Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Population
2.3. Primary Exposure
2.4. Data Source
2.5. Measure Outcomes
2.6. Immunosuppression
2.7. Drug Exposure Assay
2.8. Special Considerations
2.9. Pre-Transplant Management of HCC
2.10. Post-Transplant Management of Recurrent HCC
2.11. Cut-Offs and Definitions
2.12. Statistical Analyses
3. Results
3.1. Demographics and Clinical Characteristics of the Original Cohort
3.2. Stabilized IPTW Effect
3.3. Results in the Balanced Groups
3.4. Re-Transplantation
3.5. HCC Recurrence
3.6. Immunosuppression
3.7. Risk Factors for Recurrence-Free and Overall Survival
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AFP | alpha-fetoprotein |
Anti-HBc | antibody to the hepatitis virus B core antigen |
Anti-HBs | antibody to the hepatitis B surface antigen |
BCLC | Barcelona Clinic Liver Cancer |
BMI | body mass index |
BPAR | biopsy-proven acute rejection |
CHC | cholangiocarcinoma |
CNI | calcineurin inhibitors |
CT | computed tomography |
CyA | cyclosporine |
DAA | direct antiviral agents |
EASL | European Association for the Study of Liver Disease |
eGFR | estimated glomerular filtration rate |
EVR | everolimus |
HBc | hepatitis B core antigen |
HBIg | anti-HBs immunoglobulin |
HBs | hepatitis B surface antigen |
HBV | hepatitis B virus |
HCC | hepatocellular carcinoma |
HCV | hepatitis C virus |
HDV | hepatitis delta virus |
HR | hazard ratio |
IQR | interquartile range |
LFT | liver function tests |
LT | liver transplantation |
MACE | major adverse cardiovascular events |
MDRD | modified diet and renal disease |
MELD | model for end-stage liver function |
MPA | mycophenolic acid derivatives |
MR | magnetic resonance |
mTOR | mammalian target of rapamycin |
mTORi | mammalian target of rapamycin inhibitors |
NLR | neutrophil to lymphocyte ratio |
OS | overall survival |
PNF | primary non-function |
RFS | recurrence-free survival |
RR | relative risk |
S | steroids |
SD | standard deviation |
SRL | sirolimus |
TAC | tacrolimus |
tBPAR | treated and biopsy-proven acute rejection |
X-match | cross-match |
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Variable | EVR (#463) | CNI (#556) | p |
---|---|---|---|
Recipient | |||
Male sex, n (%) | 386 (83.4) | 487 (87.6) | 0.55 |
Age at transplant (median, IQR), years | 56 (10) | 56 (10) | 0.28 |
Indication to transplant, n (%) | |||
HCV | 237 (55.5) | 294 (52.8) | 0.59 |
HBV (±HDV) | 123 (26.5) | 153 (27.5) | 0.73 |
HCV-HBV(±HDV) | 17 (3.7) | 20 (3.5) | 0.94 |
Alcohol | 54 (11.6) | 59 (9.5) | 0.59 |
NAFLD | 20 (4.3) | 24 (4.3) | 0.99 |
Autoimmune/PSC | 12 (5.2) | 6 (1.1) | 0.67 |
Lab-MELD at transplant (median, IQR) | 7 (6) | 8 (7) | 0.45 |
DM at transplant, n (%) | 113 (24.4) | 144 (25.8) | 0.58 |
CKD at transplant, n (%) | 27 (5.8) | 39 (7.0) | 0.44 |
Hypertension at transplant, n (%) | 69 (14.9) | 76 (13.6) | 0.57 |
<2013, n (%) | 147 (31.7) | 387 (66.0) | <0.0001 |
TAC, n (%) | 403 (86.8) | 313 (56.3) | <0.0001 |
Mean TAC exposure >10 ng/mL within the first month post-transplantation | 127 (27.4) | 172 (31.0) | 0.22 |
