Timely arterial reperfusion is a critical step in liver transplantation. Technical difficulties and delays to revascularize the hepatic artery during the procedure pose a risk of critical ischemic damage to the biliary tree of the liver graft. Posttransplant compromised hepatic artery flow is a potentially devastating event, and hepatic artery thrombosis is a feared complication leading to loss of the liver graft or death in, respectively, 53% and 33% of hepatic artery thrombosis cases.1,2
Transarterial chemoembolization (TACE) is one of the locoregional therapies used in patients with hepatocellular carcinoma (HCC) listed for liver transplantation to bridge the gap between enlistment and transplantation, to prevent progression while waiting for a liver graft, or to downstage patients that progressed outside Milan criteria.2
No universally accepted protocol for the application of TACE exists. The treatment concept is to administer a high dose of chemotherapeutic drugs in the hepatic arteries supplying the tumor, followed by embolization of these vessels.3 TACE can be administered into the tumor, liver segment, or liver lobe, nowadays selective administration of TACE is preferred.4 The chemotherapeutic drugs and combination of drugs used for TACE vary and include mono, double, and triple therapies.3 For embolization, both permanent and temporary embolization devices are used.5 Drug-eluting beads used in TACE combine the 2 functions of a drug delivery system and embolic agent.6
TACE may cause several direct complications, such as hepatic failure, postembolization syndrome, abscess formation, access site injury, and pulmonary embolism.7-9 Intra-arterial manipulation of the hepatic artery before liver transplantation as part of neoadjuvant TACE for HCC has raised concerns of increasing risk of arterial and biliary complications posttransplantation. The incidence of arterial and/or biliary complications after liver transplantation in patients treated with TACE has been explored in observational studies, however the majority of these studies lack power to detect a clinically significant difference.10-23 We aimed to investigate the impact of TACE before liver transplantation on occurrence of hepatic artery and biliary tract complications after liver transplantation by pooled analyses of published cohorts.
MATERIALS AND METHODS
The Cochrane Handbook for Interventional Systematic Reviews was followed to conduct the systematic review and meta-analysis.24 The article was written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.25 The systematic review protocol was registered prospectively in PROSPERO.26
Comprehensive searches were performed in Embase, MEDLINE OvidSP, Web of Science, Google Scholar, and the Cochrane databases. The search was performed for articles written in English and published until March 2016, concerning patients with HCC waitlisted for liver transplantation. Included articles studied posttransplant complications of the hepatic artery or biliary tract, in patients treated with TACE before deceased or living-donor liver transplantation, compared with liver transplantation recipients who had not undergone TACE. We included articles describing transarterial embolization or chemoinfusion alone, embolization with drug eluting beads or chemoembolization, and excluded articles describing radioembolization. Case reports, letters, and editorials were excluded, as well as pediatric and nonhuman studies. We expected most studies to be of relatively small sample size and to achieve adequate power potentially relevant abstracts in conference proceedings were included. Search terms for each database are provided in Appendix I, SDC,https://links.lww.com/TP/B484.
Studies were independently evaluated for inclusion by 2 observers (T.H., D.S.) and disagreement was resolved by consensus with a third reviewer (H.H.). Studies were screened based on title and abstract first. Subsequently, full-texts were acquired if available. Finally, manual cross-referencing was performed to identify other potentially relevant studies.
Quality of selected articles was assessed using the validated checklist of Downs and Black, consisting of 27 items grouped in 5 subscales (quality of reporting, external validity, potential of bias, confounding, and power analysis).27 The maximum score is 32 points. Item 27 (power analysis) was modified as we anticipated a majority of observational studies in which it would be rarely feasible to reach a power greater than 80%. Instead of the original 5-point scale, we assigned a score of “0” if no power calculation was provided, “3” if a power calculation was provided but the impact of the difference between groups used in the calculation was unclear, and “5” if the difference between groups was clearly defined as a clinically important difference. Additionally, the risk of bias and quality of evidence categorization per the GRADE score was applied.28
Data were extracted from the full-text articles independently by 2 observers (T.H., D.S.) with use of a standard extraction table, disagreement was resolved by consensus with a third reviewer (H.H.). The standard extraction table included the incidence of postoperative hepatic artery (primary outcome) and biliary complications (secondary outcome), anastomotic technique, reinterventions after liver transplantation and death from hepatic artery complications, follow-up schedule, diagnostic methods, type of TACE, number of TACE procedures, type of donor, etiology of liver disease, model for end-stage liver disease scores, and tumor characteristics. If for a patient, the same complication was reported multiple times, this was considered a single complication in the pooled analysis.
