Efficacy of Technical Modifications to the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) Procedure: A Systematic Review and Meta-Analysis : Annals of Surgery Open

Secondary Logo

Journal Logo

Meta-Analysis

Efficacy of Technical Modifications to the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) Procedure

A Systematic Review and Meta-Analysis

Khajeh, Elias MD, MPH*,†; Ramouz, Ali MD*; Dooghaie Moghadam, Arash MD*; Aminizadeh, Ehsan MD, MPH*; Ghamarnejad, Omid MD*; Ali-Hassan-Al-Saegh, Sadeq MD*; Hammad, Ahmed MD*; Shafiei, Saeed MD*; Abbasi Dezfouli, Sepehr MD*; Nickkholgh, Arash MD*; Golriz, Mohammad MD*; Goncalves, Gil MD; Rio-Tinto, Ricardo MD; Carvalho, Carlos MD§; Hoffmann, Katrin MD*; Probst, Pascal MD*; Mehrabi, Arianeb MD*

Author Information
Annals of Surgery Open: December 2022 - Volume 3 - Issue 4 - p e221
doi: 10.1097/AS9.0000000000000221

Abstract

INTRODUCTION

Posthepatectomy liver failure is one of the leading causes of mortality in patients undergoing extended hepatectomy, and the main reason for liver failure is the small remnant liver volume.1,2 Estimating the future liver remnant (FLR) before hepatectomy is important because it indicates which patients will need radiological or surgical interventions to increase their FLR (insufficient FLR is <25%–30% of the liver size in patients with a healthy liver and <35% in those with cirrhosis).3–6 In the late 1980s, Kinoshita et al7 introduced portal vein embolization, which increases the FLR volume and improves posthepatectomy outcomes in patients with a small FLR. Despite these advantages, FLR hypertrophy remains insufficient and dropout rates are high after embolization.8–10 This can lead to disease progression while patients wait for their hepatectomy to be completed.11

To improve FLR hypertrophy, Schnitzbauer et al12 introduced Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) in 2011. Although ALPPS increases hypertrophy, it is still associated with a high risk of postoperative morbidity and mortality.13–17 Several studies have shown that events leading to negative post-ALPPS outcomes occur after the first stage of the procedure.17–20 To address this problem, conventional ALPPS has been modified to minimize the first stage of the procedure, thereby decreasing complications during and after surgery.21–24

Some of the modifications applied to the ALPPS procedures include partial ALPPS (p-ALPPS), Radiofrequency-assisted ALPPS (RALPPS), and Associating Liver Tourniquet and Portal vein ligation for Staged hepatectomy (ALTPS).22–24 The advantages and disadvantages of these modified procedures over conventional ALPPS is still debated among hepatobiliary surgeons. To address this issue, we performed a pooled data analysis of outcomes following modified ALPPS. We also conducted a meta-analysis to evaluate the efficacy of modified ALPPS techniques and to compare the outcomes of modified versus conventional ALPPS.

MATERIALS AND METHODS

The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Meta-analysis of Observational Studies in Epidemiology checklists (https://links.lww.com/AOSO/A184), and recommendations of the Study Center of the German Society of Surgery.25–27

Eligibility Criteria

The research question was formulated based on the Population, Intervention, Comparison, Outcome, and Study design strategy. Studies were included in the analysis if they met the following criteria:

  • Population: all patients undergoing ALPPS.
  • Intervention: any type of modified ALPPS.
  • Comparator: none in the pooled data analysis; conventional ALPPS in the comparative analysis.
  • Outcome: blood loss and operation time during the first and second stage of the procedure, hypertrophy rate, interval between the 2 stages, dropout rate, postoperative complications, and in-hospital/up to 90-day mortality.
  • Study design: studies of any design were eligible for inclusion.

Experimental studies, conference abstracts, reviews, common overviews, and case series with less than 5 cases were excluded. To prevent repeated inclusion of the same cases, all articles were cross-checked and double publications were excluded. No language restriction was applied.

Literature Search

PubMed, Web of Science, and Cochrane databases were systematically searched using a combination of the following search terms: “Associating liver partition and portal vein ligation for staged hepatectomy ” OR “ALPPS” OR “In-situ liver splitting” OR “In situ split” OR “In-situ parenchymal division” OR “Associating liver tourniquet and portal vein ligation for staged hepatectomy” OR “ALTPS” OR “Radio-frequency assisted liver partition and portal vein ligation” OR “RALPPS” OR “partial parenchymal transection” OR “laparoscopic microwave ablation and portal vein ligation for staged hepatectomy.” The search was not restricted by year of publication and the last search was performed in May 2022. The reference lists of the retrieved articles were screened for additional relevant studies.