Donor | |||
Male sex, n (%) | 241 (52.0) | 281 (50.5) | 0.63 |
Age, median (IQR) | 69 (25) | 67 (26) | 0.78 |
ICU stay, median (IQR) days | 3 (4) | 3 (4) | 0.67 |
CVA as cause of death, n (%) | 333 (71.9) | 411 (73.9) | 0.47 |
Anti-HCV-positive, n (%) | 4 (0.86) | 0 (0) | 0.58 |
Anti-HBc-positive, n (%) | 60 (12.9) | 77 (13.8) | 0.67 |
Cardiac arrest episodes, n (%) | 43 (9.3) | 42 (7.5) | 0.31 |
Use of inotropes, n (%) | 407 (87.9) | 483 (86.8) | 0.62 |
HCC | |||
Tumor nodules *, median (IQR) | 2 (1) | 2 (1) | 0.78 |
Largest nodule size *, median (IQR) (mm) | 28 (18) | 25 (15) | 0.04 |
Total tumor size *, median (IQR) (mm) | 39.5 (25) | 36.5 (36) | 0.003 |
Exceeding Milan criteria at transplant *, n (%) | 152 (32.8) | 101 (18.1) | <0.0001 |
Pre-transplant treatment, n (%) | |||
None, n (%) | 141 (30.4) | 209 (37.6) | 0.01 |
TACE, n (%) | 229 (49.4) | 307 (55.2) | 0.06 |
RFA/MW, n (%) | 33 (7.1) | 22 (3.9) | 0.02 |
PEI, n (%) | 6 (1.3) | 12 (2.1) | 0.29 |
Resection, n (%) | 6 (1.3) | 4 (0.7) | 0.35 |
TACE + RFA/MW, n (%) | 42 (9.1) | 2 (0.5) | <0.0001 |
TARE, n (%) | 6 (1.3) | 0 (0) | 0.008 |
Successful downstaging **, n (%) | 75 (16.2) | 45 (8.1) | 0.0006 |
AFP at transplant, median (IQR) (ng/mL) | 46.3 (28) | 4.7 (19) | 0.002 |
Milan-out at explant histology, n (%) | 120 (25.9) | 167 (30.0) | 0.98 |
G3-4, n (%) | 148 (31.9) | 140 (25.1) | 0.01 |
Microvascular infiltration, n (%) | 88 (39.5) | 182 (32.7) | 0.02 |
Transplantation | |||
CIT, median (IQR) (min) | 424 (89) | 420 (101) | 0.09 |
MP, n (%) | 9 (1.9) | 7 (1.2) | 0.89 |
Re-transplantation, n (%) | 18 (3.8) | 23 (4.1) | 0.45 |
B cell and/or T cell positive X-match, n (%) | 35 (7.5) | 48 (8.6) | 0.53 |
NLR, median (IQR) | 2.2 (0.2) | 2.1 (0.3) | 0.68 |
Variables | Pre-IPTW | Post-IPTW | ||||
---|---|---|---|---|---|---|
EVR (n = 463) | CNI (n = 556) | Cohen’s D-Value | EVR (n = 233) | TAC (n = 278) | Cohen’s D-Value | |
Mean (±SD) | Mean (±SD) | |||||
Patient male sex | 0.83 ± 0.15 | 0.87 ± 0.14 | 0.05 | 0.81 ± 0.17 | 0.82 ± 0.15 | 0.05 |
Patient age, years | 55.9 ± 3.92 | 56.4 ± 3.46 | −0.20 | 55.1 ± 0.55 | 55.3 ± 0.53 | −0.03 |
HCV | 55.5 ± 0.70 | 55.8 ± 0.58 | −0.42 | 24.3 ± 0.56 | 24.1 ± 0.52 | 0.01 |
Patient diabetes | 0.24 ± 0.50 | 0.26 ± 0.45 | 0.12 | 0.23 ± 0.50 | 0.24 ± 0.50 | 0.00 |
Patient CKD | 0.05 ± 0.02 | 0.07 ± 0.42 | 0.42 | 0.05 ± 0.01 | 0.05 ± 0.01 | 0.01 |
MELD | 0.07 ± 0.26 | 0.11 ± 0.33 | −0.15 | 0.08 ± 0.38 | 0.07 ± 0.37 | 0.01 |
Donor male sex | 0.52 ± 0.38 | 0.50 ± 0.41 | −0.08 | 0.51 ± 0.28 | 0.50 ± 0.28 | 0.01 |
Donor age, years | 0.69 ± 0.65 | 0.67 ± 0.64 | 0.01 | 0.68 ± 0.38 | 0.67 ± 0.37 | 0.03 |
Donor cause of death (CVA) | 0.71 ± 0.50 | 0.73 ± 0.40 | 0.13 | 0.71 ± 0.46 | 0.72 ± 0.45 | −0.02 |
MP | 0.09 ± 0.02 | 0.08 ± 0.02 | 0.01 | 0.08 ± 0.02 | 0.08 ± 0.02 | 0.00 |
CIT, minutes | 431.77 ± 79.02 | 423.50 ± 85.79 | 0.10 | 0.53 ± 0.50 | 0.53 ± 0.50 | 0.01 |
Milan-out stage, radiologic | 32.8 ± 2.33 | 19 ± 1.65 | 0.42 | 29.2 ± 1.2 | 26.3 ± 0.9 | 0.02 |