Meta-analyses were performed with OpenMetaAnalyst, using a binary random-effects model (DerSimonian Laird method) because we anticipated heterogeneity between studies. A 0.5 correction factor was used, if the number of events was 0.29 For each outcome, the results were presented in forest plots with an odds ratio (OR) and 95% confidence interval (CI). A P value less than 0.05 was considered statistically significant. Potential heterogeneity between studies was assessed with I2 tests. A sensitivity analysis was performed for the primary and secondary outcomes, testing for the effect of 3 factors: overall quality of the studies (≥50% of available points), full text studies compared with abstracts, and whether or not a clear definition of hepatic artery or biliary tract complications was reported in Materials and Methods section. The estimates of the sensitivity analyses were compared with the analyses including all studies with a Z test to check for significant differences.
Literature Search Results
Of 4002 records in the initial search, 14 records (8 full articles, 6 conference proceedings) met our inclusion criteria (Figure 1).10-23 Combined, these retrospective studies represent a total of 1122 patients who underwent neoadjuvant TACE or trans arterial embolization for HCC before liver transplantation, and 2703 patients not bridged with TACE. Seven studies described solely hepatic artery complications, 3 studies described both hepatic artery and biliary tract complications, and 4 studies described biliary tract complications only. A meta-analysis of hepatic artery complications comprised data of 10 studies.11,13-18,20,21,23 Meta-analysis of biliary tract complications comprised data of 7 studies.10-12,15,17,19,22 One study with a limited follow-up time of 7 days was excluded from the analysis.30
The quality assessment is presented in Table 1. All included studies are of observational and retrospective design. Goel et al11 represented the largest cohort to date and was the only study performing a power analysis. The sample size in most studies is limited ranging from 19 to 328 TACE cases per study, and no study shows a large effect size. According to our quality assessment tool, all included studies are prone to confounding. Five of 8 of the full text studies obtained more than 50% of the available points (median, 17/32 points; n = 8), compared with none of the congress abstracts (median, 12/32 points; n = 6).
Five studies provided a clear definition of hepatic artery complications, including thrombosis, stenosis, (pseudo)-aneurysms, and anastomotic disruption established by radiological evaluation of the artery.11,13,16,20,23 Detection of arterial complications by a standardized protocol during long-term clinical follow-up by Doppler ultrasound or CT angiography was reported in 4 studies.13,15,17,20 Four studies defined biliary tract complications clearly, which included anastomotic cstrictures, nonanastomotic strictures, and/or biliary leaks.10-12,19
Six studies are at risk for selection bias. In 4 of these studies, the control group was flawed by inclusion of non-HCC cases,10,12,16,20 2 studies excluded patients that died within 30 days postoperatively,10,13 and 1 study did not clearly report their source population.18
Risk of bias from selective reporting of outcomes was identified in 6 studies, which did not report a definition of hepatic artery or biliary tract complications in Materials and Methods section.14,15,17,18,21,22 Therefore, the quality of all included studies according to GRADE is low to very low.
Table 2 shows the baseline characteristics of the individual studies. Follow-up was longer than 6 months in 10 studies. Four studies did not report the exact follow-up time.16,20,22,23
Hepatic Artery Complications
Data on postoperative hepatic artery complications are summarized in Table 3. Posttransplant hepatic artery complications occurred more frequently in TACE recipients (76/837) compared with non-TACE recipients (145/2294). We observed a significant association between preliver transplantation TACE and posttransplantation occurrence of hepatic artery complications, including thrombosis, stenosis, and (pseudo)-aneurysms (OR, 1.57; 95% CI, 1.09-2.26; P = 0.016; I2 = 0%) (Figure 2).11,13-18,20,21,23 No evidence of an association between pretransplant TACE and posttransplant occurrence of hepatic artery thrombosis, alone, was found (OR, 1.31; 95% CI, 0.74-2.35; I2 = 0%) (Figure 3).11,14,16-18,20,21 There was no significant heterogeneity between studies in both analyses (Figure 2 and Figure 3). Series of Lin et al14 was the only study reporting exclusively results of living-donor liver transplantation in contrast to deceased donor liver transplantation, but exclusion of this study from pooled analyses did not change the magnitude or direction of the association. Two other studies reported inclusion of a small proportion living donor living transplantation cases, respectively, in 3% and 1.7% of the study population.10,11 Sensitivity analysis revealed that the overall estimate was not influenced by the quality of the studies, publication type, or the use of a restricted definition (Appendix II, SDC,https://links.lww.com/TP/B485). Nevertheless, when restricting the analysis to full-text articles, the association between preliver transplantation TACE and posttransplantation occurrence of hepatic artery complications was stronger (OR, 2.2; 95% CI, 1.3-3.6).