Study Selection and Data Extraction

Based on the predefined Population, Intervention, Comparison, Outcome, and Study criteria, all titles and abstracts were independently screened by 2 authors (S.S. and A.H.). Eligible full-text articles were then independently reviewed by 2 authors (A.R. and A.D.M.) for inclusion and data extraction. Any disagreement was resolved by the first and senior authors (E.K. and A.M.). Data extracted were type of study, country, sample size, indication of surgery, type of modified ALPPS, operation time and blood loss during each stage, hypertrophy rate, interstage interval, dropout rate, type of hepatectomy, complications, and mortality.

Definition of Extracted Data

Preoperative and First-Stage Outcomes. 

Indication for surgery was either primary or secondary liver tumors. Any modification to the conventional ALPPS technique was defined as modified ALPPS. Intraoperative blood loss and operation time during the first stage of the ALPPS procedure were also analyzed.

Interstage Outcomes. 

We extracted the interstage FLR hypertrophy rate, which was defined as ([FLR before the second stage–FLR before the first stage]/total liver volume) × 100. We also recorded the interstage interval, which was the time between the first and second stages of the ALPPS. The rate of major complications (defined as ≥3a complications based on the Clavien-Dindo classification) during the interstage interval was also extracted.28 Dropout was defined as a failure to complete the second stage of the hepatectomy because of insufficient FLR hypertrophy, complications, or mortality.

Second-Stage Outcomes. 

Intraoperative blood loss and operation time during the second stage of the procedure were quantified in patients undergoing conventional and modified ALPPS techniques. The surgical strategy was classified as right/left hemihepatectomy or right/left extended hepatectomy.

Post Second-Stage Outcomes. 

Overall complications (defined as any type of complication) and major complications (defined as above) occurring after the second stage were also extracted. Postoperative mortality was defined as all death events up to 90 days or in hospital after the ALPPS procedure.

Quality Assessment

The quality of comparative studies included in the double-arms meta-analysis was assessed by 2 independent reviewers (E.A. and S.A.-H.-A.-S.) using the methodological index for nonrandomized studies.29 Quality was determined based on 12 methodological index for nonrandomized studies items and was scored as 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate). The best total score was 24 for comparative studies. Studies with 12 or fewer points were considered to be at high risk of bias, studies with 13–18 points at intermediate risk of bias, and studies with 19 or more points at low risk of bias.30 The overall quality of the evidence for each outcome was also assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.31

Statistical Analysis

Review Manager (RevMan version 5.3.5; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Comprehensive Meta-Analysis software (Version 3; Biostat, Englewood, NJ) were used to perform meta-analyses. Because of expected clinical heterogeneity between the included studies, the random-effects model was used. Dichotomous data are presented as odds ratios (ORs) or event rate and continuous data as weighted mean differences (MDs). Summary effect measures are presented together with their corresponding 95% confidence intervals (CIs). The methods of Hozo et al32 were applied to estimate mean and SD values for studies that reported only medians and ranges. Heterogeneity was evaluated using the X2 test and I2 index. An I2 index between 50% and 75% indicated moderate heterogeneity and an I2 index of >75% indicated considerable heterogeneity. A P value <0.050 was considered significant in all analyses.

RESULTS

The systematic literature search yielded 1877 articles (Supplementary Figure 1, https://links.lww.com/AOSO/A185). After removing duplicates and screening the titles and abstracts, 76 articles were selected for full-text evaluation, 59 of which were excluded from further analysis because they did not include modified ALPPS, contained irrelevant or redundant information, duplicated a reported dataset, or did not sufficiently report the endpoints of interest. Seventeen studies reporting on 335 patients who underwent p-ALPPS, ALTPS, or RALPPS were included in the pooled data analysis.22,23,33–47 None of these compared conventional ALPPS with ALTPS, 1 compared conventional ALPPS with RALPPS, and 7 (including 215 patients) compared conventional ALPPS with p-ALPPS. These 7 studies were included in the comparative meta-analysis.

Qualitative Analysis

Table 1 depicts the details and characteristics of all included studies. In total, 17 studies were included in the meta-analysis. Seven of these articles were included in the single-arm and comparative meta-analysis; 5 were prospective studies and 2 were retrospective studies. In these 7 studies, 113 patients (52.55%) underwent conventional ALPPS and 102 patients (47.44%) underwent p-ALPPS. Ten studies on 233 patients were included in the pooled data analysis; 6 of these were retrospective and 4 were prospective. In total, 335 patients were included in pooled data analysis. The most common indication for ALPPS reported in the 17 included studies was colorectal liver metastasis (56.6% of patients). The most common types of hepatectomy were extended right hepatectomy (50.7%) and right hemihepatectomy (38.9%).

