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. 2012 Oct 22;15(5):327–336. doi: 10.1111/j.1477-2574.2012.00590.x

Surrogate endpoints in liver surgery related trials: a systematic review of the literature

Liliane Mpabanzi 1,2, Kim MC Mierlo 1, Massimo Malagó 2, Cornelis HC Dejong 1, Dimitrios Lytras 2, Steven WM Olde Damink 1,2,✉
PMCID: PMC3633033  PMID: 23323939

Abstract

Background Although the safety of liver surgery has improved enormously, hepatic surgery continues to face challenging complications. Therefore, improvements supported by evidence-based guidelines are still required. The conduct of randomized controlled trials in liver surgery using dichotomous outcomes requires a large sample size. The use of surrogate endpoints (SEPs) reduces sample size but SEPs should be validated before use.

Aim The aim of this review was to summarize the SEPs used in hepatic surgery related trials, their definitions and recapitulating the evidence validating their use.

Method A systematic computerized literature search in the biomedical database PubMed using the MeSH terms ‘hepatectomy’ or ‘liver resection’ or ‘liver transection’ was conducted. Search was limited to papers written in the English language and published between 1 January 2000 and 1 January 2010.

Results A total of 593 articles met the search terms and 49 articles were included in the final selection. Standard biochemical liver functions tests were the most frequently used SEP (32 of 49 the studies). The used definitions of SEPs varied greatly among the studies. Most studies referred to earlier published material to justify their choice of SEP. However, no validating studies were found.

Conclusion Many SEPs are used in liver surgery trials however there is little evidence validating them.

Introduction

In the last decades, liver surgery has been a constantly evolving field and its prominent role in the treatment of primary, secondary, malignant or non-malignant liver diseases has been well established.1 Although considerable improvements in mortality and morbidity rates have been achieved in many surgical centres, complications as a result of surgically induced liver damage still represent challenging events.2 Consequently, trials evaluating surgical techniques and therapeutic interventions with appropriate endpoints are still needed in this field.

Randomized controlled trials (RCTs) are considered mandatory in evaluating the significance of clinical interventions and their potential implementation in daily clinical practice.3 However, conducting adequately powered RCTs is frequently not feasible in many medical fields such as hepatic surgery.3–6 In spite of calls for more rigorous surgical research trials, the overall number and quality of RCTs in surgery remains suboptimal.6 The introduction of standards in reporting RCTs such as the Consolidated Standards of Reporting Trials (CONSORT)7 has led to the necessity of defining primary and, if required, secondary outcomes.7 Thus, it is imperative to standardize the definitions of the endpoints reported in hepatic surgery trials. Currently, the chosen outcomes are mostly clinical endpoints and can be divided in short- (e.g. peri-operative complications and peri-operative or 30 days mortality) and long-term outcomes (e.g. survival and disease-free survival). Van den Broek et al. recently demonstrated that conducting an adequately powered RCT in liver surgery using the clinical dichotomous outcomes mortality and morbidity was not feasible because of the required large sample size.8The introduction of surrogate endpoints (SEPs) in RCTs is considered a potential solution for solving the problems which usually compromise the conduct of a sound trial such as complexity, sample size, long-term follow-up and costs.9

A SEP is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives.10,11,12 Ideally, changes on a SEP induced by a therapy should reflect a clinically meaningful endpoint. In practice, this requirement frequently fails.13 Moreover, SEPs should be validated before being used to assess clinical outcomes. Nonetheless, validation is usually overlooked, especially if biologically plausible grounds are given.14 In practice, a correlation is often considered as validation for a SEP. However, it has been demonstrated that a correlate does not make a surrogate.13

Objectives of this paper

The aim of the present systematic review was to summarize the SEPs representing the effect of surgically induced damage used in liver surgery trials. Additionally, this study aimed at finding common definitions of the used SEPs and at recapitulating the evidence or validation justifying the use of those particular endpoints.

Methods

Search strategy

Three authors (K.v.M., D.L. and S.O.D.) performed a systematic computerized literature search according to the methodology recommended by the Cochrane Collaboration. The worldwide database of biomedical literature PubMed was searched using the Medical Subject headings (MeSH) terms: ‘hepatectomy’ or ‘liver resection’ or ‘liver transection’. Additionally, the three authors (L.M., K.v.M. and D.L.) manually reviewed all the articles' references lists for identification of relevant studies. Search results were stored in an Endnote file (Endnote X2, Philadelphia, PA, USA).

