Table 1. Overview of publications investigating the effects of immunosuppression on HCC recurrence after liver transplantation.
| Reference | Year | Centre | Evidence level (40) | Patients (n) | Immunosuppressive drug | Recurrence rate (%) | Results | P |
|---|---|---|---|---|---|---|---|---|
| Vivarelli et al. (41) | 2002 | Policlinico Sant’Orsola-Malpighi, Bologna University, IT | 4 | 82 | CyA, STER, AZA (n=34); CyA, STER (n=35); TAC, STER (n=6); TAC, STER, AZA (n=4); CyA switch to TAC (n=3) |
12.2 | 5-yr OS: 64%; 70% of recurrences within first year after LT; CyA dose-dependent 5-yr DFS: 93% low dose vs. 76% high dose |
0.01 |
| Kneteman et al. (42) | 2004 | Walter C. Mackenzie Centre, Alberta University, Edmonton, CA | 3b/4 | 40 | SRL de novo CNI (n=40); CNI tapered to 0 (3 to 6 mo) |
12.5 | MC in, n=19: 1- and 4-yr OS 94% and 87%; MC out, n=21: 1- and 4-yr OS 91% and 83%; MC in vs. MC out |
0.68 |
| Vivarelli et al. (43) | 2005 | Policlinico Sant’Orsola-Malpighi, Bologna University, IT | 4 | 70 | CyA, STER, AZA (n=44); CyA, STER (n=26) |
10.0 | RR: 0% vs. RR: 33.3%; DFS related to CyA exposure independent risk factor |
<0.001 |
| Decaens et al. (44) | 2006 | Hôpital Henri Mondor, Créteil, FR | 4 | 412 | CyA based (n=284); TAC based (n=128) |
31.8 | 5-yr DFS and OS: 57.1% and 57.9%; 5-yr DFS CyA vs. TAC: 52.5% vs. 70.8% |
0.003 |
| Decaens et al. (44) | 2006 | Hôpital Henri Mondor, Créteil, FR | 4 | 412 | ATG/OKT3 induction (n=55); no induction (n=357) |
31.8 | 5-yr DFS: 58.8% vs. 5-yr DFS: 45.4% | 0.02 |
| Zhou et al. (45) | 2006 | Zhongshan Hospital, Fudan University, Shanghai, CN | 4 | 36 | All switched to SRL: SRL, TAC (n=26); SRL, TAC, STER (n=10) |
27.4 | Group A (early switch for advanced HCC, n=11): 1-yr OS 68%; Group B (switch after HCC recurrence, n=18): 1-yr OS 67%; Group C (switch for CNI nephrotoxicity, n=7): no recurrence |
NA |
| Chen et al. (46) | 2007 | Tongji Hospital, Huazhong University, Wuhan, CN | 3 | 44 | STER withdrawal at 3 mo (n=28); STER maintenance (n=26) |
53.7 | 6-mo recurrence rate: 25.0% vs. 42.3%; 1-yr survival rate: 64.2% vs. 46.1%; 1-year tumour recurrence rate: 39.2% vs. 69.2% |
>0.05; >0.05; <0.05 |
| Toso et al. (47) | 2007 | Walter C. Mackenzie Centre, Alberta University, Edmonton, CA | 3b/4 | 70 | SRL, de novo CNI (n=70) | 11.4 | 1- and 4-yr OS: 85% and 75%; 1- and 4-yr DFS (MC in): 85% and 73%; 1- and 4-yr DFS (MC out): 84% and 74% |
0.9 |
| Zimmerman et al. (48) | 2007 | UCH, Colorado University, Denver, US | 3b | 130 | CNI based (n=81); SRL based (n=49) |
12.4 | 1-, 3-, and 5-yr DFS: 84%, 74%, and 67% | >0.05 |
| Vivarelli et al. (49) | 2008 | Policlinico Sant’Orsola-Malpighi, Bologna University, IT | 3b | 139 | CyA based (n=79); TAC based (n=60) |
15.1 | 3-yr DFS CyA vs. Tac: 89% vs. 79%; dosage-dependent DFS survival for TAC and CyA patients |
0.047 |
| Nocera et al. (50) | 2008 | Ospedale San Martino, Genoa University, IT | 4 | 18 | SRL de novo CNI (n=11); CNI based, later SRL mono (n=7) |
5.6 | 1 of 18 died within 12 mo because of pneumonitis; 1 of 18 experienced HCC recurrence at 14 mo post-LT |
NA |