Table 1. - Details and Characteristics of Included Studies
Authors Study Type Centers Groups Sample Size Indications for ALPPS Type of Modified ALPPS Type of Hepatectomy
CRLM HCC CC Others RH LH ERH ELH
Robles et al, 22 2014 Retro Spain Modified 22 17 1 0 4 ALTPS 7 0 15 0
Alvarez et al, 33 2015 Pro Argentina Modified 21 19 3 2 6 p-ALPPS 8 0 20 1
Conventional 9
Gall et al, 23 2015 Pro United Kingdom Modified 5 5 0 0 0 RALPPS 5 0 0 0
Petrowsky et al, 34 2015 Retro Switzerland Modified 6 16 1 2 5 p-ALPPS 3 0 2 1
Conventional 18 ND
Cai et al, 35 2017 Retro China Modified 12 0 12 0 0 ALTPS 9 1 0 0
Chan et al, 36 2017 Pro China Modified 12 0 12 0 0 p-ALPPS ND
Conventional 13 0 13 0 0
Linecker et al, 37 2017 Pro Switzerland, Germany Modified 23 23 0 0 0 p-ALPPS 7 15
Conventional 22 22 0 0 0 4 18
Stavrou et al, 38 2017 Retro Germany Modified 25 19 0 3 3 p-ALPPS 2 0 19 0
Conventional 33 22 11 2 0 29 0
Wang et al, 39 2017 Pro China Modified 10 0 10 0 0 RALPPS 4 0 4 0
Jiao et al, 40 2019 Pro United Kingdom Modified 26 20 1 5 0 RALPPS 18 0 6 0
Kumar et al, 41 2019 Pro United Kingdom Modified 8 6 0 2 0 p-ALPPS ND
Truant et al, 42 2019 Retro France Modified 5 5 0 0 0 p-ALPPS ND
Rassam et al, 43 2020 Pro The Netherlands Modified 9 6 2 0 1 p-ALPPS 8 0 1 0
Conventional 12 11 0 0 1 7 0 5 0
Robles-Campos et al, 44 2020 Pro Spain Modified 40 ND ALTPS ND
Kong et al, 45 2021 Retro China Modified 45 10 31 4 0 RALPPS 14 0 21 0
Conventional 34 24 8 2 0 9 0 17 0
Li et al, 46 2021 Retro China Modified 60 13 44 3 0 p-ALPPS 32 0 28 0
Robles-Campos et al, 47 2021 Pro Spain Modified 6 6 0 0 0 p-ALTPS ND
Conventional 6 6 0 0 0
ALPPS indicates associating liver partition and portal vein ligation for staged hepatectomy; Pro, prospective; Retro, retrospective; HCC, hepatocellular carcinoma; CRLM, colorectal liver metastasis; CC, cholangiocarcinoma; RH, right hemihepatectomy; LH, left hemihepatectomy; ERH: extended right hepatectomy; ELH: extended left hepatectomy; ALTPS, associating liver tourniquet and portal vein ligation for staged hepatectomy; p-ALPPS, partial associating liver partition and portal vein ligation for staged hepatectomy; p-ALTPS, partial associating liver tourniquet and portal vein ligation for staged hepatectomy; RALPPS, radio-frequency assisted liver partition and portal vein ligation; ND, not defined.

Risk of Bias Assessment

The quality of included comparative studies is shown in Supplementary Table 1 (https://links.lww.com/AOSO/A185). Three studies scored low risk of bias and 4 studies judged moderate risk of bias. No studies included a prospective calculation of the sample size.

Quantitative Analysis

Pooled Data Analysis of Modified ALPPS

Seventeen studies involving 335 patients were included in the pooled data analysis; 175 patients underwent p-ALPPS, 74 patients underwent ALTPS, and 86 underwent RALPPS.

Intraoperative First Stage Outcomes. 

Nine studies reported blood loss in a total of 194 patients. The mean estimated blood loss was 267 ± 29 mL (95% CI, 210–324 mL; I2 = 87%; P < 0.001; Fig. 1A). Subgroup analysis showed that blood loss was 308 ± 47 mL in the ALTPS group, 228 ± 49 mL in the RALPPS group, and 259 ± 56 mL in the p-ALPPS group. Eight studies reported operation time in a total of 186 patients. The mean operation time was 166 ± 18 minutes (95% CI, 131–202 minutes, I2 = 95%; P < 0.001; Fig. 1B) and was longer for the ALTPS procedure (246 ± 96 minutes) than for the p-ALPPS (176 ± 30 minutes) and RALPPS (156 ± 24 minutes) procedures.

F1
FIGURE 1.:
Forest plots of intraoperative first-stage outcomes of modified ALPPS. Forest plots of pooled analysis of (A) blood loss and (B) operation time during the first stage of modified ALPPS.

Interstage Outcomes. 

