Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial.

BACKGROUND: Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival. METHODS: TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18-65 years, with Eastern Cooperative Oncology Group performance score 0-1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0-29·0) versus 17·0 cycles (12·0-24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6-10 ng/mL days 1-14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5-8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete. FINDINGS: Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0-59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4-60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2-74·1) for liver transplantation plus chemotherapy and 12·6% (5·2-30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21-0·65]; p=0·0003) and 73·3% (95% CI 59·6-90·0) and 9·3% (3·2-26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure. INTERPRETATION: In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases. FUNDING: French National Cancer Institute and Assistance Publique-Hôpitaux de Paris.

Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

BACKGROUND & AIMS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes. METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to six groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. Kaplan-Meier estimates of the 18-month risk of dropout for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post-LT survival rates were compared. RESULTS: Median waiting-time in the DS group was 910 days. Pre-LT dropout probability was significantly lower in the DS group compared to other groups (13% vs. 19%, p = 0.0043) and significantly higher in the T1 group (25.4%, p = 0.05). Post-LT HCC recurrence rate in the multiple nodules group was significantly higher (19.6%, p = 0.019), while 5-year post-LT survival did not differ among groups and was 74% in the DS group (p = 0.22). CONCLUSION: The DELTA-HCC study shows that DS does not negatively impact either pre- nor post-LT patient outcomes, and has the potential to allow for redistribution of organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpectedly high risk of dropout in T1 patients seems related to the MELD-based offering rules underserving this subgroup. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy was adopted in France in 2015. It involves postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA-HCC study was conducted to evaluate this nationwide strategy. It shows in a European LT program that delayed strategy does not negatively impact pre- nor post-LT patient outcomes and is relevant to up to 20% of LT candidates; thus, it could potentially enable the redistribution of organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpectedly high risk of dropout in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

Comparison of a robotic surgery program for rectal cancer: short- and long-term results from a comparative, retrospective study between two laparoscopic and robotic reference centers.

BACKGROUND: It is assumed that robotic-assisted surgery (RAS) may facilitate complex pelvic dissection for rectal cancer compared to the laparoscopic-assisted resection (LAR). The aim of this study was to compare perioperative morbidity, short- and long-term oncologic, and functional outcomes between the RAS and LAR approaches. METHODS: Between 2015 and 2021, all rectal cancers operated on by (LAR) or (RAS) were retrospectively reviewed in two colorectal surgery centers. RESULTS: A total of 197 patients were included in the study, with 70% in the LAR group and 30% in the RAS group. The tumor location and stage were identical in both groups (not significant = NS). The overall postoperative mortality rate was not significantly different between the two groups. (0% LAR; 0.5% RAS; NS). The postoperative morbidity was similar between the two groups (60% LAR vs 57% RAS; NS). The number of early surgical re-interventions within the first 30 days was similar (10% for the LAR group and 3% for the RAS group; NS). The rate of complete TME was similar (88% for the LAR group and 94% for the RAS group; NS). However, the rate of circumferential R1 was significantly higher in the LAR group (13%) compared to the RAS group (2%) (p = 0.009). The 3-year recurrence rate did not differ between the two groups (77% for both groups; NS). After a mean follow-up of three years, the incidence of anterior resection syndrome was significantly lower in the LAR group compared to the RAS group (54 vs 76%; p = 0.030). CONCLUSIONS: The use of a RAS was found to be reliable for oncologic outcomes and morbidity. However, the expected benefits for functional outcomes were not observed. Therefore, the added value of RAS for rectal cancer needs to be reassessed in light of new laparoscopic technologies and patient management options.

Prognostic benefit of preoperative transarterial chemoembolization in upfront resectable large hepatocellular carcinoma: a multicentric propensity score based analysis of European high-volume centers.

BACKGROUND: Hepatocellular carcinoma (HCC) have a dismal prognosis and any effective neoadjuvant treatment has been validated to date. We aimed to investigate the role of neoadjuvant transarterial chemoembolization (TACE) in upfront resectable HCC larger than 5 cm. METHODS: This is a multicentric retrospective study comparing outcomes of large HCC undergoing TACE followed by surgery or liver resection alone before and after propensity-score matching (PSM). RESULTS: A total of 384 patients were included of whom 60 (15.6%) received TACE. This group did not differ from upfront resected cases neither in terms of disease-free survival (p = 0.246) nor in overall survival (p = 0.276). After PSM, TACE still did not influence long-term outcomes (p = 0.935 and p = 0.172, for DFS and OS respectively). In subgroup analysis, TACE improved OS only in HCC ≥10 cm (p = 0.045), with a borderline significance after portal vein embolization/ligation (p = 0.087) and in single HCC (p = 0.052). CONCLUSIONS: TACE should not be systematically performed in all resectable large HCC. Selected cases could however potentially benefit from this procedure, as patients with huge and single tumors or those necessitating of a PVE.

Comparing indications, complexity and outcomes of laparoscopic liver resection between centers with and without a liver transplant program: a French nationwide study.

