Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: systematic review and meta-analyses

Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC). A systematic literature review was performed to identify published studies on the use of TARE in intermediate and advanced stages HCC exploring the efficacy and safety of this innovative treatment. Twenty-one studies reporting data on overall survival (OS) and time to progression (TTP), were included in a meta-analysis. The pooled post-TARE OS was 63% (95% CI: 56-70%) and 27% (95% CI: 21-33%) at 1- and 3-years respectively in intermediate stage HCC, whereas OS was 37% (95% CI: 26-50%) and 13% (95% CI: 9-18%) at the same time intervals in patients with sufficient liver function (Child-Pugh A-B7) but with an advanced HCC because of the presence of portal vein thrombosis. When an intermediate and advanced case-mix was considered, OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1- and 3-years respectively. As for TTP, only four studies reported data: the observed progression probability was 56% (95% CI: 41-70%) and 73% (95% CI: 56-87%) at 1 and 2 years respectively. The safety analysis, focused on the risk of liver decompensation after TARE, revealed a great variability, from 0-1% to more than 36% events, influenced by the number of procedures, patient Child-Pugh stage and treatment duration. Evidence supporting the use of radioembolization in HCC is mainly based on retrospective and prospective cohort studies. Based on this evidence, until the results of the ongoing randomized trials become available, radioembolization appears to be a viable treatment option for intermediate-advanced stage HCC.


INTRODUCTION
Hepatocellular carcinoma represents the third most common cause of cancer death, causing nearly 746,000 deaths per year in the world [1,2]. In almost all cases, one risk factor can be identified alone or in combination with others, with cirrhosis being the most frequent of them [3]. Prognosis of patients with HCC is poor, with a ratio of mortality to incidence of 0.95 [2]. Indeed HCC represents a major global health problem, also considering that its incidence increases progressively with aging of population [4].
The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly cirrhosis [5]. Patients are classified according to different expected survivals from A to C (two year survival: A 85%, B 57%, C 35%) based on five clinical measures of liver disease (total bilirubin, serum albumin, prothrombin time, ascites, hepatic encephalopathy). The American and European Societies for the Study of the Liver endorse the Barcelona Clinic

Review
Liver Cancer (BCLC) classification system for staging and allocation to treatment in patients with HCC [6]. Using this classification, as others applied in the Asia-Pacific Countries, the therapeutic algorithm varies depending on the stage of disease, ranging from curative treatments (such as resection, ablation or transplantation) to palliation and best supportive care. Overall, only a minority of patients with HCC receive curative treatments and no more than 5% are eligible for liver transplantation [7].
In current practice, advanced stage patients present as such in 60-70% of cases while the rest progresses to this stage despite treatment of more precocious cancer presentations [6]. Prospective randomized controlled trials (RCTs) have shown that sorafenib prolongs survival in all subtypes of advanced HCC patients [8,9] but side effects may lead to discontinuation of this treatment in up to 45% of patients. As a consequence, a significant number of advanced HCC patients may be precluded from the therapeutic benefit of sorafenib for related toxicities [10,11].
In the intermediate HCC stage, a wide range of interventional loco-regional treatments are available and trans-arterial chemoembolization (TACE) variously administered, is considered as the standard of care [4,6]. Also in advanced HCC -particularly when tumour extension is confined to the liver and when it is associated with a preserved hepatic function -the search for a tolerated loco-regional intervention able to challenge systemic therapy has been repeatedly investigated.
Trans-arterial radioembolization (TARE), often referred as a form of selective internal radiation therapy (SIRT) is a recognized, although not explicitly recommended therapy in several guidelines on clinical management of non-resectable HCC [4,6,12]. According to the latest release of the ESMO guidelines, however, TARE may compete with sorafenib in intermediate stage patients with prior TACE failure or advanced patients with tumoural macrovascular invasion (i.e. portal vein thrombosis, PVT) with no extra-hepatic spread and good liver function [12].
On technical grounds, TARE is a catheter-based interventional procedure that allows the emission of β-radiations at therapeutic levels directly into the tumour through its feeding arteries. Such a delivery mechanism, as for TACE, is aimed at minimizing the damage to the healthy liver parenchyma adjacent to the tumour. The main mechanism of action of TARE is a local brachytherapy and, unlike TACE, it doesn't result in microvascular embolization and tumour ischemia [13]. Devices for radioembolization are commercially available in both form of implantable glass (Therasphere ® ) or biocompatible resin-based (SIR-Spheres ® ) radioactive (Yttrium 90 -Y 90 ) spheres [13].
In the light of the increasing use of this innovative therapy in clinical practice, this study aims to systematically review the available evidence for the clinical efficacy and safety of TARE (glass or resin-based) in patients with intermediate-advanced stages HCC.