Study eligibility

The search was limited to patients older than 18 years, and to articles published between 1 January 2000 and 1 January 2010. Exclusion criteria were non-human studies and papers published in languages other than English. Studies were eligible if they used SEPs as primary or secondary outcome measures. They were excluded if they reported only on dichotomous outcomes, such as mortality and morbidity, or only reported on survival. Papers using outcome measures that were not considered as surrogate markers for liver injury, i.e. the need for a blood transfusion, the amount of operative blood loss or transection time, were also excluded as well as studies reporting on surgical procedures other than liver resection or assessing the effects of different therapeutic modalities such as chemotherapy, radio-frequency ablation or liver transplantation. Trials focusing on non-surgical interventions such as imaging, the effect of portal vein embolization as well as on liver regeneration were also excluded.

Search of evidence justifying the use of SEPs

All included studies were further scrutinized for references justifying the choice of the used SEPs. All references related to the endpoints mentioned either in the ‘introduction’ or in the ‘materials and methods’ sections were considered as references providing evidence and justification for the choice of the SEP. All references were assessed for compliance with the Boissel criteria for validation of SEPs.15 Briefly, SEPs were checked upon three criteria: convenience, prediction validity and relationship with clinical endpoint.

Data collection and analysis

Two authors (K.v.M. and L.M.) extracted the data and the results were reviewed independently by two other authors (D.L. and S.O.D.). Disagreements were solved by discussion. The following data were recorded systematically after formation of the final list of studies fulfilling the inclusion criteria: first author, year of publication, study design, number of patients, defined endpoints and the association of defined endpoints with morbidity, mortality or survival. The references given by the authors to explain the choice of the surrogate endpoints were also recorded in a separate Endnote file.

Results

Quality and quantity of evidence

A total of 593 articles met the search terms. Overall, 552 were excluded. Of those, 320 were excluded after reading the abstracts and 232 were excluded after reading the full text. Cross-checking through the references of the included papers delivered an additional 8 studies, resulting in a total of 49 articles being included in this review (Fig. 1). All studies were either RCTs or consecutive case series. The search for references justifying the choice of endpoints delivered 125 articles. These studies were mainly reviews or previously published clinical trials (data not shown).

Figure 1.

Figure 1

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Flowchart selection articles. LR, liver resection

Used SEPs and their definitions

Several biomarkers of hepatic functions as well as systemic parameters were used as SEPs (Table 1). Standard biochemical liver functions tests to quantify hepatocellular damage [post-operative plasma alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (AP)] were the most frequently used SEPs (32 of the 49 studies). Hepatic synthetic function quantified with various haematological factors such as prothrombin time (PT) and platelets counts was also frequently used (29 studies). Only two studies used a single SEP. The remaining studies examined a combination or two or more SEPs. Eleven studies did not find a correlation between the used SEP and a clinical outcome.

Table 1.

Functions and events used as surrogate endpoints (SEPs)

Function and/or event measured Surrogate endpoints Number of papers using SEPs
• Hepatic parameters
Hepatocellular damage ALT, AST, GGT, AP 32
Uptake, conjugation, excretion Serum (total or conjugated) bilirubin 29
Cholestasis Alkaline phosphatase 2
Hepatic synthetic function Coagulation factors, platelets, INR, PT, glycogen content, albumin 23
Hepatic perfusion, anion excretion ICG (k), ICG-PDR 6
Hepatic anaerobe metabolism Transhepatic oxygen pressure gradient, hepatic oxygenation, transhepatic lactate gradient 2
Hepatocyte urea synthesis capacity Ammonia 1
• Systemic parameters
Oxidative stress SOD, MDA, MPO, gluthatione, gluthatione disulfide 6
Anaerobe metabolism Lactate, pyruvate 6
Inflammation Cytokines, PMNL activation, CRP 12
Apoptosis Caspases, Bcl2, beclin-1 1
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ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma glutamyl transpeptidase; AP, alkaline phosphatse; INR, international normalized ratio; PT, prothrombin time; ICG, indocyanine green; SOD, superoxide dismutase; MDA, malondialdehyde; MPO, myeloperoxidase; PMNL, polymorphonuclear leucocyte; CRP, C-reactive protein.