Thirteen studies reported the major morbidity rate after the first stage. Major morbidity occurred in 25 of 255 patients (weighted incidence = 14%; 95% CI, 9%–22%; I2 = 33%; P = 0.107; Fig. 2A). The rate of major morbidity was higher in the ALTPS group (26%; 95% CI, 14%–44%) than in the p-ALPPS (11%; 95% CI, 5%–23%) and RALPPS (8%; 95% CI, 3%–17%) groups. Thirteen studies reported the FLR hypertrophy rate after the first stage in 281 patients (overall mean FLR hypertrophy rate: 65.2% ± 5%; 95% CI, 55%–75%; I2 = 95%; P < 0.001; Fig. 2B). The FLR hypertrophy rate was 68% ± 8% in the ALTPS group, 66% ± 10% in the RALPPS group, and 62% ± 8% in the p-ALPPS group. The mean interval between the 2 stages was 16 ± 1 days (95% CI, 14–17; I2 = 94%; P = 0.1; Fig. 2C). Fourteen studies reported the dropout rate in 303 patients after the first stage; the pooled dropout rate was 9% (95% CI, 5%–15%; I2 = 25%; P = 0.19; Fig. 2D) and subgroup analysis showed a higher dropout rate in the p-ALPPS group (10%; 95% CI, 4%–20%) and the RALPPS group (9%; 95% CI, 4%–20%) than in the ALTPS group (5%; 95% CI, 1%–25%).

F2
FIGURE 2.:
Forest plots of interstage outcomes of modified ALPPS. Forest plots of pooled analysis of interstage (A) major morbidity, (B) FLR hypertrophy, (C) interval duration, and (D) dropout rate for modified ALPPS.

Intraoperative Second-Stage Outcomes. 

Nine studies reported intraoperative blood loss during the second stage in 194 patients. The mean blood loss was 662 ± 51 mL (95% CI, 562–762; I2 = 68%; P = 0.001; Fig. 3A) and subgroup analysis showed that blood loss was 898 ± 472 mL in the ALTPS group, 691 ± 81 mL in the p-ALPPS group, and 637 ± 67 mL in the RALPPS group. The mean operation time was 225 ± 19 minutes (95% CI, 188–263; I2 = 97%; P < 0.001; Fig. 3B) and subgroup analysis revealed an operation time of 251 ± 34 minutes in the p-ALPPS group, 243 ± 46 minutes in the RALPPS group, and 204 ± 27 minutes in the ALTPS group.

F3
FIGURE 3.:
Forest plots of intraoperative second-stage outcomes of modified ALPPS. Forest plots of pooled analysis of (A) blood loss and (B) operation time during the second stage of modified ALPPS.

Post Second-Stage Outcomes. 

Twelve studies reported the overall complication rates and complications were observed in 160 of 260 patients (weighted incidence = 46%; 95% CI, 37%–56%; I2 = 61%; P = 0.003; Fig. 4A). The overall complication rate was higher in the p-ALPPS group (63%; 95% CI, 33%–85%) than in the RALPPS (53%; 95% CI, 31%–74%) and ALTPS (42%; 95% CI, 31%–53%) groups. Fourteen studies reported major complications in 73 of 281 patients (weighted incidence = 20%; 95% CI, 14%–26%; I2 = 65%; P < 0.001; Fig. 4B). An approximately twofold higher rate of major complications was reported in the p-ALPPS group (32%; 95% CI, 19%–48%) than in the RALPPS (16%; 95% CI, 9%–25%) and ALTPS (14%; 95% CI, 7%–26%) groups.

F4
FIGURE 4.:
Forest plots of post second-stage outcomes of modified ALPPS. Forest plots of pooled analysis of (A) overall complication rate, (B) major complication rate, and (C) in-hospital/up to 90-day mortality rates for modified ALPPS.

Fifteen studies on 307 patients reported in-hospital/up to 90-day mortality. Postoperative mortality was reported in 16 of 307 patients (weighted incidence = 7%; 95% CI, 4%–11%; I2 = 2%; P = 0.42; Fig. 4C) and subgroup analysis revealed a higher postoperative mortality rate in the ALTPS group (13%; 95% CI, 4%–36%) and p-ALPPS group (6%; 95% CI, 3%–12%) than in the RALPPS group (5%; 95% CI, 2%–13%).

Comparison of Modified and Conventional ALPPS

Seven studies on 215 patients were included in the comparative meta-analysis of partial versus conventional ALPPS. Six studies reported on the p-ALPPS procedure and 1 study on the partial Associating Liver Tourniquet and Portal vein ligation for Staged hepatectomy procedure. No study compared conventional ALPPS with ALTPS and only 1 study compared conventional ALPPS with RALPPS; therefore, we could not compare these modifications.

Intraoperative First-Stage Outcomes. 

Only 1 study reported intraoperative blood loss and operation time during the first stage.47 This study reported the lowest blood loss in the modified ALPPS group, although blood loss was not significantly different between groups. Operation time was significantly shorter in the modified ALPPS group (90 minutes) than in the conventional ALPPS group (135 minutes) (P = 0.023).

