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Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study
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https://doi.org/10.1016/j.hpb.2020.01.010
ORIGINAL ARTICLE
Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study Federico Tomassini1, Yves D’Asseler2, Michael Linecker3, Mariano C. Giglio4, Carlos Castro-Benitez5, Stéphanie Truant6, Rimma Axelsson7, Pim B. Olthof8,9, Roberto Montalti4,10, Matteo Serenari11, Thiery Chapelle12, Valerio Lucidi13, Ernesto Sparrelid14, René Adam5, Thomas Van Gulik8, François-René Pruvot6, Pierre-Alain Clavien3, Dario Bruzzese10, Karen Geboes15 & Roberto I. Troisi1,4 1
Department of Human Structure and Repair, Ghent University Faculty of Medicine, 2Department of Nuclear Medicine, Ghent University Hospital, C Heymanslaan 10, B-9000 Ghent, Belgium, 3Swiss HPB Center, University Hospital Zurich, Switzerland, 4Department of Clinical Medicine and Surgery, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, Italy, 5University Paris Sud, Unité INSERM 935, Paul Brousse University Hospital, F-94804 Villejuif, 6Department of Digestive Surgery and Transplantation, Lille University Hospital, F-59037 Lille, France, 7Karolinska University Hospital, Imaging and Function, Medical Radiation Physics and Nuclear Medicine, Karolinska Institutet, Department of Clinical Science, Intervention and Technology, Division of Radiology, Stockholm, Sweden, 8Department of Surgery, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, 9 Department of Surgery, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands, 10Department of Public Health, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, 11Department of Medical and Surgical Sciences, University of Bologna, Italy, 12Department of Hepatobiliary, Transplantation, and Endocrine Surgery, Antwerp University Hospital, Antwerp, 13Department of Digestive Surgery, Unit of Hepato-Biliary Surgery and Transplantation, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, 14Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, and 15Department of Gastroenterology-Digestive Oncology, Ghent University Hospital, C Heymanslaan 10, 9000 Ghent, Belgium
Abstract Background: Post hepatectomy liver failure (PHLF) after ALPPS has been related to the discrepancy between liver volume and function. Pre-operative hepatobiliary scintigraphy (HBS) can predict postoperative liver function and guide when it is safe to proceed with major hepatectomy. Aim of this study was to evaluate the role of HBS in predicting PHLF after ALPPS, defining a safe cut-off. Methods: A multicenter retrospective study was approved by the ALPPS Registry. All patients selected for ALPPS between 2012 and 2018, were evaluated. Every patient underwent HBS during ALPPS evaluation. PHLF was reported according to ISGLS definition, considering grade B or C as clinically significant. Results: 98 patients were included. Thirteen patients experienced PHLF grade B or C (14%) following ALPPS-2. The HBS and the daily gain in volume (KGRFLR) of the future liver remnant (FLR) were significantly lower in PHLF B and C (p = .004 and .041 respectively). ROC curves indicated safe cut-offs of 4.1%/day (AUC = 0.68) for KGRFLR, and of 2.7 %/min/m2 (AUC = 0.75) for HBSFLR. Multivariate analysis confirmed these cut-offs as variables predicting PHLF after ALPPS-2. Conclusion: Patients presenting a KGRFLR 4.1%/day and a HBSFLR 2.7%/min/m2 are at high risk of PHLF and their second stage should be re-discussed. Received 19 November 2019; accepted 19 January 2020
Correspondence Roberto I. Troisi, Department of Clinical Medicine and Surgery, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, Italy. Tel: +39 081 7462732. E-mail: [email protected]
Introduction Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to extend resectability due to its unique capacity to prompt a faster regeneration of the future
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liver remnant (FLR), compared with conventional two-stage procedures.1 However, the initial enthusiasm regarding this technique has been counterbalanced by the high morbidity and mortality rates reported in the first series.2
© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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FLR volumetric analysis still represents the standard assessment to reduce the risk of PHLF after major hepatectomy.3,4 However, additional factors besides volume influence quality and function of the FLR.5– 7 During the last years, several risk scores for patient selection have been proposed to improve ALPPS safety. Recently, a risk score on futile ALPPS to predict 90-day mortality before stage-1 and -2 has been proposed.5,8 Regarding indications, several studies have demonstrated that ALPPS for colorectal liver metastases (CRLM) is accompanied by minor morbidity and better results.2,7 –13 The recent Scandinavian LIGRO trial showed an overall resectability rate of 92% for CRLM treated by ALPPS, compared to only 57% for conventional two-stage procedure, with lower 90-days