The definitions of the used SEPs varied greatly among studies (Table 2). The most frequently used SEPs (biochemical liver function tests) were often defined as plasma peak values over a period of 3 to 7 days post-operatively. These discrepancies in definitions and timing of measurement of the SEPs were seen throughout the studies included in this review (Table 2). Authors aimed at showing a correlation between clinical outcomes (mortality and/or morbidity) or an independent predictor factor of these dichotomous outcomes.

Table 2.

Surrogate endpoints and definitions used

First author, year Liver-related SEP (primary or secondary) Timepoints of measurement and definition endpoint
Taura, 201036 Portal and hepatic veins pressures; hepatic artery and portal vein blood flow; lactate; bilirubin, INR Haemodynamic, oxygenation and liver functions at the time of abdominal closure, liver function also peak value over PODs 1, 2 and 4
Pietsch, 201037 Lactate and pyruvate levels in arterial and hepatic venous blood and hepatic oxygenation Values during liver manipulation, 15 min after hilus occlusion, 10 min after end of LR, at the time of abdominal closure and on POD 1
Domart, 200938 Caspases 3,8,9, Bcl2, beclin-1, light chain type II expressions, vacuoles; ALT, AST, bilirubin, AP, GGT, PT Values just prior to IP and after liver reperfusion and liver function on POD 7
Xia, 200939 ALT, AST, bilirubin, HA, IL-6 Peak values over 1, 3 and 7 PODs
de Liguori, 200940 ICG PDR, PLF; AST, ALT, bilirubin Correlation between ICG PDR and onset PLF; correlation ICG PDR and AST, ALT, bilirubin on PODs 1, 5, 10
Arkadopoulos, 200941 AST, bilirubin, PT, IL-6, IL-8, MDA Liver function: daily till discharge; IL: at 12, 24 and 48 h after LR; MDA: 5 min prior to occlusion and 1 h after reperfusion
Wen, 200942 ALT, T-bilirubin Values over postoperative course
Beck-Schimmer, 200843 AST and ALT Peak AST and ALT over 7 PODs
Akita, 200844 ICG-R15 and T-bilirubin ICG-R15 (after opening abdomen, during clamping phase and at abdomen closure) and peak T-bil over hospitalization period
Ko, 200845 TLV, graft volume, RLV, AST, ALT, T-Bil, PT, albumin, blood urea nitrogen Values after closure abdomen and over PODs 1, 2, 3, 5, 7 and 30
Scheingraber, 200846 ICG PDR, PT and bilirubin Peak over 7 PODs
Kim, 200747 ALT, AST, Tbil, IL-6 IL-6: values before and after 30 min Pringle, and liver function tests: values over postoperative course
Pulitano, 20072 PT-INR, AT III, mean platelet count, fibrinogen, D-dimer, platelets count; IL-6, TNF-a Values over PODs 1, 2 and 5
Tang, 200248; 49 Glycogen, MDA and ATP content, SOD activity; AST, ALT, AKP Glycogen content: before occlusion, ATP, MDA and SOD: after occlusion and after 1 hr reperfusion, Liver functions: PODs 1 and 5
Brooks, 200750 Partial pressure carbon dioxide in liver tissue, partial pressure oxygen, bilirubin, ALT Pressures after 10 min clamping and 5 min reperfusion or 10 min clamp and 20 min reperfusion, Liver function: POD 2
Mullen, 200730 Bilirubin, INR Peak bilirubin and INR over 90 days
Kostopanagiotou, 200751 Fibronectin Concentration on POD 1
Schmidt, 200752 IL-6, IL-8, IL-10, TNF-a, HLA-DR, LPS-induced TNF-a, CRP Mean values over PODs 1, 2, 3 and 7
Petrowsky, 200653 AST, ALT, bilirubin and PT Peak values and area under the curve over 5 PODs
Kostopanagiotou, 200654 MDA AST, PT and bili MDA: values 5 min after reperfusion, at the end of LR and on PODs 1, 3 and 6, Liver function: On PODs 1, 3 and 6
Theodoraki, 200655 Lactate, transhepatic lactate gradient, transhepatic oxygen pressure gradient Values 50 min after reperfusion
Dunschede, 200656 Lactate, CHE, AST, ALT and ATP content Lactate, CHE, ATP content, ALT and AST: opening abdomen, 30 min ischaemia, 30 min reperfusion, POD1, AST, ALT: peak PODs 1–3