Interstage Outcomes. 

The rate of major morbidity after the first stage was reported in 146 patients from 4 studies. Major morbidity was reported in 10 of 84 patients (morbidity rate 11.9%) in the conventional ALPPS group and in no patients in the modified ALPPS group. However, there was no statistically significant difference in major morbidity between the 2 groups (OR, 5.22; 95% CI, 0.89–30.73; P = 0.07; Fig. 5A). Furthermore, major morbidity rates were not heterogeneous between studies (I2 = 0%).

F5
FIGURE 5.:
Forest plots comparing interstage outcomes between modified and conventional ALPPS. Forest plots comparing interstage (A) major morbidity, (B) FLR hypertrophy, (C) interval duration, and (D) dropout rate between modified and conventional ALPPS. df indicates degrees of freedom. IV, inverse variance; M-H, Mantel–Haenszel.

Three studies reported the FLR hypertrophy rate in 87 patients and found no statistically significant difference between groups (MD, –5.01; 95% CI, –19.16 to 9.14; P = 0.49; Fig. 5B), although there was considerable heterogeneity between studies (I2 = 64%). Two studies reported the interstage interval in 69 patients and the mean interval was 9.5 days lower in patients who underwent modified ALPPS than in patients who underwent conventional ALPPS (MD, 9.43; 95% CI, 3.29–15.58; P = 0.003; Fig. 5C). No heterogeneity between studies was found (I2 = 0%). Five studies reported the dropout rate in 173 patients and the mean dropout rate after the first stage was 4% after conventional ALPPS and 10.6% after modified ALPPS. However, this difference was not statistically significant (OR, 0.36; 95% CI, 0.10–1.25; P = 0.11; Fig. 5D). No heterogeneity between studies was found (I2 = 0%; P = 0.99).

Intraoperative Second-Stage Outcomes. 

Only 1 study reported intraoperative blood loss and operation time during the second stage.47 This study found lower blood loss in the modified ALPPS group than in the conventional ALPPS group, but this difference was not statistically significant.

Post Second-Stage Outcomes. 

Two studies reported the overall complication rate (n = 54) and 5 studies reported the major complication rate (n = 166) after the second stage. The overall complication rate was approximately 10-fold higher following conventional ALPPS (88.8%) than following modified ALPPS (40.7%) (OR, 10.10; 95% CI, 2.11–48.35; P = 0.004; Fig. 6A). However, the rate of major complications was not different between the 2 groups (OR, 1.04; 95% CI, 0.40–2.71; P = 0.93; Fig. 6B). Major complications occurred in 23% of patients in the conventional ALPPS group and in 20% of patients in the modified ALPPS group. There was no heterogeneity in overall complication rates and major complication rates between studies. Five studies reported postoperative in-hospital/up to 90-day mortality in 172 patients and the mortality rate was 3.7-fold higher in the conventional ALPPS group (20.4%) than in the modified ALPPS group (4%) (OR, 3.74; 95% CI, 1.36–10.26; P = 0.01; Fig. 6C). Heterogeneity was low between studies (I2 = 26%).

F6
FIGURE 6.:
Forest plots comparing post second-stage outcomes between modified and conventional ALPPS. Forest plots comparing (A) overall complication rate, (B) major complication rate, and (C) in-hospital/up to 90-day mortality rates between modified and conventional ALPPS. df indicates degrees of freedom. M-H, Mantel–Haenszel.

Quality of Evidence

According to the Grading of Recommendations Assessment, Development, and Evaluation approach, the overall certainty of evidence was low for interstage major morbidity, interval duration, dropout, overall complications, and in-hospital/up to 90-day mortality and very low for FLR hypertrophy and overall major complications. The present study has an evidence level of 3a according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence.

DISCUSSION

Techniques such as 2-stage hepatectomy and ALPPS have been introduced to improve liver resection outcome in patients with advanced liver tumors. Although ALPPS has numerous advantages, including better resection rates,48 it still has a high perioperative morbidity and mortality.49–51 Recent studies have highlighted the importance of an uneventful interstage phase for positive outcomes, forcing hepatobiliary surgeons to find better alternatives to the original technique.19 Numerous technical modifications have been made to the conventional ALPPS technique22,34,52 to reduce damage to the parenchyma and manipulation of the hepatic hilum with the goal of reducing problems in the interstage phase and improving post second-stage outcomes.53 In this meta-analysis, we investigated whether modified ALPPS improves perioperative outcomes compared with conventional ALPPS. Many modifications have been described in the literature, but there is still not enough published evidence to perform a meta-analysis of these new modifications. Furthermore, only p-ALPPS has been directly compared with the conventional technique.