mortality and comparable morbidity.14 Nevertheless, despite efforts to select the best candidates, the incidence of post-hepatectomy liver failure (PHLF) after ALPPS still ranges between 7 and 30%, representing the main cause of 90-day mortality.5,10,14– 20 The occurrence of PHLF despite apparently adequate FLR has been explained by the absence of reciprocity between increase in volume and function.15,21 For this reason the functional assessment of the FLR using hepato-biliary-scintigraphy (HBS) has been introduced in the preoperative work-up.15,22–24 In this context, HBS based on administration of 99mTcmebrofenin is seen as a valuable method to predict liver function in extended hepatectomy. De Graaf et al. identified a mebrofenin uptake inferior to 2.69%/min/m2 as predictive of PHLF after major liver resection.25,26 However, this evaluation was based on a single center experience regarding 55 patients, which did not include two-stage procedures. As compared with indocyanine green, the advantage of HBS is represented by the possibility to obtain quantitative information on the segmental liver function, providing visual information about liver segments with inferior function, crucial to the riskassessment before major or two stage hepatectomies.27 The present study has been particularly designed to identify and evaluate the role of HBS in predicting PHLF after ALPPS, with the attempt to define a safe cut-off value for HBS. Liver volumetry, functional assessment with HBS and analysis of the kinetic growth rate (KGR) were therefore evaluated and compared in a cohort of patients undergoing ALPPS in centers who had routinely adopted HBS and were contributing to the ALPPS Registry.
Methods An investigator-driven multicenter study involving 9 highly specialized European hepatobiliary units evaluating the liver function through HBS was approved by the ALPPS Registry (www.alpps.net). The Internal Review Board of the principal investigators from the Ghent University Hospital approved this study (BE670201421317).
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Patients’ selection and data collection All patients selected for an ALPPS procedure or undergoing a rescue-ALPPS (ALPPS performed after failed portal vein embolization or ligation) between 2012 and 2018, were retrospectively evaluated. Patients were selected on an “intention-totreat” basis, including also those who failed to complete the planned two-stage procedure. Patients included were evaluated by liver volumetric and functional assessment by HBS. Every participating center decided independently to perform an ALPPS following its own local policy. Pre-stage-1 and inter-stage HBS evaluation were considered; in the case of a patient received multiple HBS over time, the one right before ALPPS-2 was considered. Demographic data, indications for ALPPS, operative and post-operative data were recorded and retrospectively analysed. Data collection was finalized on May 2018. Final assessment following reading of the DICOM files containing dynamic data acquisition was completed by January 2019. This acquisition was needed in order to make a uniform assessment of the HBS, avoiding center variation in calculations. Liver volumetry Liver volumetric analysis was based on an Angio-CT volumetry. For Rescue ALPPS, the CT volumetry performed before ALPPS-1 was recorded. Total liver volume (TLV) and FLR volumes were calculated, as well as the ratio between FLR and body weight (FLR/BW) and the FLR/TLV. Variations of the FLR volume after ALPPS-1 were expressed as absolute difference (FLRinterstage − FLRbaseline) and percentage increase, calculated as: (FLRinterstage − FLRbaseline)/FLRbaseline. The kinetic growth rate of the FLR (KGRFLR) was calculated as the mean daily volumetric increase, expressed as volume percentage increase/day (%/day) from ALPPS-1 (even for rescue-ALPPS), or from PVE when performed post-operatively, to pre-ALPPS-2 radiological assesment. Standard Total liver volume (sTLV) was calculated using the Vauthey formula.28 Centralization of the HBS data and analysis All HBS data coming from each center were sent to the Department of Nuclear Medicine of the Ghent University Hospital and analysed by one of the authors (YD), who was blinded to clinical outcomes, accordingly with the aim to standardize the methodology eventually minimizing bias of interpretation across institutions. Image processing was performed on Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden). Geometric mean images were calculated and region of interest were drawn on the liver and heart. Time activity curves were obtained for liver, blood pool (based on the heart region) and total activity within the field of view. Time activity curves were then used to calculate liver uptake rate (expressed as %/min) between 150 and 350 s after the injection, according to Ekman et al.29 Liver uptake rate was corrected for the body surface area, generating corrected uptake rates in %/min/m2. Finally, function
© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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of the FLR was calculated as a fraction of the corrected uptake of the remaining segments. The HBS of the total liver volume and of the FLR were analysed.30 Variations of the HBSFLR were expressed as absolute difference (HBSinterstage − HBSbaseline) or percentage increase [(HBSinterstage − HBSbaseline)/HBSbaseline] after ALPPS-1. Peri-operative outcomes Data on intraoperative and 90-day morbidity and mortality were recorded. Complications were classified according to the Clavien-Dindo classification.31 PHLF was reported according to the definition of the International Study Group of Liver Surgery.32 PHLF grade B or C were considered as clinically significant.33
inadequate regeneration and left hepatic vein thrombosis with PHLF after ALPPS-1. Moreover two PHLF Grade B were observed after ALPPS-2. Patients’ characteristics are depicted in Table 1. All patients affected by CRLM received upfront chemotherapy. ALPPS was performed as first choice procedure in 75 patients (76%), with PVE-ALPPS performed in five patients. The remaining 23 patients (23%) underwent rescue ALPPS after failed portal vein embolization or ligation. Before ALPPS-1, the median FLR/TLV was 24% (19–29), FLR/sTLV was 26% (19–29) and the FLR/BW was 0.5 (0.4–0.6). The median FLR function (HBSFLR) was of 2.1%/min/m2 (1.7–2.7). Additional volumetric and functional data are shown in Table 2. Table 1 Age, BMI, operative time and estimated blood losses are
Statistical analysis Numerical variables were synthesized using median and interquartile range. Categorical variables were described as frequency and percentage. Pearson’s correlation coefficient r was used to measure the correlation between numerical variables. Wilcoxon’s and Mann–Whitney’s test were used for assessing within and between group differences. The area under a Receiving Operator Characteristics (ROC) curve (AUC) was used to estimate the accuracy of variables in discriminating PHLF Grade B/C. The optimal cut-off values were chosen by maximizing the Youden’s index. Univariable analyses were performed considering the defined cut-offs and other risk factors for PHLF, as gender, age, ASA Score and CRLM. Multivariable logistic model was finally built by including, as explicative factors, those significantly associated with outcome in univariate analysis. However, due to the small numbers of observed events, the multivariable model should not be intended as a clinical prediction model but was built to confirm the independent association between KGRFLR, HBSFLR and PHLF. For the same reason, interactions between independent variables were not tested in the multivariable model. Fagan’s nomograms were elaborated to show how positive or negative test change the probability of developing PHLF after ALPSS-2.34 The pre-test probability of developing PHLF corresponds with the prevalence of PHLF within the study (14%). A p-value .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Mac (Version 20.0. Armonk, NY: IBM Corp.). STATA Statistical software (StataCorp. 2017. Release 15. College Station, TX: StataCorp LLC) was used for Fagan’s nomograms.
presented as median (interquartile range)
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n (%)
Age (years)
62 (55–69)
Sex Male
59 (60)
Female a
39 (40) 2
BMI (kg/m )
26 (22–28)
ASA scoreb I/II
76 (78)
III
22 (22)
Indication for ALPPSc Colorectal liver metastases
80 (82)
Hepatocellular carcinoma
7 (7)
Intra-hepatic cholangiocarcinoma
3 (3)
Hilar cholangiocarcinoma
3 (3)
Other
5 (5)
Intraoperative characteristics Operative time (min) ALPPS 1
337 (269–410)
ALPPS 2
230 (100–300)
Estimated blood losses (ml) ALPPS 1
500 (300–900)
ALPPS 2
400 (200–725)
Associated procedures on the FLR (%) Wedge resection + Microwave ablation
Results Patients’ characteristics and ALPPS stage-1 A total of 130 patients receiving ALPPS were collected and evaluated. Centralization of the HBS was feasible in 98 patients that were included in the analysis, while the remaining 32 were excluded due to incomplete HBS data. In these excluded patients ALPPS-2 was performed in all but two, due to respectively
Patients’ characteristics (n [ 98)
25 (25) 8 (8)
Multiple wedge resection
5 (5)
+ Microwave ablation
1 (1)
Radiofrequency ablation
1 (1)
Microwave ablation
2 (2)
Caudatectomy
1 (1)
a
Body Mass Index. American Society of Anesthesiologists Score. c Associating Liver Partition and Portal vein ligation for Staged hepatectomy. b
© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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Table 2 Volumetric and functional variation observed between
ALPPS-1 and -2 Before ALPPS-1
Before ALPPS-2
p
1637 (1472–1865)
1774 (1548–2192)
<.001
FLR (ml)
396 (300–474)
593 (503–708)
<.001
FLR/TLV (%)
24 (19–29)
32 (27–38)
<.001
FLR/sTLV (%)
26 (19–29)
35 (31–43)
<.001
TLV (ml)
FLR/BW
0.5 (0.4–0.6)
0.8 (0.6–0.9)
<.001
HBSTLV (%/min/m2)
8.8 (7–10)
9.0 (7–11)
.512
HBSFLR (%/min/m2)
2.1 (1.7–2.7)
2.7 (2–4)
<.001
Values are presented as median (interquartile range). p-value .05 statistically significant (in bold).