Tumor downstaging | 0.17 ± 0.05 | 0.08 ± 0.04 | 0.43 | 0.10 ± 0.02 | 0.08 ± 0.08 | 0.04 |
AFP at transplant | 0.45 ± 0.27 | 0.04 ± 0.02 | 0.38 | 0.23 ± 0.04 | 0.19 ± 0.06 | 0.14 |
Milan-out stage, histology | 26.1 ± 1.5 | 29.1 ± 2.3 | 0.16 | 24.0 ± 2.3 | 22.0 ± 2.8 | 0.12 |
G3–G4 | 32.0 ± 2.4 | 25 ± 1.8 | 0.23 | 29.0 ± 2.3 | 28.2 ± 2.0 | 0.21 |
Microinfiltration | 40.2 ± 1.2 | 33.7 ± 1.7 | 0.26 | 38.1 ± 2.3 | 32.5 ± 1.9 | 0.20 |
Mean TAC exposure > 10 ng/mL within the first month | 0.28 ± 0.04 | 0.32 ± 0.45 | 0.13 | 0.15 ± 0.02 | 0.13 ± 0.03 | 0.00 |
Variable | EVR (#233) | TAC (#278) | p |
---|---|---|---|
Recipient | |||
Male sex, n (%) | 192 (82.4) | 228 (82.0) | 0.90 |
Age at transplant (median, IQR), years | 55.5 (9) | 55.3 (10) | 0.89 |
HCV, n (%) | 58 (24.3) | 69 (24.8) | 1 |
Lab-MELD at transplant (median, IQR) * | 8 (6) | 7 (7) | 0.78 |
DM at transplant, n (%) | 53 (22.7) | 66 (23.7) | 0.83 |
CKD at transplant, n (%) | 12 (5.1) | 14 (5.0) | 1 |
Mean TAC exposure >10 ng/mL within the first-month post-transplantation | 35 (15.0) | 36 (12.9) | 0.52 |
Donor | |||
Male sex, n (%) | 118 (50.6) | 140 (50.3) | 1 |
Age, median (IQR) | 68.0 (23) | 67 (26) | 0.89 |
CVA as cause of death, n (%) | 181 (77.7) | 200 (71.9) | 0.15 |
HCC | |||
Exceeding Milan criteria at transplant *, n (%) | 67 (28.7) | 72 (25.8) | 0.48 |
Successful downstaging **, n (%) | 24 (10.3) | 23 (8.2) | 0.44 |
AFP at transplant, median (IQR) (ng/mL) | 23.3 (18) | 19 (11) | 0.56 |
Milan-out at explant histology, n (%) | 55 (23.6) | 62 (22.3) | 0.75 |
G3–4, n (%) | 67 (28.7) | 78 (28.1) | 0.92 |
Microvascular infiltration, n (%) | 88 (37.8) | 91 (32.7) | 0.26 |
Transplantation | |||
CIT, median (IQR) (min) | 432 (89) | 489 (101) | 0.06 |
MP, n (%) | 9 (1.9) | 7 (1.2) | 0.89 |
B cell and/or T cell positive X-match, n (%) | 16 (6.9) | 21 (7.5) | 0.76 |
NLR, median (IQR) | 2.3 (0.2) | 2.1 (0.2) | 0.89 |
Variable | EVR (#233) | TAC (#278) | p |
---|---|---|---|
Death, n (%) | 62 (26.6) | 105 (37.8) | 0.007 |
HCC recurrence, n (%) | 16 (6.8) | 42 (15.1) | 0.003 |
HCV recurrence, n (%) | 16 (6.9) | 15 (5.4) | 0.48 |
Incomplete/delayed graft function, n (%) | 1 (0.4) | 2 (0.7) | 0.22 |
MACE, n (%) | 2 (0.8) | 6 (2.1) | 0.30 |
Intra/peri-operative, n (%) | 2 (0.8) | 3 (1.1) | 1 |
Ischemic cholangiopathy, n (%) | 4 (1.7) | 7 (2.5) | 0.76 |
Infection/sepsis, n (%) | 12 (5.1) | 16 (5.7) | 0.84 |
De novo malignancy, n (%) | 5 (2.1) | 11 (3.9) | 0.31 |
Stroke, n (%) | 4 (1.7) | 3 (1.1) | 0.70 |
Re-transplantation, n (%) | 9 (3.9) | 11 (3.9) | 1 |
Ischemic cholangiopathy, n (%) | 3 (1.3) | 3 (1.1) | 1 |
PNF, n (%) | 3 (1.3) | 5 (1.8) | 0.73 |
HAT, n % | 2 (0.8) | 1 (0.3) | 0.59 |
Chronic rejection, n (%) | 1 (0.4) | 1 (0.3) | 1 |
HCV recurrence, n (%) | 0 (0) | 1 (0.3) | 0.99 |
HCC recurrence, n (%) | 18 (7.7) | 47 (16.9) | 0.002 |
Liver only, n (%) | 7 (3.0) | 15 (5.4) | 0.19 |
Liver and lung, n (%) | 1 (0.4) | 8 (2.8) | 0.04 |
Liver and bone, n (%) | 0 (0) | 4 (1.4) | 0.12 |
Lung only, n (%) | 4 (1.7) | 9 (1.8) | 0.39 |