Hypertrophy during the interstage phase was not lower following p-ALPPS than following conventional ALPPS. Reducing parenchymal damage and incomplete dissection of the vascular connection between the hepatic lobules in p-ALPPS has been shown to reduce hepatocyte proliferation and/or edema. However, Linecker et al20 showed that the FLR volume and hypertrophy rate are not correlated to morbidity and mortality after ALPPS. The present study suggests that modified ALPPS provides enough hypertrophy to prevent posthepatectomy liver failure and mortality. It has been suggested that modified ALPPS can increase the dropout rate because of inadequate hypertrophy between stages; however, the present meta-analysis revealed no significant difference in dropout after the first stage between the conventional and p-ALPPS groups. To accurately determine ALPPS success, the dropout rate should be interpreted in light of the overall mortality rate after the first and second stages of ALPPS, which was lower in the p-ALPPS group.

We also found that the overall complication rate was significantly lower during the second stage of p-ALPPS than during conventional ALPPS. In-hospital/up to 90-day mortality rates were also higher in the conventional ALPPS group than in the p-ALPPS group. These findings indicate that modifying the first stage so that it is less invasive improves the interval between stages, thereby improving ALPPS outcomes. However, it should be noted that some studies were conducted in high-volume centers with extensive experience in ALPPS surgery, and the mortality and complication rates reported in these studies were lower than the overall rates determined in this meta-analysis.54 These differences may also be due to patient selection, which can affect final patient outcomes.55 Linecker et al56 evaluated the world ALPPS registry and reported that a risk adjustment of patient selection and ALPPS technique reduced early mortality and major postoperative morbidity, both of which are considered standard outcome measures of major liver surgery. The authors concluded that ALPPS modifications could have been one of the most important factors in the reduction of mortality from 17% to 4% in 2015. This is in line with our findings that the mortality rate following p-ALPPS was fourfold lower than that following conventional ALPPS. Despite these remarkable results, there is still room for improvement in the procedure-related safety and oncological outcome of ALPPS.

There are some limitations to the present study. The main weakness are the diverse surgical indications, such as underlying liver disease, tumor stage, preoperative liver function, and extent of hepatectomy, which increased heterogeneity between studies. Some of the included studies showed temporal bias because the centers had started to perform modified ALPPS after using the conventional method. In 2 of the included studies, surgeons switched from conventional ALPPS to modified ALPPS, after which all patients were operated with modified methods. Six studies reported that they started with conventional ALPPS and then continued to use both methods. The remaining studies did not report on whether they continued to perform conventional ALPPS after modified techniques were introduced. Although initial experience with the conventional method may be an important source of bias, a study of 436 patients from the ALPPS registry showed that the improved outcome following modified ALPPS procedures is not exclusively a result of a potential learning curve bias from early cases.56 Furthermore, the included studies were all cohorts and comparative studies with a high risk of bias and none were randomized prospective trials. Another limitation is that no studies reported an intention-to-treat analysis to consider the effects of dropout and mortality on the ALPPS success rate. In addition, 3 studies did not report the dropout rates. The type of modification was also heterogeneous between studies. Furthermore, the negative resection margin (R0) was not compared between modified and conventional ALPPS in the included studies, so we could not include the rate of R0 resections in our meta-analysis. We were also not able to include blood loss and operation time during the first and second stages in our meta-analysis. Stavrou et al38 compared the clinical outcomes of ALPPS before and after a world expert meeting in Hamburg in 2015, and 3 of the 33 patients who underwent ALPPS before the meeting underwent partial transaction of the parenchyma. The results from these 3 patients could not be extracted and all 33 patients who underwent ALPPS before the meeting were assigned to the conventional ALPPS group.

In conclusion, minimizing the first stage of ALPPS did not decrease the hypertrophy rate before the second stage. The rate of overall postoperative morbidity and mortality was lower in the p-ALPPS group than in the conventional ALPPS group. Further well-designed and larger-scale randomized controlled trials with intention-to-treat analyses are needed to address the limitations of the present meta-analysis and to confirm superior outcomes of p-ALPPS compared with conventional ALPPS.

ACKNOWLEDGMENTS

E.K. involved in conception and design, data analysis and interpretation, article writing, and final approval of article. A.R. and S.A.-H.-A.-S. involved in collection and assembly of data, data analysis and interpretation, article writing, and final approval of article. A.D.M. involved in data analysis and interpretation, article writing, and final approval of article. E.A. involved in data analysis and interpretation, article writing, critical revision, and final approval of article. O.G. involved in article writing and final approval of article. A.H. and S.S. involved in collection and assembly of data, article writing, and final approval of article. S.A.D. involved in collection and assembly of data and final approval of article. A.N., M.G., G.G., R.R.-T., C.C., and K.H. involved in critical revision and final approval of article. P.P. involved in data analysis and interpretation, critical revision, and final approval of article. A.M. involved in conception and design, critical revision, and final approval of article.