RESULTS
Out of 6641 references screened, 26 studies met the selection criteria. The study selection process is summarized in Figure 1.
The vast majority of included studies were observational cohorts, however three comparative studies were found: two RCTs comparing TARE with either TARE + sorafenib [14] or TACE [15] and a propensityscore matching design study with sorafenib [16]. In Supplementary  All studies showed low to medium methodological quality. One study [20] did not present clearly inclusion and exclusion criteria and only 3 studies [15,27,36] were conducted in more than one centre. No therapy was reported as concurrently administered but in 7 studies follow-on treatments were described. Nine studies had a prospective design while dropouts were adequately described in only 3 studies.

Outcome measures
Studies presenting OS or TTP data, stratified by presence or absence of PVT were all included in the metaanalyses except for two studies, one which did not report survival curves [17] and the second [37] which reported only survival data stratified by treatment dose, good or poor candidate groups and surgery vs. no surgery groups.
Studies considering patients with extrahepatic spread [26] or patients with deteriorated liver function (Child-Pugh C stage) [18] or patients awaiting liver transplantation [14] were excluded from the analysis.
Details on the 21 studies included in the quantitative analyses are listed in Table 1 together with patients and treatment characteristics.
When the entire population of patients receiving TARE was considered, with no stratification on PVTi.e. with a case-mix of intermediate and advanced HCC -the OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1-and 3-years respectively (Supplementary  Figure 1). In the cumulative analysis the percentage of patients with PVT was 38% while those with suboptimal liver function (Child-Pugh non-A) were 21%. Both these well-known prognostic variables likely influenced the observed results, although a direct evidence of that could not be inferred from the available data.
All results were confirmed in fixed effect metaanalysis models (data not shown).

Liver impairment after TARE
As described above, tumour progression after TARE was reported as a late event mainly due to deterioration of performance status and of Child-Pugh stage.
More specifically, the analysis on the adverse events related to TARE was focused on liver decompensation and/or failure following treatment. There was a large heterogeneity in definition of liver decompensation in the included studies and with that bias the percentage of patients suffering liver decompensation after TARE is reported in Table 2. In particular, TARE-related liver impairment events ranged from 0-1% in some studies to 36.5% in others depending on the number of treatments received, performance status, duration and type of pre-TARE treatments. Liver decompensation was more likely in patients with multiple pre-TARE therapies and borderline cirrhosis (HR: 3.2; 95% CI: 1.8-9.7) as previously reported [40]. Medium time from TARE to liver decompensation was 3 months (range: 1-6).

DISCUSSION
In the last decade trans-arterial radioembolization has emerged as a viable loco-regional treatment option for patients with unresectable hepatocellular carcinoma associated or not with portal vein thrombosis, although its use is still not formally recommended in clinical guidelines due to lack of prospective randomized studies. While large RCTs have been implemented and likely to be reported in the near future, the present study aimed at identifying the available evidence around the efficacy and safety of TARE through a systematic review of published  Included studies suggest that median OS in patients receiving TARE for intermediate-advanced HCC falls in the range of 12-24 months, halved to 6-12 months should PVT be present. Pooled survival rates at 3-years after TARE were estimated as 13% (with PVT) and 27% (without PVT). These results are consistent with those presented in other published studies reporting median OS of 7-41.6 months in BCLC B to C patients [41].
Residual heterogeneity among studies -as measured by I 2 -was observed particularly in TTP while being less evident for OS. This reflected different schedules and protocols for definition and identification of tumour progression, which is considered a secondary endpoint in the large majority of studies [42]. High heterogeneity was detected also when definition of liver decompensation related to TARE was taken into account; this forced us to compute and summarize data on adverse events only in a qualitative fashion. Despite such limitation, TARErelated liver toxicity was registered in less than 30% of patients with near to zero mortality directly related to the procedure and an average hospital stay claimed as shorter or equal compared to conventional chemoembolization [13].
This review has a number of limitations. First, only English language studies were included: considering that several clinical studies retrieved were conducted in non-English speaking countries, it is possible that some evidence on the clinical role of TARE has been overlooked. Moreover, individual level data used in the selected studies were not accessible. Individual rather than aggregate data, would have enriched the overall analysis [43].
As regards to the clinical outcomes, the number of papers in which post-progression survival after TARE is described is very limited, although sorafenib is used quite often as second-line therapy after TARE, thus affecting post-progression and overall survival. This was an unavoidable bias assumed to be equally distributed among the studies and therefore not considered as an exclusion driver. Inclusion of post-progression therapies reflected in fact the field practice adopted in the management of HCC patients.
The evidence that supports the use of radioembolization in HCC is based on retrospective or prospective cohort studies and no RCTs have been published comparing TARE with systemic therapies, in particular sorafenib, currently the mainstay for treating advanced HCC.
Large-scale randomized controlled trials with overall survival as a primary endpoint exploring this comparison have been started (SIRveNIB NCT01135056, SARAH NCT01482442, YES-P NCT01887717). These  Overall survival rates at different follow-up times in advanced HCC patients with PVT receiving TARE trials and future prospective randomized studies of TARE vs. suitable comparators, are crucial to provide direct evidence to evaluate comparative effectiveness because, at least in advanced HCC radioembolization may achieve overall survivals in the range of 6-10 months [27] competitive with the survival range (6.5-10.7 months) reported in the phase III clinical trials registering sorafenib as a standard of care. Unfortunately, a pooled analysis focused on tumor response was not feasible due to high heterogeneity in reporting this outcome across the included studies. In fact, different response criteria (i.e. Response Evaluation Criteria In Solid Tumors -RECIST, mRECIST, World Health Organization -WHO criteria), imaging techniques, and time of radiological evaluation prevented a reliable assessment of this secondary endpoint. However, tumor response usually represents only a surrogate endpoint whereas OS, which is universally considered the primary outcome in oncological studies, was consistently assessed in our meta-analysis.
Among the studies comparing TACE versus TARE, two used Drug Eluting Beads TACE (DEB-TACE) [26,29] and five conventional TACE (cTACE) [15,20,22,35,36]. Although subgroup analysis according to the adopted TACE regimen was unfeasible due to the low number of studies, we know from previous cohort studies that DEB-TACE and cTACE lead to similar outcomes and comparable side effects in HCC patients [44,45].
Observational data allow a preliminary assessment of the incremental costs vs. incremental effectiveness (i.e. cost-effectiveness) of TARE vs. sorafenib and help in this setting to assess the value of presumably similar treatment options in field practice. In a recent cost-effectiveness analysis of TARE vs. TACE, patients with advanced BCLC-C were found to benefit from radioembolization at an increased cost [46] while in patients with BCLC-A disease, who formally lack survival benefit from radioembolization, cost-efficacy could be obtained in some specific subgroups, such as PVT or technical unfeasibility of curative approaches. In the future, a cost-effectiveness analysis could be performed comparing TARE with the other available therapies, particularly sorafenib, to identify whether this procedure is cost-effective or not, and to profile HCC subgroups which could benefit from TARE at a reasonable cost. This analysis could be instrumental in helping policy-decision making, while additional postmarketing evidence is collected.
Given the findings of this systematic review, based on safety and efficacy data from included studies, until the results of the ongoing trials become available, radioembolization appears to be a viable treatment option for patients with intermediate-advanced stage HCC.