Esaki, 200657 Bilirubin ration calculated as serum T-bil on POD2 divided by preoperative level; PT, AST, ALT Values over 10 PODs
Azoulay, 200658 AST, ALT, T-bil, GST, PT ALT: peak over PODs 1, 7, 30 (primary endpoint), GST, AST (peak), PT, T-bil: values over PODs 1, 7 and 30
Kim, 200659 IL-6; AST, ALT, PT, Tbil, ICG R15 IL-6: after LR but before reperfusion, at closure abdomen and on POD1, Liver function: Peak over PODs 1, 3 and 7
Sugimoto, 200660 ICG-K values, T-bil, albumin Values over PODs 1, 2, 3, 5 and 7, Liver function: on POD1
Balzan, 200529 Bilirubin and PT Values at over 7 PODs
Figueras, 200561 ALT, AST, lactate, PT, bilirubin Liver function: over PODs 1, 2, 3, 5 and 6, Lactate: at the beginning of mobilization, after 10 min reperfusion
Chouker, 200562 PMNL activation, MPO, IL-6, IL-8, ALT PMNL: 3, 15, 30, 120 min after LR, POD1, MPO: 30 min after LR, ALT: on PODs 1, 2; IL-6, IL-8: 30, 60 min after LR and POD1
Chouker, 200563 ALT, AST, a-GST Values at 3, 15, 30, 60 min, 24 h and 48 h after LR
Kaiho, 200564 Ammonia Values over 5 PODs
Bartels, 200465 ALT, AST Values over PODs 1, 10, 30 min after reperfusion, 6, 12 h after ICU admission, PODs 1, 2, 4 and 6
Li, 200466 AST, ALT, T-bil, albumin, caspase-3 activity, TUNEL assay Values over PODs 1, 3 and 7
Nishiyama, 200467 ALT, AST, T-bil, albumin, AKP, CHE, PT and platelet count Values over PODs 1, 3 and 7
Nuzzo, 200468 AST, ALT, bilirubin, PT Values over PODs 1, 3 and 7
Clavien, 200369 AST, ALT, bilirubin, PT, hepatic ATP Peak AST and ALT over 7 PODs; ATP: 30 min after reperfusion
Smyrniotis, 200370 PT, bilirubin, AST, ALT; IL-6, IL-8; MDA Liver function : Peak over PODs 1 to 6; Cytokines: 3, 12, 24 and 48 h after LR; MDA: 30 min after reperfusion
Wu, 200371 IL-6, endostatin Values over 2, 4, 8 h and PODs 1, 3, 5, 7, 9
Capussotti, 200372 AST, ALT, Tbil Peak over PODs 1, 3 and 7
Man, 200373 ET1 expression, eNOS and iNOS activity Correlation between ET-1 and eNOS activity with hepatic ultrastructural changes
Muratore, 200374 IL-6, AST, ALT IL-6: 1, 4 and 24 h after LR; Liver function: 1, 4 and 24 h after LR
Tang, 200248 Glycogen, ATP and MDA contents, SOD activity, AST, ALT, AKP At the end of the vascular occlusion and 1 h after reperfusion; Liver function: values over PODs 1 and 5
Vriens, 200275 MDA, glutathione, glutathione disulfide, vitamin C liver enzymes and blood clotting factors –
Kim, 200276 ALT, AST, bilirubin, TNF-α, IL-1b, IL-6 Liver function: values over PODs 1, 3 and 7; Cytokines: laparotomy, at completion of parenchymal transection, 1 h post reperfusion
Okochi, 200277 T-bil, platelet, AST, ALT, PT, ICGk Values over PODs 1, 2, 3, 5 and 7
Wiezer, 200178 Plasma amino acid patterns, coagulation and fibrinolytic cascade systems and neutrophil functions –
Orii, 200179 ALT, AST, ICGk, lactate Values just after reperfusion and 1 h after reperfusion; Liver function: values over 1 h after LR, PODs 1 and 3
Noie, 200180 AST, Tbil, alb, PT; UTI-urinary trypsin inhibitor in plasma pUTI and urine uUTI, CRP Values over postoperative course
Yamashita, 200181 IL-6, IL-10 peritoneal and venous Values over 0, 6, 12 h after reperfusion and on PODs 1, 3 and 7
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ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma glutamyl transpeptidase; AP, alkaline phosphatse; INR, international normalized ratio; PT, prothrombin time; ICG, indocyanine green; ICG PDR, indocyanine green plasma disappearance rate; SOD, superoxide dismutase; MDA, malondialdehyde; MPO, myeloperoxidase; PMNL, polymorphonuclear leucocyte; CRP, C-reactive protein; IL, interleukin; HA, hyaluronic acid; LR, liver resection; POD, postoperative day; IP, intermittent pringle manoeuver; PLF, post-resectional liver failure; TLV, total liver volume; RLV, rest liver volume; CHE, cholinesterase.