A total of 54 (55%) patients underwent a right trisectionectomy. Other liver resections planned were: right hepatectomy (n = 40, 41%), left trisectionectomy (n = 3, 3%) and one left hepatectomy. After ALPPS-1, 52 patients (53%) experienced complications. According to Clavien-Dindo classification, 13 patients (13%) had a grade 3a complication. Two patients (2%) developed PHLF grade C after ALPPS-1. One died after 7 days (pre-operative HBSFLR of 1.3%/min/m2). In the second patient, ALPPS-2 was performed after 55 days, but the patient required urgent liver transplantation after 6 days. Volumetric and functional variations between ALPPS stage-1 and stage-2 CT-volumetry before ALPPS-2 was performed after a median of 7 days (6–13) while HBS after a median of 8 days (6–13). In five patients incomplete data regarding pre-ALPPS-1 volumetry were collected, while the pre-ALPPS-2 total liver volume was missing in 3 patients. Changes in liver volume and function following ALPPS-1 are shown in Table 2. The FLR volume increased by 52% (26–79), with a KGRFLR of 5.9%/day (3–11). The FLR function increased by 22% (1–51), with a median HBSFLR of 2.7%/min/m2 (2–4). The increase in volume after ALPPS-1 showed a correlation with the increase in function (r = 0.4, p < .001, R2 = 0.15). Moreover, smaller baseline FLR (ml) presented faster regeneration (r = −0.5, p < .001, R2 = 0.25). Liver fibrosis and/or chemotherapy injury of the FLR was observed in 26 patients (24%) presenting a median HBSFLR of 2.9%/min/m2 (2–4) with no significant difference from patients without histological anomalies (2.8%/min/m2 (2–3); p = .534). Outcomes after ALPPS stage-2 The second stage was performed in 92 patients (94%) after a median period of 10 days (7–15) from ALPPS-1; 2 days (1–4) from the CT-volumetry and 1 (1–4) from HBS. Six patients (6%) failed to proceed to the second stage due to post-stage-1 death (n = 1), insufficient FLR growth (n = 3), and tumour progression (n = 2).
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Postoperative hospital stay was of 15 days (8–23). Fifty-five patients (60%) had postoperative complications, with 31 patients (34%) developing severe complications (ClavienDindo 3a). PHLF grade B occurred in 6 patients (7%), while 7 developed PHLF grade C (8%). In patients underwent ALPPS-2 the minimum FLR/sTLV was of 20%, while the minimum HBSFLR of 0.6%/min/m2 was recorded in a patient experienced PHLF grade C and received liver transplantation, still alive at 36 months follow-up. Ten patients (11%) died within 90-days, due to PHLF grade C (n = 6), tumour progression (n = 3), and sepsis from an intestinal fistula (n = 1). Predictors of liver failure after ALPPS stage-2 Thirteen patients (14%) developed clinically significant PHLF after ALPPS-2. At pre-ALPPS-2 evaluation, these patients had lower FLR function (HBSFLR, p = .004) and slower FLR regeneration (KGRFLR, p = .041) than patients without clinically significant PHLF. On the contrary, there was no significant difference in FLR volume (FLR/TLV, FLR/sTLV and FLR/BW) between these groups of patients (Table 3). Receiver Operating Characteristic (ROC) curve analysis confirmed the prognostic role of FLR function in discriminating clinically significant PHLF (AUC = 0.75; 95% CI: 0.61–0.88) with a cut-off value of 2.7%/min/m2 (sensitivity 0.85 and specificity 0.55 – Fig. 1a). KGRFLR showed a slight lower discriminatory accuracy with an AUC equal to 0.68 (95% CI: 0.50–0.85), with a cut-off value of 4.1%/day (sensitivity 0.62 and specificity 0.73 – Fig. 1a). The subgroup analysis of the KGRFLR excluding rescue ALPPS confirmed a slower regeneration in patients developed clinically significant PHLF (5.5 vs 2.1%/day, p = .023) with the ROC curve analysis pointing out the same cut-off value of 4.1%/day (AUC = 0.75; 95% CI: 0.62–0.91, sensitivity 0.75 and specificity 0.69). Table 3 Volumetric and functional differences observed in patients
experienced PHLF Grade B and C after ALPPS-2 p
PHLF None–Grade A Grade B–C FLR (ml)
602 (505–705)
653 (496–769)
.520
FLR/TLV (%)
33 (28–39)
31 (24–43)
.508
FLR/sTLV (%)
35 (32–43)
39 (31–44)
.692
FLR/BW
0.78 (0.65–0.94) 0.82 (0.64–0.94) .779
FLR increase (ml)
198 (134–299)
FLR increase (%)
54 (34–80)
43 (6–81)
.378
KGRFLR (Volume gain/day) (%)
6.4 (3–11)
2.2 (1–7)
.041
2.8 (2.3–3.6)
2 (1.4–2.6)
.004
HBSFLR (%/min/m2) 2
170 (33–350)
.564
HBSFLR increase (%/min/m ) 0.4 (0.1–1.2)
0.1 (−0.1 to 0.8) .231
HBSFLR increase (%)
5 (−11 to 32)
24 (2–51)
.192
Values are presented as median (interquartile range). p-value .05 statistically significant (in bold).
© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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Figure 1 a: ROC curve of factors influencing PHLF after ALPPS-2. b: Association between the defined cut-off for HBSFLR and daily volume gain
in predicting PHLF. c: Fagan’s nomograms showing as negative (A) or positive (B) tests change the probability of a developing liver failure following ALPPS 2
The association between KGRFLR and HBSFLR and the occurrence of PHFL grade B/C is shown in Fig. 1b. Among 14 patients showing both low function (HBSFLR < 2.7%/min/m2) and slow regeneration (KGRFLR < 4.1%/day) clinically significant PHLF was observed in 7. Moreover, the majority (7/13) of patients developing clinically significant PHLF showed both low function and regeneration. Only one patient with PHLF was observed in the higher function and growth quadrant (1/29, p < .001). This 58 y.o. male, defined as ASA III and affected by CRLM, received a challenging right trisectionectomy with an EBL of 5600 ml during ALPPS-1. Following ALPPS-2, performed one week from the first stage with a HBSFLR of 2.9%/min/m2 and a KGRFLR of 9.4%/day (CT volumetry performed at 6 days), the patient developed pulmonary embolism and subsequent PHLF Grade B with discharge after 25 days. Fagan’s nomograms show how the probability of a developing liver failure following ALPPS-2 changes after positive or negative tests (Fig. 1c). At multivariate analysis, in addition to the low function and slow regeneration of the FLR, indication for surgery other than CRLM was associated with the occurrence of clinically significant PHLF (Table 4).
Discussion This study found HBS to be more accurate than liver volumetry in predicting PHLF following ALPPS stage 2. Additionally, the KGRFLR has been found to be indicative of the risk of PHLF. The importance of performing functional evaluation of the liver through HBS before extended hepatectomy, has been highlighted by several studies.15,24,35–37 The result of the ROC curve regarding HBS confirmed the cut-off value of 2.7%/min/m2 pointed out by Graaf et al. on a cohort of patients undergoing major hepatectomy.25 Moreover, a similar HBS cut-off value of 2.3%/min/m2 was previously identified as an accurate selecting tool to predict PHLF grade B/C after PVE.38,39 Of note, in the present study, the increase in volume of the FLR correlated with its increase in function. Nevertheless, the current
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results do not show that volume and function are equivalent parameters. Indeed, despite a correlation showing that in most patients the volumetric increase corresponds to some increase in function, the low R2 indicates that a high variability of data exists, with patients having a considerable increase in the FLR volume but only a modest increase in function, and vice versa. This observation confirms that liver volume is not a reliable predictor of liver function, supporting the necessity of a functional assessment as recently reported in a multicenter study.15 Moreover, in this series, liver fibrosis and/or chemotherapy injury of the FLR didn’t affect the functional regeneration process. The present study also points out the importance of the velocity of growth of the FLR during ALPPS. Shindoh et al. first focused on the KGRFLR after portal vein embolization, identifying it as a more accurate predictor of PHLF than liver volume. In particular, a KGRFLR >2%/week was associated to a lower risk of PHLF.40 On this background, the current study focused on the KGRFLR. As ALPPS triggers faster regeneration than portal vein embolization, volume gain was calculated per day, rather than per week.41 The results show that patients with slower volumetric regeneration (<4.1%/day), presented higher incidence of PHLF after ALPPS-2. This result confirms the importance of KGRFLR in the ALPPS setting, suggesting the paradigm that “faster regeneration” could be synonymous of “better regeneration”. Kambakamba et al. also focused on KGRFLR in ALPPS. In this study conducted on 36 patients, the incidence of PHLF was 0% in those having a FLR/TLV >30% and a KGR 6%/day.41 These results were based on a single center experience where volumetric assessment was routinely performed within one week after ALPPS-1. However, kinetic growth of the liver is not linear and the time interval assessed for calculation is crucial. In the current multicenter study, volumetry was performed after a median of 7 days presenting anticipated centres’ variations. This lack of standardization is certainly a limit, making difficult the comparison with different cut-offs described in literature. Additional studies focusing on KGRFLR are necessary to standardize the definition of the time interval to use for calculation.