Literature search
This review adopts the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [47]. In May 2015, a systematic search was conducted on PubMed, Embase, the Cochrane Library and Web of Science databases to retrieve clinical evidence on TARE for HCC. The search strategy was developed using the PICOS (Patient, Intervention, Comparator, Outcome, Study) framework. Boolean operators "AND" and "OR" were used to combine terms, while "NOT" operator was not included following Cochrane indications. Studies were considered if published in English and related to an adult population (≥18 years old). Reference lists of the retrieved articles were screened to find additional studies not identified through the original search.

Selection criteria
Inclusion criteria are shown in Table 3. Given common indications emerging for Y 90 , the review was conducted with a focus on patients with intermediate and advanced HCC stages according to BCLC staging system (stages B and C), the latter particularly when presenting with PVT.

Data extraction
Abstracts and full-text selection was conducted independently by two expert reviewers (CR, SS). In case of debate on study eligibility a third senior reviewer (AF) was involved to reach consensus. Data were extracted using a customized template developed in Microsoft Excel based on the PICOS statement. Information recorded included study features, participants', intervention's and comparator's characteristics, safety and efficacy outcomes.

Data analysis
Data referring to TARE were retrieved from all comparative and non-comparative studies identified. Relevant efficacy outcomes (i.e. overall survival -OSand time to progression -TTP -rates) were summarized and graphically presented through forest plots. When necessary, survival rates were derived from digitalization of Kaplan-Meier survival curves using the software Plot Digitizer 2.6.6©. OS was calculated as the difference between the date of the first treatment and the date of death from any cause, or last observation date in case of censoring. TTP was calculated from the first TARE treatment to the first progression at any site. Main adverse events, such as liver impairment, were tabulated and discussed qualitatively.
Survival rates for OS and TTP from different studies were pooled through a random effect meta-analysis of proportions with exact binomial confidence intervals [48]. A test on the summary effect measure is given, as well as a test for heterogeneity, also quantified using the I 2 metric [49]: the higher the values (from 0% to 100%) the larger the heterogeneity across studies. Fixed effect metaanalyses were also performed to check the robustness of obtained estimates to alternative models specification. Results are displayed in forest plots according to followup time and relevant patient subgroups. Analyses were performed using Stata ® software (StataCorp, version 14).

Quality assessment
The methodological quality of included studies was assessed according to a modified version of the National Health Service Centre of Review and Dissemination criteria [50]. Following this guidance, no scoring system was adopted; quality assessments were used for descriptive purposes [51].