BACKGROUND: There are no data to evaluate the difference in populations and impact of centers with liver transplant programs in performing laparoscopic liver resection (LLR). METHODS: This was a multicenter study including patients undergoing LLR for benign and malignant tumors at 27 French centers from 1996 to 2018. The main outcomes were postoperative severe morbidity and mortality. RESULTS: A total of 3154 patients were included, and 14 centers were classified as transplant centers (N = 2167 patients, 68.7 %). The transplant centers performed more difficult LLRs and more resections for hepatocellular carcinoma (HCC) in patients who more frequently had cirrhosis. A higher rate of performing the Pringle maneuver, a lower rate of blood loss and a higher rate of open conversion (all p < 0.05) were observed in the transplant centers. There was no association between the presence of a liver transplant program and either postoperative severe morbidity (<10 % in each group; p = 0.228) or mortality (1 % in each group; p = 0.915). CONCLUSIONS: Most HCCs, difficult LLRs, and cirrhotic patients are treated in transplant centers. We show that all centers can achieve comparable safety and quality of care in LLR independent of the presence of a liver transplant program.

Open Versus Laparoscopic Right Hepatectomy for Hepatocellular Carcinoma Following Sequential TACE-PVE: A Multicentric Comparative Study.

BACKGROUND: Right hepatectomy (RH) for hepatocellular carcinoma (HCC) is ideally preceded by transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE). Laparoscopic approach improves short-term outcome and textbook outcome (TO), which reflects the "ideal" surgical outcome, after RH. However, laparoscopic RH on an underlying diseased liver and after TACE/PVE remains a challenging procedure. The aim of this study was to compare the outcomes in patients who underwent laparoscopic liver resection (LLR) or open liver resection (OLR) following TACE/PVE. PATIENTS AND METHODS: All patients with HCC who underwent RH after TACE/PVE in five French centers were retrospectively included. Outcomes were compared between the LLR group and the OLR group using propensity score matching (PSM). Quality of surgical care was defined by TO. RESULTS: Between 2005 and 2019, 117 patients were included (41 in LLR group, 76 in OLR group). Overall morbidity was comparable (51% versus 53%, p = 0.24). In LLR group, TO was completed in 66% versus 37% in OLR group (p = 0.02). LLR and absence of clamping were the only factors associated with TO completion [hazard ratio (HR) 4.27, [1.77-10.28], p = 0.001]. After PSM, 5-year overall survival (OS) and progression-free survival (PFS) were 55% in matched LLR versus 77% in matched OLR, p = 0.35, and 13% in matched LLR versus 17% in matched OLR, p = 0.97. TO completion was independently associated with a better 5-year OS (65.2% versus 42.5%, p = 0.007). CONCLUSION: Major LLR after TACE/PVE should be considered as a valuable option in expert centers to increase the chance of TO, the latter being associated with a better 5-year OS.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

In situ normothermic regional perfusion versus ex situ normothermic machine perfusion in liver transplantation from donation after circulatory death.

In situ normothermic regional perfusion (NRP) and ex situ normothermic machine perfusion (NMP) aim to improve the outcomes of liver transplantation (LT) using controlled donation after circulatory death (cDCD). NRP and NMP have not yet been compared directly. In this international observational study, outcomes of LT performed between 2015 and 2019 for organs procured from cDCD donors subjected to NRP or NMP commenced at the donor center were compared using propensity score matching (PSM). Of the 224 cDCD donations in the NRP cohort that proceeded to asystole, 193 livers were procured, resulting in 157 transplants. In the NMP cohort, perfusion was commenced in all 40 cases and resulted in 34 transplants (use rates: 70% vs. 85% [p = 0.052], respectively). After PSM, 34 NMP liver recipients were matched with 68 NRP liver recipients. The two cohorts were similar for donor functional warm ischemia time (21 min after NRP vs. 20 min after NMP; p = 0.17), UK-Donation After Circulatory Death risk score (5 vs. 5 points; p = 0.38), and laboratory Model for End-Stage Liver Disease scores (12 vs. 12 points; p = 0.83). The incidence of nonanastomotic biliary strictures (1.5% vs. 2.9%; p > 0.99), early allograft dysfunction (20.6% vs. 8.8%; p = 0.13), and 30-day graft loss (4.4% vs. 8.8%; p = 0.40) were similar, although peak posttransplant aspartate aminotransferase levels were higher in the NRP cohort (872 vs. 344 IU/L; p < 0.001). NRP livers were more frequently allocated to recipients suffering from hepatocellular carcinoma (HCC; 60.3% vs. 20.6%; p < 0.001). HCC-censored 2-year graft and patient survival rates were 91.5% versus 88.2% (p = 0.52) and 97.9% versus 94.1% (p = 0.25) after NRP and NMP, respectively. Both perfusion techniques achieved similar outcomes and appeared to match benchmarks expected for donation after brain death livers. This study may inform the design of a definitive trial.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

BACKGROUND AND AIMS: To report 5-year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.