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Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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Table 4 Logistic regression analysis of the predictive variables of PHLF Grade B and C
Variables
PHLF B and C
Univariate analysis
n
p
OR
95% CI
.186
0.37
0.85–1.65
.480
0.62
0.17–2.29
.456
0.62
0.17–2.18
.006
5.91
1.6–21
.335
0.55
0.16–1.83
.427
0.61
0.18–2.03
.041
4.3
1.1–17.09
.713
0.6
0.06–6.22
.235
0.4
0.1–1.5
.013
0.14
.020
0.2
Age (y.o.) 73
10/81
>73
3/11
ASA score I/II
9/71
III
4/21
Gender Male
9/55
Female
4/37
CRLM Yes
7/76
No
6/16
FLR/BW <0.8
5/47
0.8
8/45
Multivariate analysis p
OR
95% CI
.021
6.4
1.4–30
.110
0.2
0.05–1.3
0.03–0.6
.023
0.13
0.02–0.75
0.7–8
.015
0.15
0.03–0.66
Complications ‡3a after ALPPS-1 Yes
3/10
No
10/82
FLR/TLV (%) <25
4/11
25
9/78
FLR/sTLV (%) <25
1/5
25
12/87
Rescue-ALPPS Yes
5/22
No
8/70 2
HBSFLR (%/min/m ) <2.7
11/45
2.7
2/47
KGRFLR (%) <4.1
8/28
4.1
5/59
p-value .05 statistically significant (in bold).
In line with the current findings, Chiba et al. recently showed that KGRFLR after ALPPS-1 was inversely correlated to initial FLR volumes, with smaller FLR growing more rapidly.22 This paradigm has been described by the authors’ previous experience evaluating hemodynamic stress in ALPPS: smaller FLR result in better volume regeneration, possibly related to the higher portal perfusion recorded at the end of stage-1.6 Therefore, in patients with very small FLR volume before ALPPS-1, a functional assessment with HBS could help in identifying those that will significantly respond to surgical interventions of volume enhancement. HPB xxxx, xxx, xxx
In the present study, both HBSFLR and KGRFLR predicted with good accuracy PHLF and is therefore necessary to understand if these two tests are complementary and they must be performed both. This question is of value, as data on KGRFLR are immediately available at the time of volumetric assessment, while HBS requires specific expertise and logistics, eventually leading to additional costs. As observed in Fig. 1b, using the abovediscussed cut-offs for HBSFLR and KGRFLR different groups of patients at risk of PHLF were selected (those on the left and below the vertical and horizontal lines, respectively). However, in both groups, a number of false positive examinations (patients
© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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who will not develop PHLF) do exist. Using both criteria (i.e. slow regeneration and low function) allows identifying a group of patients (left-bottom part of the scatter plot) in whom the incidence of PHLF becomes very high. The Fagan’s nomograms confirm the highest probability of developing PHLF after ALPPS2 in this group of patients with a clear graphic expression. As consequence, HBSFLR and KGRFLR analysis work in synergistic way, by enhancing the specificity of the other. On this background, patients having both slow regeneration and low function of the FLR at the inter-stage assessment, should be thoroughly scrutinized and their stage-2 eventually postponed after reevaluated a second time. Other risk factors were analysed at the univariate analysis, as advanced age, gender, ASA score, FLR/BW <0.8, FLR/sTLV <25%, rescue ALPPS and complications defined as 3a after ALPPS-1, but were not found to be predictive factors for PHLF Grade B/C after ALPPS-2. However TLV/FLR <25%, calculated by CT-volumetry before ALPPS-2, was indicated as risk factor for PHLF at the univariate analysis but was not confirmed at the multivariate. Indication for ALPPS other than CRLM was confirmed as risk factor for PHLF.7 As shown in the first report of the International ALPPS Registry, treatment of CRLM is associated with the lowest morbidity and mortality rates compared with other malignancies.2 ALPPS has clearly expanded the treatment options and resectability for patients with CLRM once defined as unresectable (bilobar diffusion and small FLR), representing nowadays a safe and valid chance for cure. This study has some limitations. Due to the retrospective fashion of the study, the decision to proceed or not to ALPPS-2 according to the calculated FLR, liver function and/or other different parameters (as FLR/BW, FLR/TLV, FLR/sTLV and patients’ clinical condition) was taken independently by every participating center. Moreover, volumetric analysis was not centralized, but performed