REFERENCES

1. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149:713–724.
2. Nakanishi Y, Tsuchikawa T, Okamura K, et al. Risk factors for a high Comprehensive Complication Index score after major hepatectomy for biliary cancer: a study of 229 patients at a single institution. HPB. 2016;18:735–741.
3. Clavien P-A, Petrowsky H, DeOliveira ML, et al. Strategies for safer liver surgery and partial liver transplantation. NEJM. 2007;356:1545–1559.
4. Ferrero A, Viganò L, Polastri R, et al. Postoperative liver dysfunction and future remnant liver: where is the limit? World J Surg. 2007;31:1643–1651.
5. Coimbra FJF, Pires TC, da Costa Junior WL, et al. Advances in the surgical treatment of colorectal liver metastases. Rev Assoc Med Bras. 2011;57:215–222.
6. Earl TM, Chapman WC. Conventional surgical treatment of hepatocellular carcinoma. Clin Liver Dis. 2011;15:353–370, vii–x.
7. Kinoshita H, Sakai K, Hirohashi K, et al. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg. 1986;10:803–808.
8. Enne M, Schadde E, Björnsson B, et al. ALPPS as a salvage procedure after insufficient future liver remnant hypertrophy following portal vein occlusion. HPB. 2017;19:1126–1129.
9. Ulmer T, De Jong C, Andert A, et al. ALPPS procedure in insufficient hypertrophy after portal vein embolization (PVE). World J Surg. 2017;41:250–257.
10. Sparrelid E, Gilg S, Brismar TB, et al. Rescue ALPPS is efficient and safe after failed portal vein occlusion in patients with colorectal liver metastases. Langenbecks Arch Surg. 2017;402:69–75.
11. Hoekstra LT, van Lienden KP, Doets A, et al. Tumor progression after preoperative portal vein embolization. Ann Surg. 2012;256:812–817; discussion 817–818.
12. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255:405–414.
13. Li J, Girotti P, Königsrainer I, et al. ALPPS in right trisectionectomy: a safe procedure to avoid postoperative liver failure? J Gastrointest Surg. 2013;17:956–961.
14. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg. 2014;38:1510–1519.
15. Nadalin S, Capobianco I, Li J, et al. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons learned from 15 cases at a single centre. Z Gastroenterol. 2014;52:35–42.
16. Kremer M, Manzini G, Hristov B, et al. Impact of neoadjuvant chemotherapy on hypertrophy of the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy. J Am Coll Surg. 2015;221:717–728.e1.
17. Truant S, Scatton O, Dokmak S, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): impact of the inter-stages course on morbi-mortality and implications for management. Eur J Surg Oncol (EJSO). 2015;41:674–682.
18. Schadde E, Raptis DA, Schnitzbauer AA, et al. Prediction of mortality after ALPPS Stage-1. Ann Surg. 2015;262:780–785; discussion 785–786.
19. Linecker M, Kuemmerli C, Kambakamba P, et al. Performance validation of the ALPPS risk model. HPB. 2019;21:711–721.
20. Linecker M, Stavrou GA, Oldhafer KJ, et al. The ALPPS risk score. Ann Surg. 2016;264:763–771.
21. Machado MA, Makdissi FF, Surjan RC, et al. Transition from open to laparoscopic ALPPS for patients with very small FLR: the initial experience. HPB. 2017;19:59–66.
22. Robles R, Parrilla P, López-Conesa A, et al. Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. Br J Surg. 2014;101:1129–1134; discussion 1134.
23. Gall TM, Sodergren MH, Frampton AE, et al. Radio-frequency-assisted liver partition with portal vein ligation (RALPP) for liver regeneration. Ann Surg. 2015;261:e45–e46.
24. de Santibañes E, Alvarez FA, Ardiles V, et al. Inverting the ALPPS paradigm by minimizing first stage impact: the Mini-ALPPS technique. Langenbeck’s Arch Surg. 2016;401:557–563.
25. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA-Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–341.
26. Kalkum E, Klotz R, Seide S, et al. Systematic reviews in surgery—recommendations from the Study Center of the German Society of Surgery. Langenbecks Arch Surg. 2021;406:1723–1731.
27. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012.
28. Clavien PA, Barkun J, De Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250:187–196.
29. Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (MINORS): development and validation of a new instrument. ANZ J Surg. 2003;73:712–716.
30. de Vos-Kerkhof E, Geurts DH, Wiggers M, et al. Tools for ‘safety netting’in common paediatric illnesses: a systematic review in emergency care. Arch Dis Child. 2016;101:131–139.
31. Group GW. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
32. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:1–10.