| Zimmerman et al. (51) | 2008 | UCH, Colorado University, Denver, US | 3b | 97 | SRL based (n=45); CNI based (n=52) |
12.4 | 1- and 5-yr OS: SRL vs. CNI: 96% vs. 83% and 80% vs. 62%; 1- and 5-yr DFS: SRL vs. CNI: 93% vs. 75% and 79% vs. 54% |
0.087; 0.03 |
| Chinnakotla et al. (52) | 2009 | Baylor University Medical Center, Dallas, US | 3b | 227 | SRL based (n=121); TAC based (n=106) |
11.0 | 1-, 2-, and 5-yr probability for recurrence for SRL based: 5.2%, 9.2% and 11% vs. TAC 5-yr OS: SRL vs. Tac: 80% vs. 59% | 0.0001; 0.0001 |
| Vivarelli et al. (53) | 2010 | Policlinico Sant’Orsola-Malpighi, Bologna University, IT | 3b | 62 | SRL containing (n=31); TAC based (n=31) |
25.8 | 3-yr DFS: SRL vs. Tac: 86% vs. 56% | 0.04 |
| Toso et al. (54) | 2010 | Walter C. Mackenzie Centre, Alberta University, Edmonton, CA | 3b/4 | 2,491 | SRL: (n=109); no SRL: (n=2,382) |
– | 3- and 5-yr OS: on SRL vs. off SRL: 86% vs. 79% and 83% vs. 69% | ≤0.05 |
| Vivarelli et al. (55) | 2010 | Policlinico Sant’Orsola-Malpighi, Bologna University, IT | 4 | 86 | SRL based (n=86) | 16.0 | Only detection of risk factors for recurrence | NA |
| Liang et al. (56) | 2011 | First Affiliated Hospital, Sun Yat-sen University, Guangzhou, CN | 2 | 2,950 | SRL: (n=332); no SRL: (n=2,618) |
– | 1-yr OS OR 4.53, 95% CI =2.31–8.89; 3-yr OS OR 1.97, 95% CI =1.29–3.00; 5-yr OS OR 2.47, 95% CI =1.72–3.55; recurrence OR 0.42, 95% CI =0.21–0.83, SRL vs. no SRL |
<0.05 |
| Rodríguez-Perálvarez et al. (57) | 2013 | Reina Sofía University Hospital, Córdoba, ES | 4 | 219 | High CNI exposure (n=48); reduced CNI exposure (n=171) |
17.6 | 1-yr DFS 90.6 vs. 95.7; 5-yr DFS 72.3 vs. 85.3 |
0.007 |
| Xing et al. (58) | 2013 | First People’s Hospital, Shanghai Jiao Tong University, CN | 4 | 178 | Basiliximab, TAC, MPA (n=78); STER, TAC, MPA (n=100) |
41.0 | 5-yr OS 42.5% vs. 50.5%; 5-yr DFS 38.9% vs. 39.2% |
0.734; 0.913 |
| Cholongitas et al. (59) | 2014 | Thessaloniki Hippokration General Hospital, Aristotle University, GR | 4 | 43 | EVL, CyA or MPA (n=21); CyA (n=22) |
9.3 | Recurrence 0% vs. 18.5% after a mean of 49 mo | >0.05 |
| Geissler et al. (60) | 2016 | Multicentric, University Hospital, Regensburg, DE | 2 | 525 | Mix IS without SRL (n=264); mix IS with SRL (n=261) |
32.7 | DFS 64.5% vs. 70.2% at 8 yrs (end-point); OS 68.4% vs. 74.6% at 8 yrs (end-point); DFS 72.3% vs. 80.6% at 3 yrs; OS 70.3% vs. 79.4% at 5 yrs |
0.28; 0.21; <0.05; <0.05 |
| Yanik et al. (61) | 2016 | Multicentric, National Cancer Institute, Rockville, US | 3,936 | SRL (n=234); no SRL (n=3,702) |
6.1 | All-cause mortality, HCC recurrence and cancer-specific mortality without differences; among recipients ≤55 years old, worse outcomes for SRL: all-cause mortality HR =1.76, 95% CI =1.12–2.75; recurrence HR =1.49, 95% CI =0.62–3.61; cancer-specific mortality HR =1.54, 95% CI =0.71–3.32 |
>0.05; <0.05 |
95% CI, 95% confidence interval; AZA, azathioprine; CNI, calcineurin inhibitor; CyA, cyclosporine A; DFS, disease-free survival; LT, liver transplantation; MC, Milan criteria; MPA, mycophenolic acid; OR, odds ratio; OS, overall survival; SRL, sirolimus; STER, steroid; TAC, tacrolimus, mo, month; yr, year.