in each participating center according to local protocols. Hence, some inter-center variations in volumetric calculations exist, due to the use of different softwares and protocols. The KGRFLR as risk factor for PHLF is an important additional finding, which confirms previous studies. However, in the present study no patients were effectively managed according to the KGRFLR value, which was not used to decide whether or not to proceed to ALPPS-2. Moreover, the heterogeneity of the study population with both PVE-ALPPS and rescue ALPPS included, represents another limit due to the difficulties to define the time interval for KGRFLR calculation. Therefore, while this parameter is very promising, further studies are needed to confirm its value prior to take clinical decisions based on it. Finally, the small number of PHLF B or C, prevented us from developing a clinical prediction model to assess the predictive performance of both KGRFLR and HBSFLR. In conclusion, during ALPPS inter-stage, analysis of the kinetic growth rate and function of the FLR are more accurate than liver volume alone in predicting the risk of PHLF. Two cut-offs for both analyses were identified. In particular, lower incidence of PHLF
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was observed in patients with HBSFLR 2.7%/min/m2 (4.3%, n = 2/47) while in KGRFLR 4.1%/day the incidence was of 8.5% (n = 5/59). Moreover, considering the two parameters together, patients presenting slow growth (<4.1%/day) and limited function of the FLR, calculated as an HBS uptake <2.7%/min/m2, have to be considered at high risk (50%) of PHLF and should be rediscussed and wait to proceed to ALPPS-2. These two analyses, especially HBS, should be considered in the decisional work-up during ALPPS being an useful tool to define the preoperative functional liver assessment before major hepatectomy. Author’s contributions FT: acquisition of data, writing the manuscript. MCG: data collection, statistical analysis. YD: centralisation of HBS DICOM data and analysis. DB: Statistical analysis. MCG, ML, CCB, ST, RA, PO, RM, LC, TC, VL, ES, RA, TVG, RFP, PAC, KG: critical revision and data interpretation. RIT: study conception and design, critical revision, supervision. Funding The authors received no funding for this research and no competing financial interest. Conflicts of interest None to declare. References 1. Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA et al. (2012) Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2staged extended right hepatic resection in small-for-size settings. Ann Surg 255:405–414. 2. Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R et al. (2014) Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 260:829–836. discussion 36–8. 3. Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore SJ, Edinburgh Liver S et al. (2005) The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 54:289–296. 4. Hammond JS, Guha IN, Beckingham IJ, Lobo DN. (2011) Prediction, prevention and management of postresection liver failure. Br J Surg 98: 1188–1200. 5. Linecker M, Stavrou GA, Oldhafer KJ, Jenner RM, Seifert B, Lurje G et al. (2016) The ALPPS risk score: avoiding futile use of ALPPS. Ann Surg 264:763–771. 6. Tomassini F, D’Asseler Y, Giglio MC, Lecluyse C, Lambert B, SainzBarriga M et al. (2019) Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study. HPB 21: 557–565. 7. Lang H, de Santibanes E, Schlitt HJ, Malago M, van Gulik T, Machado MA et al. (2019) 10th anniversary of ALPPS-lessons learned and quo vadis. Ann Surg 269:114–119. 8. Huiskens J, Schadde E, Lang H, Malago M, Petrowsky H, de Santibanes E et al. (2019 Jul) Avoiding postoperative mortality after
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https://doi.org/10.1016/j.hpb.2020.01.010
ORIGINAL ARTICLE
Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study Federico Tomassini1, Yves D’Asseler2, Michael Linecker3, Mariano C. Giglio4, Carlos Castro-Benitez5, Stéphanie Truant6, Rimma Axelsson7, Pim B. Olthof8,9, Roberto Montalti4,10, Matteo Serenari11, Thiery Chapelle12, Valerio Lucidi13, Ernesto Sparrelid14, René Adam5, Thomas Van Gulik8, François-René Pruvot6, Pierre-Alain Clavien3, Dario Bruzzese10, Karen Geboes15 & Roberto I. Troisi1,4 1
