740 | 56.73 | 0.3961 | 0.74 (0.66-0.81) | 0.73 (0.60-0.84) | |
3-year | ||||||||
CP_A >80% | 11 | 769 | 0.0001 | 71.44 | 0.7695 | 0.66 (0.63-0.69) | 0.65 (0.58-0.72) | 0.0216 |
CP_A ≤80% | 5 | 543 | 0.0095 | 70.12 | 0.4854 | 0.54 (0.50-0.58) | 0.52 (0.43-0.61) | |
mSize <3.5 cm | 7 | 783 | 0.0024 | 70.55 | 0.2785 | 0.65 (0.62-0.69) | 0.67 (0.60-0.74) | 0.0488 |
mSize ≥3.5 cm | 8 | 488 | <0.0001 | 77.54 | 0.9648 | 0.55 (0.51-0.60) | 0.55 (0.45-0.65) | |
Median BED ≥100 GyE10 | 9 | 846 | <0.0001 | 84.51 | 0.7053 | 0.62 (0.59-0.65) | 0.63 (0.54-0.71) | 0.4894 |
Median BED <100 GyE10 | 7 | 486 | 0.0314 | 56.67 | 0.7397 | 0.60 (0.55-0.64) | 0.59 (0.51-0.67) | |
PVTT <20% | 6 | 294 | 0.0052 | 69.95 | 0.4491 | 0.70 (0.64-0.75) | 0.69 (0.58-0.78) | 0.0095 |
PVTT ≥20% | 3 | 110 | 0.8862 | 0.00 | 0.1256 | 0.50 (0.40-0.59) | 0.50 (0.40-0.59) | |
5-year | ||||||||
CP_A >80% | 8 | 650 | <0.0001 | 78.98 | 0.6883 | 0.55 (0.51-0.59) | 0.56 (0.47-0.65) | 0.0009 |
CP_A ≤80% | 5 | 770 | <0.0001 | 88.58 | 0.2195 | 0.36 (0.33-0.40) | 0.32 (0.22-0.43) | |
mSize <3.5 cm | 7 | 783 | 0.0006 | 74.51 | 0.3558 | 0.51 (0.47-0.54) | 0.53 (0.45-0.61) | 0.1924 |
mSize ≥3.5 cm | 5 | 403 | <0.0001 | 94.36 | 0.9484 | 0.38 (0.33-0.42) | 0.38 (0.18-0.60) | |
Median BED ≥100 GyE10 | 10 | 1,088 | <0.0001 | 91.87 | 0.7846 | 0.43 (0.40-0.46) | 0.44 (0.33-0.55) | 0.3464 |
Median BED <100 GyE10 | 4 | 367 | 0.2563 | 25.89 | 0.7088 | 0.50 (0.44-0.55) | 0.50 (0.43-0.58) | |
PVTT <20% | 6 | 294 | <0.0001 | 85.19 | 0.8998 | 0.53 (0.48-0.59) | 0.53 (0.38-0.68) | 0.0043 |
PVTT ≥20% | 1 | 40 | 1.0000 | - | - | 0.22 (0.11-0.37) | 0.22 (0.11-0.37) |
Study | Toxicity criteria | Hepatic toxicity ≥Gr 3 (%) | Classic RILD (%) | Non-classic RILD (%) | GI toxicity ≥Gr 3 (%) | Skin toxicity ≥Gr 3 (%) | |
---|---|---|---|---|---|---|---|
Uchinami et al., 202323 | CTCAE | - | 0 | 5 | - | - | |
Iizumi et al., 202324 | CTCAE 4.0 | 7 | - | - | 7 | 0 | |
Bush et al., 202325 | CTCAE 5.0 | 11 | - | - | 6 | 0 | |
Lin et al., 202126 | CTCAE 4.0 | 0 | - | 0 | 0 | 2 | |
Kim et al., 202118 | CTCAE 3.0 | 0 | 0 | 0 | 0 | 0 | |
Iwata et al., 202127 | CTCAE 4.0 | 0 | 0 | 0 | 0 | 1 | |
Iwata et al., 202128 | CTCAE v4.0 | 0 | 2 | 0 | 0 | 0 | |
Yoo et al., 202029 | CTCAE 5.0 | 4 | 6 | 1 | 1 | 0 | |
Tamura et al., 202030 | CTCAE 5.0 | 0 | - | - | 3 | - | |
Hojo et al., 202031 | CTCAE 4.0 | 2 | - | 4 | - | - | |
Sanford et al., 201932 | Not specify | - | - | 8 | - | - | |
Kim et al., 201933 | CTCAE v4.0 | 0 | - | 0 | 0 | - | |
Chadha et al., 201934 | CTCAE v4.03 | 13 | 0 | 9 | 2 | 2 | |
Mizuhata et al., 201835 | CTCAE v4.0 | 3 | - | - | 3 | 0 | |