Evidence justifying the choice of SEPs

A total of 26 studies referred to earlier published studies to support their choice of SEP (Table 3). From the retrieved studies justifying the SEP, 46% were experimental studies and 77% were clinical studies. Only 6 studies used RCTs as a reference for the selection of their endpoint. Of these none was a validating study for a SEP.

Table 3.

Studies used as references for the choice of the surrogate endpoints (SEPs)

First author, year References for validation of SEPs Characterization of studies used as references
Taura, 201036 No specific mention of validating studies No specific mention of validating studies
Pietsch, 201037 No specific mention of validating studies No specific mention of validating studies
Domart, 200938 No specific mention of validating studies No specific mention of validating studies
Xia, 200939 No specific mention of validating studies No specific mention of validating studies
de Liguori, 200940 SEPs adopted from an earlier trial RCT
Arkadopoulos, 200940 No specific mention of validating studies No specific mention of validating studies
Wen, 200942 No specific mention of validating studies No specific mention of validating studies
Beck-Schimmer, 200843 SEPs adopted from clinical and experimental studies RCTs and experimental studies
Akita, 200844 No specific mention of validating studies No specific mention of validating studies
Ko, 200845 No specific mention of validating studies No specific mention of validating studies
Scheingraber, 200846 No specific mention of validating studies No specific mention of validating studies
Kim, 200747 No specific mention of validating studies No specific mention of validating studies
Pulitano, 20072 SEPs adopted from earlier trials RCT and consecutive case series
Tang, 200749 SEP adopted from earlier trials Experimental studies
Brooks, 200750 SEPs adopted from earlier trials Observational clinical studies and experimental studies
Mullen, 200730 SEP initially adopted an earlier trial RCT
Kostopanagiotou, 200751 SEP adopted from a review Review
Schmidt, 200752 No specific mention of validating studies No specific mention of validating studies
Petrowsky, 200653 SEPs adopted from earlier trials RCTs
Kostopanagiotou, 200654 No specific mention of validating studies No specific mention of validating studies
Theodoraki, 200655 No specific mention of validating studies No specific mention of validating studies
Dunschede, 200656 SEPs adopted from earlier trials Experimental study and clinical study
Esaki, 200657 SEPs adopted from clinical experience No study was used but clinical experience
Azoulay, 200658 SEPs adopted from earlier studies Clinical studies and an experimental study
Kim, 200659 SEP adopted from earlier studies Experimental and clinical studies
Sugimoto, 200660 SEPs adopted from earlier trials Several clinical studies (RCTs and consecutive case series)
Balzan, 200529 SEPs adopted from two trials RCTs
Figueras, 200561 SEPs adopted from earlier trials Clinical studies
Chouker, 200562 No specific mention of validating studies No specific mention of validating studies
Chouker, 200563 SEPs adopted from earlier studies Clinical trials and experimental studies
Kaiho, 200564 No specific mention of validating studies No specific mention of validating studies
Bartels, 200465 No specific mention of validating studies No specific mention of validating studies
Li, 200466 SEPs adopted from an earlier trial RCT
Nishiyama, 200467 No specific mention of validating studies No specific mention of validating studies
Nuzzo, 200468 SEPs adopted from an earlier trial RCT
Clavien, 200369 SEP adopted from an earlier trial Non-randomized pilot study
Smyrniotis, 200370 SEP adopted from earlier studies Experimental and clinical studies
Wu, 200371 SEPs adopted from earlier trials Experimental studies
Capussotti, 200372 No specific mention of validating studies No specific mention of validating studies
Man, 200373 SEPs adopted from earlier studies Experimental and clinical studies
Muratore, 200374 SEPs adopted from earlier studies Experimental and clinical studies
Tang, 200248 No specific mention of validating studies No specific mention of validating studies
Vriens, 200275 No specific mention of validating studies No specific mention of validating studies
Kim, 200276 SEPs adopted from earlier studies Experimental studies
Okochi, 200277 SEP adopted from an earlier trial Clinical study
Wiezer, 200178 No specific mention of validating studies No specific mention of validating studies
Orii, 200179 SEPs adopted from earlier studies Several clinical studies in the transplantation setting
Noie, 200180 No specific mention of validating studies No specific mention of validating studies
Yamashita, 200181 SEPs adopted from an earlier trial Clinical trial
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RCT, randomized controlled trial.