33. Alvarez FA, Ardiles V, de Santibañes M, et al. Associating liver partition and portal vein ligation for staged hepatectomy offers high oncological feasibility with adequate patient safety: a prospective study at a single center. Ann Surg. 2015;261:723–732.
34. Petrowsky H, Györi G, de Oliveira M, et al. Is partial-ALPPS safer than ALPPS? A single-center experience. Ann Surg. 2015;261:e90–e92.
35. Cai X, Tong Y, Yu H, et al. The ALPPS in the treatment of hepatitis B-related hepatocellular carcinoma with cirrhosis: a single-center study and literature review. Surg Innov. 2017;24:358–364.
36. Chan AC, Chok K, Dai JW, et al. Impact of split completeness on future liver remnant hypertrophy in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in hepatocellular carcinoma: complete-ALPPS versus partial-ALPPS. Surgery. 2017;161:357–364.
37. Linecker M, Kambakamba P, Reiner CS, et al. How much liver needs to be transected in ALPPS? A translational study investigating the concept of less invasiveness. Surgery. 2017;161:453–464.
38. Stavrou GA, Donati M, Fard-Aghaie MH, et al. Did the international ALPPS meeting 2015 have an impact on daily practice the Hamburg Barmbek experience of 58 cases. Visc Med. 2017;33:456–461.
39. Wang Q, Yan J, Feng XB, et al. Safety and efficacy of radiofrequency-assisted ALPPS (RALPPS) in patients with cirrhosis-related hepatocellular carcinoma. Int J Hyperthermia. 2017;33:846–852.
40. Jiao LR, Fajardo Puerta AB, Gall TMH, et al. Rapid Induction of Liver Regeneration for Major Hepatectomy (REBIRTH): a randomized controlled trial of portal vein embolisation versus ALPPS assisted with radiofrequency. Cancers (Basel). 2019;11:302.
41. Kumar N, Duncan T, O’Reilly D, et al. Partial ALPPS with a longer wait between procedures is safe and yields adequate future liver remnant hypertrophy. Ann Hepatobiliary Pancreat Surg. 2019;23:13–19.
42. Truant S, El Amrani M, Baillet C, et al. Laparoscopic partial ALPPS: much better than ALPPS!. Ann Hepatol. 2019;18:269–273.
43. Rassam F, Olthof PB, van Lienden KP, et al. Comparison of functional and volumetric increase of the future remnant liver and postoperative outcomes after portal vein embolization and complete or partial associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Ann Transl Med. 2020;8:436.
44. Robles-Campos R, Navarro-Barrios A, Martínez-Caceres C, et al. The contribution of the deportalized lobe to liver regeneration in tourniquet-ALPPS. Ann Surg. 2020;271:e94–e96.
45. Kong YL, Xing Y, Li J, et al. Modified procedures for ALPPS based on a risk-reduced strategy: paralleled clinical evaluation at multiple institutions. Yonsei Med J. 2021;62:918–927.
46. Li J, Yang GS, Sun KJ, et al. Clinical evaluation of modified ALPPS procedures based on risk-reduced strategy for staged hepatectomy. Ann Hepatol. 2021;20:100245.
47. Robles-Campos R, Brusadín R, López-López V, et al. A new surgical technique variant of partial ALPPS (Tourniquet Partial-ALPPS). Ann Surg. 2021;273:e22–e24.
48. Sandström P, Røsok BI, Sparrelid E, et al. ALPPS improves resectability compared with conventional two-stage hepatectomy in patients with advanced colorectal liver metastasis: results from a Scandinavian multicenter randomized controlled trial (LIGRO Trial). Ann Surg. 2018;267:833–840.
49. Olthof PB, Coelen RJ, Wiggers JK, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB. 2017;19:381–387.
50. Figueras J, Belghiti J. The ALPPS approach: should we sacrifice basic therapeutic rules in the name of innovation? World J Surg. 2014;38:1520–1521.
51. Herman P, Krüger JAP, Perini MV, et al. High mortality rates after ALPPS: the devil is the indication. J Gastrointest Cancer. 2015;46:190–194.
52. Machado MAC, Makdissi FF, Surjan RCJAos. Totally laparoscopic ALPPS is feasible and may be worthwhile. Ann Surg. 2012;256:e13.
53. Cai Y-L, Song P-P, Tang W, et al. An updated systematic review of the evolution of ALPPS and evaluation of its advantages and disadvantages in accordance with current evidence. Medicine. 2016;95:e3941.
54. Wanis KN, Ardiles V, Alvarez FA, et al. Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy. Surgery. 2018;163:691–697.
55. Li J, Ewald F, Gulati A, et al. Associating liver partition and portal vein ligation for staged hepatectomy: from technical evolution to oncological benefit. World J Gastrointest Surg. 2016;8:124–133.
56. Linecker M, Björnsson B, Stavrou GA, et al. Risk adjustment in ALPPS is associated with a dramatic decrease in early mortality and morbidity. Ann Surg. 2017;266:779–786.
Keywords:

conventional ALPPS; meta-analysis; modified ALPPS

Supplemental Digital Content

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.