Kimura et al., 201736 | CTCAE v4.0 | 0 | - | 13 | 0 | 8 | |
Kim et al., 201537 | CTCAE v3.0 | 0 | 0 | 0 | 0 | 0 | |
Lee et al., 201438 | CTCAE v3.0 | 0 | 0 | 0 | 0 | - | |
Mizumoto et al., 201139 | CTCAE v3.0 + RTOG/EORTC | 0 | - | - | 1 | 1 | |
Komatsu et al., 201140 | CTCAE v2.0 | 1 | 2 | - | 0 | 2 | |
Kawashima et al., 201141 | CTCAE v3.0 | - | 18 | - | 3 | - | |
Chiba et al., 200542 | RTOG/EORTC | - | 11 | - | 1 | - | |
Bush et al., 200443 | CTCAE v2.0 | - | 0 | - | 0 | 0 | |
Pooled rates |
|||||||
Group | Cohorts | Patients | I2 (%) | I2 (%) | Egger’s test |
Fixed event rate (95% CI) | Random event rate (95% CI) |
Hepatic toxicity ≥Gr 3 | 17 | 1,512 | <0.0001 | 67.12 | 0.0898 | 0.00 (0.00-0.01) | 0.01 (0.00-0.02) |
Classic RILD | 12 | 999 | <0.0001 | 80.22 | 0.3300 | 0.03 (0.02-0.04) | 0.02 (0.00-0.05) |
Non-classic RILD | 13 | 970 | 0.0002 | 67.62 | 0.0709 | 0.01 (0.00-0.01) | 0.01 (0.00-0.03) |
GI toxicity ≥Gr 3 | 19 | 1,658 | 0.6106 | 0.00 | 0.0477 | 0.00 (0.00-0.01) | 0.00 (0.00-0.01) |
Skin toxicity ≥Gr 3 | 14 | 1,135 | 0.4488 | 0.00 | 0.6103 | 0.00 (0.00-0.01) | 0.00 (0.00-0.01) |
ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCV, hepatitis C virus; CP, Child-Pugh; BCLC, Barcelona Clinic Liver Cancer Stage; PVTT, portal vein tumor thrombosis; R, retrospective study; SC, single center; CT, comparative trial; NR, not reported; ST, single-arm trial; P3, prospective phase 3 study; MC, multicenter; P2, prospective phase 2 study; P1, prospective phase 1 study. Mean value (standard deviation); Median (interquartile range); Mean value.
fx, fraction; median BED, median total dose of biologically effective dose, using a linear quadratic model with alpha/beta ratios of 10 for tumor; fu, follow-up; yr, years; LPFS, local progression-free survival; PFS, progression-free survival; OS, overall survival.
Values are presented as number (95% confidence interval). LPFS, local progression-free survival; PFS, progression-free survival; OS, overall survival.
Values are presented as number (95% confidence interval). CP, Child-Pugh; mSize, median tumor size; median BED, median total dose of biologically effective dose using a linear quadratic model with alpha/beta ratios of 10 for tumor; PVTT, portal vein tumor thrombosis. The proportion of patients with CP class of A was >80% among the whole patients; The proportion of patients with PVTT was <20% among the whole patients.
Gr, grade; RILD, radiation-induced liver disease; GI, gastrointestinal; CTCAE, common terminology criteria for adverse events; RTOG/EORTC, Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer; CI, confidence interval.