Validation of the SEPs using the three criteria defined by Boissel et al

The used SEPs occurred more often than clinical endpoints, therefore complying to the first criteria described by Boissel et al.15 The two other criteria of Boissel et al. could not be verified in this review as they required full insight of the original data and potential follow-up of the patients.

Discussion

The present systematic literature review is an attempt at a comprehensive and critical evaluation of surrogate endpoints used in liver surgery-related clinical trials. The majority of studies used biological plausible, though not validated, surrogate outcomes. As the liver is involved in a multitude of processes, many functions could serve as surrogate endpoints. In line with this, many surrogate outcomes have been used in reporting the results of trials in hepatic surgery. However, there was a lack in standardized definitions of the most commonly used SEPs.

Liver surgery has been a subject of extensive research in the past two decades.16 As a result, the safety and efficacy of surgical interventions have increased substantially while the indications for performing a liver resection are continuously extending.17–20 In spite of a decrease in mortality and morbidity rates, there is still a need for standardized outcome parameters to evaluate therapeutic efficacy or hazards of liver operations.21 Composite and surrogate outcomes are considered as statistically adequate alternatives for replacing the standard short-term dichotomous outcome of mortality and morbidity in many medical fields.21–25 Formulation of surrogate outcomes requires, first and foremost, standardization of definitions of the used SEPs. The lack of adequate definitions of outcomes impairs comparison and evaluation of diagnostic and therapeutic trials. Recently, van den Broek et al.21 conducted a survey among hepato-biliary surgeons to reach a consensus on definitions of complications after liver surgery. These definitions were extracted from the currently available literature and standardized by the authors before being subjected to discussion by experts. The need for the aforementioned survey on the definitions was because of the lack of uniformity on definitions as shown in the present review. To reach a consensus on the definitions of the SEPs frequently used in liver surgery related trials, a questionnaire similar to the survey above stated should be designed. Defining SEPs for hepatic surgery trials should take into account the numerous targets of interventions in liver surgery-related trials. As all the currently used SEPs are yet to be validated, many definitions can be proposed and adapted to the different effects expected from various interventions.