Time from liver transplantation to diagnosis of hepatic artery complications was reported in 3 studies. The median time to diagnosis was 12.5 days (range, 1-120; n = 14) in patients treated with TACE compared with 57.5 days (range, 2-91; n = 8) in patients not treated with TACE.13,14,17
Mechanical Damage to Hepatic Artery After TACE
Microscopic changes of the hepatic artery were systematically studied in 3 studies, and mechanical injuries to the hilar hepatic artery or anastomotic site were described in most patients after TACE.13,14,17 Lin et al14 observed hepatic artery intima dissection in 23 (58%) of 40 patients that underwent preliver transplantation after TAE versus 4 (28%) of 14 patients in the no-TACE group. Two other studies reported histological injuries, such as wall edema, fibrosis, or thrombosis, at the hilar hepatic artery of explants in 12 (38%) of 32 and 98 (88%) of 111 TACE pretreated patients compared with 3 (9%) of 35 and 9 (3%) of 339, respectively, of no-TACE patients.13,17
Intraoperative Salvage and Postoperative Outcomes for Hepatic Artery Complications
Technical data on the arterial anastomosis was reported in 3 studies.14-16 Intraoperative salvage by alternative arterial reconstructions or immediate revision of the arterial anastomosis was reported in 23 (14%) of 170 (95% CI, 9-20%) TACE patients versus 20 (5%) of 381 (95% CI, 3-8%) in no-TACE patients.
The incidence of endovascular or surgical reinterventions because of hepatic artery complications was not consistently reported. In 5 studies comprising 584 TACE and 714 non-TACE patients, cumulative numbers of reinterventions related to hepatic artery complications was 42 (7.2%, 95% CI, 5.4-9.6%) in TACE patients versus 29 reinterventions (4.1%, 95% CI, 2.8-5.8%) in non-TACE patients.11,13,14,17,18
Biliary Tract Complications
Data on biliary tract complications are summarized in Table 4. No strong evidence of a significant association was observed between preliver transplantation TACE and occurrence of biliary tract complications posttransplantation (OR, 1.30; 95% CI, 0.96-1.76; P = 0.087; I2 = 0%) (Figure 4).10-13,15,17,19,22 There was no significant between-study heterogeneity in the analyses. Sensitivity analysis revealed that the overall estimate was not influenced by the quality of the studies, publication type, or the use of a restricted definition (Appendix II, SDC,https://links.lww.com/TP/B485).
With this meta-analysis, we aimed to determine whether TACE is a safe technique securing hepatic artery quality for subsequent liver transplantation in HCC patients. The relation between pretransplantation TACE and posttransplantation arterial and biliary complications has only been explored by observational approach, limiting the evaluation of a causal relation. Majority of studies exhibited flaws in study design and reporting of data. The strength of this meta-analysis is the pooled sample size resulting in additional power to explore the evidence for an association between TACE and posttransplant arterial and biliary complications.
Although no prior study showed strong evidence of an association, our pooled meta-analysis demonstrates a significant association of preliver transplantation TACE and posttransplant occurrence of hepatic artery complications.
The occurrence of hepatic artery complications after liver transplantation in patients treated with TACE could be related to mechanical effects of arterial instrumentation or to inflammatory changes of the arterial wall in response to infusion of chemotherapeutic or embolic agents. This hypothesis is supported by reports of structural injuries to the anastomotic site of the hepatic artery in a large proportion of patients after TACE. In 14% of post-TACE cases, alternative arterial reconstructions were needed to facilitate hepatic artery reperfusion. Despite frequent intraoperative salvage of arterial anastomosis during liver transplantation in TACE patients, our meta-analysis shows evidence of no more than a modest effect on postprocedural hepatic artery complications (point estimate: OR, 1.6), clinically translating into an estimated increase of hepatic artery complications from 6% to 9% in TACE pretreated patients, or affecting by estimation approximately 1:30 patients undergoing TACE before transplantation. The modest increased risk may reflect the fact that immediate recognition and adequate intraoperative salvage of the arterial anastomosis may successfully avert more severe postoperative sequelae.
Nevertheless, complications of the hepatic artery may have devastating consequences for the individual and lead to unnecessary waste and limited durability of scarce donor organs. A potential higher need for alternative arterial reconstructions may challenge the decision to accept high-risk grafts in TACE pretreated recipients.
A previous study identified TACE as a risk factor for hepatic artery thrombosis, along with pediatric liver transplantation and aberrant arterial anatomy.31 Other risk factors for hepatic artery thrombosis reported in the literature are cytomegalovirus mismatch, retransplantation, and donor age.1,32 Recipient risk factors are infrequently identified as potential risk factors for hepatic artery complications; however, it is conceivable that age, history of smoking, diabetes, and atherosclerosis of the recipient may confer additional risks to the arterial revascularization. In our meta-analysis, it was not possible to control for these risk factors.