Bone only, n (%) | 4 (1.7) | 1 (0.2) | 0.18 |
Lung and bone, n (%) | 1 (0.4) | 4 (1.4) | 0.38 |
Nodes, n (%) | 1 (0.4) | 6 (2.1) | 0.13 |
>2 organs, n (%) | 2 (0.8) | 16 (5.7) | 0.002 |
Variable | EVR (#233) |
---|---|
Reason for EVR use, n (%) | |
HCC recurrence prophylaxis, n (%) | 212 (91.0) |
Deteriorating renal function, n (%) | 14 (6.0) |
Neurologic complication, n (%) | 4 (1.7) |
MACE, n (%) | 3 (1.2) |
Timing of EVR introduction, median (IQR) (days) | 30 (16) |
Duration of EVR treatment, median (IQR) (months) | 46.6 (36.1) |
EVR whole-blood exposure, median (IQR) (ng/mL) | 5.8 (1.7) |
EVR monotherapy, n (%) | 177 (75.9) |
EVR ± TAC, n (%) | 56 (24.1) |
EVR discontinuation, n (%) | 12 (5.1) |
t/BPAR, n (%) | 4 (1.7) |
Progressing proteinuria, n (%) | 5 (2.1) |
Infection, n (%) | 3 (1.3) |
Variable | Recurring HCC (#18) | Non-Recurring HCC (#215) | p |
---|---|---|---|
Timing of EVR introduction, median (IQR) (days) | 52 (26.4) | 30 (12) | <0.001 |
Duration of EVR treatment, median (IQR) (months) | 46.5 (57.0) | 69.9 (24.8) | <0.001 |
EVR whole-blood exposure, median (IQR) (ng/mL) | 3.65 (0.55) | 5.9 (1.4) | <0.001 |
Variable | Coefficients (95%CI) | SE | z | HR | p |
---|---|---|---|---|---|
OS | |||||
Successful pre-transplant downstaging | 0.6 (0.15; 1.06) | 0.23 | 2.6 | 0.79 | 0.006 |
Within Milan criteria at transplant | −1.15 (−1.61; −0.7) | 0.23 | 5.02 | 0.67 | <0.01 |
Within Milan criteria at histology | 0.01 (0; 0.01) | 0 | 2.41 | 0.78 | 0.02 |
Micro-infiltration | 0.39 (−0.01; 0.78) | 0.2 | 1.91 | 1.13 | 0.056 |
G3-G4 | 0.25 (0.01; 0.5) | 0.12 | 2.02 | 1.18 | 0.077 |
EVR | −0.59 (−1.02; −0.16) | 0.22 | 2.7 | 0.69 | 0.009 |
RFS | |||||
Successful pre-transplant downstaging | 0.57 (0.12; 1.02) | 0.23 | 2.47 | 0.65 | 0.01 |
Within Milan criteria at transplant | −1.18 (−1.63; −0.72) | 0.23 | 5.11 | 0.56 | 0.01 |
Within Milan criteria at histology | 0.01 (0; 0.01) | 0 | 2.52 | 0.68 | 0.012 |
Micro-infiltration | 0.42 (0.02; 0.81) | 0.2 | 2.06 | 1.22 | 0.04 |
G3-G4 | 0.22 (−0.02; 0.47) | 0.13 | 1.77 | 1.27 | 0.04 |
EVR | −0.78 (1.2; −0.36) | 0.21 | 3.66 | 0.46 | <0.001 |
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De Simone, P.; Precisi, A.; Lai, Q.; Ducci, J.; Campani, D.; Marchetti, P.; Gitto, S. Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers 2024, 16, 1243. https://doi.org/10.3390/cancers16071243
De Simone P, Precisi A, Lai Q, Ducci J, Campani D, Marchetti P, Gitto S. Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers. 2024; 16(7):1243. https://doi.org/10.3390/cancers16071243
Chicago/Turabian StyleDe Simone, Paolo, Arianna Precisi, Quirino Lai, Juri Ducci, Daniela Campani, Piero Marchetti, and Stefano Gitto. 2024. "Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation" Cancers 16, no. 7: 1243. https://doi.org/10.3390/cancers16071243
APA StyleDe Simone, P., Precisi, A., Lai, Q., Ducci, J., Campani, D., Marchetti, P., & Gitto, S. (2024). Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers, 16(7), 1243. https://doi.org/10.3390/cancers16071243