In the present comprehensive literature review, we were able to retrieve references rationalizing the selection of SEPs used in the majority of the studies. These references were studies using similar endpoints either in clinical trials or in experimental settings. Unfortunately, no study using validated SEPs was found. Validation and value of SEPs has been, and still is, a matter of debate.13,16 Prentice12 developed four criteria that are sufficient to validate a SEP in phase three clinical trials. However, these criteria have been considered too stringent and difficult to verify.27,28 In a comprehensive review, Boissel et al.15 redefined the three main criteria that a SEP must meet to be considered as valid surrogate for a clinical endpoint. First, a surrogate should be convenient, i.e. it should occur more often than the corresponding clinical point. The time course of the SEP should precede that of the clinical endpoint so that disease or its progression can be recognized or predicted quicker than the actual clinical endpoint using the SEP.25 Second, the relationship between the surrogate and the clinical endpoint should be established both quantitatively and qualitatively through relevant epidemiological and clinical studies. The nature of this relationship should be understood in terms of pathophysiology or in terms of an expression of joint risk.25 Lastly, a surrogate endpoint should produce parallel estimates of risks and benefits as the clinical endpoints. The endpoints selected by the authors in the last 10 years all seemingly comply to the first criterion as they describe alterations either in hepatic or systemic parameters. However, we were not able to verify if the other criteria were met challenging the validity of the obtained results in the studies included in this review. The complexity of validation is perhaps clearly illustrated by two elegant studies which attempted to validate surrogates for mortality following post-resectional liver failure.29,30 Balzan et al. prospectively evaluated 704 patients undergoing hepatic resection.29 They were able to show that the 50-50 criteria (PT <50% and serum total bilirubin >50 μmol/l on day 5 post-operatively) were an accurate predictor of liver failure and death after a hepatectomy. However, their findings were soon contested by Mullen et al.30 who conducted a similar study in 1059 patients undergoing major hepatectomy in which the 50-50 criteria could not be reproduced. The authors therefore introduced a new criterion (peak bilirubin >7.0 mg/dl) that should be considered as a more reliable marker predicting post-resectional liver failure and mortality.

Several other medical fields have been trying to standardize the outcomes that are used in clinical trials. Recently, the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality in the United Kingdom convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies.31,32,33 The challenging task of validating SEPs in liver surgery related trials should follow a similar design and start by assessing and standardizing the definitions of the most commonly used SEPs. It could be achieved either by the conduct of a survey among worldwide HPB surgeons or the formation of an experts panel as demonstrated by the NIH. As a result, a common international prospective database with clear definitions of SEPs could be established. This database would allow the conduct of multicentre trials validating the SEPs in liver surgery. Alternatively, a large multi-centre, multi-national prospective study could be designed to validate the potentially most valuable SEPs. As an example, the Medical Research Council (UK) recently funded a prospective validation study of a combination of the SEPs dimethyl-arginine and ischaemia modified albumin (DASIMAR; MRC 08/H0714/8) in decompensated cirrhosis. Moreover, a recently published study presented an international, multicentre, external validation analysis of the utility interval to biochemical failure (IBF) in predicting prostate cancer mortality at the time of biochemical failure.34 IBF was chosen as prostatic cancer progression defined by prostate-specific antigen, otherwise known as biochemical failure (BF), is almost always the earliest sign of recurrent prostate cancer and can predate clinical manifestations of disease by months to years. Earlier, a large study of 221 men who experienced BF after radiotherapy, a shorter time interval between the completion of treatment and BF [i.e. interval to BF (IBF)] had been shown to be related to the development of distant metastasis and prostate cancer mortality.35 Thereafter the extensive validation study was designed to substantiate IBF as a SEP for identification of the potentially lethal prostate cancer. These studies are solid examples liver surgery researchers can follow.

In an attempt to define and validate SEPs in hepatic surgery trials, caution should be taken in the choice of SEPs considering the different types of hepatic surgery that can be studied and the patient population that is being investigated.

Conclusions

The present systematic review showed that many SEPs are used in hepatic surgery related research. Although these endpoints are biologically plausible, there is little evidence on their validity as true surrogates of clinical endpoints. It is important to standardize SEPs definitions and validate the SEPs used in liver surgery trials as the safety is steadily increasing making the differences between interventions smaller and therefore leading to enormous sample sizes. Validated SEPs could be reliable surrogates of clinical endpoints.

Conflicts of interest

None declared.

Sources of financial support

Liliane Mpabanzi is supported by a grant from the Netherlands Organization for Scientific Research (NWO Mosaic, grant nr 017-006-106).

Authors' contributions

Liliane Mpabanzi: manuscript writing, retrieval of data, analysis of results and critical review of the final manuscript.

Kim van Mierlo: search and retrieval of data.

Massimo Malago: critical review of the manuscript.

Cornelis Dejong: critical review of the manuscript.

Dimitrios Lytras: search, retrieval of data and critical review of the final manuscript.

Steven Olde Damink: original idea, search and critical review of the final manuscript.

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