Although donor risk factors will not be known until transplantation, recipient risk factors and perceived quality of the artery at time of listing (such as a fragile artery on imaging or atherosclerosis at origin of the celiac trunk) may be considered and weighed against an additional compromise of arterial quality by choosing TACE as a bridging therapy.
No evidence of an association between preliver transplantation TACE and posttransplant occurrence of biliary tract complications was found. However, data on biliary complications in included studies was frequently flawed by lack of a clear definition and variable inclusion of different posttransplant biliary problems. Hypothetically, risk of biliary tract complications after TACE would constitute indirect effects of a prolonged arterialization phase during graft implantation or late effects secondary to hepatic artery complications. Given the multifactorial nature of biliary tract complications after transplantation, a potential indirect effect of TACE on biliary tract complications may be too small or clinically irrelevant. Moreover, adequate intraoperative interventions and postoperative recognition and management of hepatic artery complications may prevent development of subsequent biliary tract complications.
Our systematic review has several limitations. Although our analysis did not show heterogeneity, we assume that the studied populations are likely to exhibit some degree of variation, such as different tumor stages, use of different donor types, and variable waiting times with unknown numbers of waitlist dropouts. Additional heterogeneity may exist due to differences in TACE techniques between institutions, such as administered drugs, selectivity and number of TACE cycles and treatment schedules. Although the treatments algorithms used for TACE differ, the treatment concept including intra-arterial manipulation and administration of chemotherapeutic drugs remains the same. Furthermore, anastomotic techniques and postoperative anticoagulation protocols may differ between transplant centers. Because of patient selection and inconsistency in the reported data of individual studies, we were not able to take potential confounders into account, such as tumor factors, etiology of HCC, MELD scores, previous treatments and other risk factors for hepatic artery thrombosis. In addition, control groups of 4 studies contained patients with non–HCC-related indications for liver transplantation and different severity of liver disease than the TACE treatment groups.10,16,18,20 Regarding the outcome parameters, the definitions of both hepatic artery and biliary tract complications used in the included studies were variable and not always clearly described. These limitations could cause overestimation or underestimation of our results and potentially reduce generalizability of our conclusions. Very limited data were available on timing of hepatic artery complications, and for meta-analysis, no distinction could be made between early versus late hepatic artery complications. Finally, based on the available data, we were not able to study the outcomes of hepatic artery complications on graft and patient survival and balance this against the benefits of TACE as a bridging strategy.
Waitlist dropout could not be assessed as an outcome parameter in the present review design. Because of the reluctance to withhold treatment in patients at risk of tumor progression beyond Milan criteria and subsequent heterogeneity of study populations, the actual effect of TACE on waitlist dropout is difficult to determine. Radiofrequency and microwave ablation are alternative bridging strategies available for patients with smaller tumors depending on tumor location.33,34 The possibility of tumor resection and salvage liver transplantation could sometimes be considered, depending on patient and tumor characteristics.34 Neoadjuvant sorafenib has been explored in smaller studies as a bridge to transplantation, however, concerns are raised in increases in biliary complications and episodes of rejection after liver transplantation after sorafenib use.35-39 In summary, no equal alternative may be available for patients with larger HCCs.
Successfully downstaged patients seem to have similar survival after liver transplantation compared with patients that initially met Milan criteria and patients with complete pathologic tumor response have better survival after liver transplantation than those with incomplete responses.33,40-43 A selection bias of patients with favorable tumor biology may, however, play a role in positive results of TACE bridged patients.40,43 Oncologic and survival end-points were not included in the present review. Only 2 studies in our meta-analyses presented long-term survival rates and showed no association with TACE, hepatic artery, or biliary tract complications.15,21
More data are needed to validate our conclusions and consolidate the hypothesis; however, given the large number of patients needed to detect a difference for outcomes with a low incidence rate, robust randomized controlled trials may be unlikely to succeed in the clinical setting of preliver transplantation TACE.
Future prospective studies focussing on microscopic damage to the arterial wall, intraoperative salvage of the arterial anastomosis, and subsequent occurrence of postoperative arterial and biliary complications could provide insight in the potential causal pathway.
Whether the potential benefits of TACE as a bridging strategy to liver transplantation for liver transplant candidates with HCC outweigh TACE-induced morbidity could not be answered by the present review. Among the many tradeoffs to balance the risks and benefits of such treatment, neoadjuvant TACE might be considered an additional recipient risk factor for the development of hepatic artery complications after liver transplantation. A more challenging arterial reperfusion may be anticipated on acceptance of a graft in TACE recipients.
The authors thank Wichor Bramer, biomedical information specialist of the medical library in the Erasmus Medical Center, for his expert assistance with the systematic literature search. The Peter Morris Centre for Evidence in Transplantation (PMCET) advised on sections of the article as part of the collaboration between the European Society for Organ Transplantation (ESOT) and PMCET.
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