Department of Human Structure and Repair, Ghent University Faculty of Medicine, 2Department of Nuclear Medicine, Ghent University Hospital, C Heymanslaan 10, B-9000 Ghent, Belgium, 3Swiss HPB Center, University Hospital Zurich, Switzerland, 4Department of Clinical Medicine and Surgery, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, Italy, 5University Paris Sud, Unité INSERM 935, Paul Brousse University Hospital, F-94804 Villejuif, 6Department of Digestive Surgery and Transplantation, Lille University Hospital, F-59037 Lille, France, 7Karolinska University Hospital, Imaging and Function, Medical Radiation Physics and Nuclear Medicine, Karolinska Institutet, Department of Clinical Science, Intervention and Technology, Division of Radiology, Stockholm, Sweden, 8Department of Surgery, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, 9 Department of Surgery, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands, 10Department of Public Health, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, 11Department of Medical and Surgical Sciences, University of Bologna, Italy, 12Department of Hepatobiliary, Transplantation, and Endocrine Surgery, Antwerp University Hospital, Antwerp, 13Department of Digestive Surgery, Unit of Hepato-Biliary Surgery and Transplantation, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, 14Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, and 15Department of Gastroenterology-Digestive Oncology, Ghent University Hospital, C Heymanslaan 10, 9000 Ghent, Belgium
Abstract Background: Post hepatectomy liver failure (PHLF) after ALPPS has been related to the discrepancy between liver volume and function. Pre-operative hepatobiliary scintigraphy (HBS) can predict postoperative liver function and guide when it is safe to proceed with major hepatectomy. Aim of this study was to evaluate the role of HBS in predicting PHLF after ALPPS, defining a safe cut-off. Methods: A multicenter retrospective study was approved by the ALPPS Registry. All patients selected for ALPPS between 2012 and 2018, were evaluated. Every patient underwent HBS during ALPPS evaluation. PHLF was reported according to ISGLS definition, considering grade B or C as clinically significant. Results: 98 patients were included. Thirteen patients experienced PHLF grade B or C (14%) following ALPPS-2. The HBS and the daily gain in volume (KGRFLR) of the future liver remnant (FLR) were significantly lower in PHLF B and C (p = .004 and .041 respectively). ROC curves indicated safe cut-offs of 4.1%/day (AUC = 0.68) for KGRFLR, and of 2.7 %/min/m2 (AUC = 0.75) for HBSFLR. Multivariate analysis confirmed these cut-offs as variables predicting PHLF after ALPPS-2. Conclusion: Patients presenting a KGRFLR 4.1%/day and a HBSFLR 2.7%/min/m2 are at high risk of PHLF and their second stage should be re-discussed. Received 19 November 2019; accepted 19 January 2020
Correspondence Roberto I. Troisi, Department of Clinical Medicine and Surgery, Federico II University Naples, Via S. Pansini 5, I-80131 Naples, Italy. Tel: +39 081 7462732. E-mail: [email protected]
Introduction Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to extend resectability due to its unique capacity to prompt a faster regeneration of the future
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liver remnant (FLR), compared with conventional two-stage procedures.1 However, the initial enthusiasm regarding this technique has been counterbalanced by the high morbidity and mortality rates reported in the first series.2
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Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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FLR volumetric analysis still represents the standard assessment to reduce the risk of PHLF after major hepatectomy.3,4 However, additional factors besides volume influence quality and function of the FLR.5– 7 During the last years, several risk scores for patient selection have been proposed to improve ALPPS safety. Recently, a risk score on futile ALPPS to predict 90-day mortality before stage-1 and -2 has been proposed.5,8 Regarding indications, several studies have demonstrated that ALPPS for colorectal liver metastases (CRLM) is accompanied by minor morbidity and better results.2,7 –13 The recent Scandinavian LIGRO trial showed an overall resectability rate of 92% for CRLM treated by ALPPS, compared to only 57% for conventional two-stage procedure, with lower 90-days mortality and comparable morbidity.14 Nevertheless, despite efforts to select the best candidates, the incidence of post-hepatectomy liver failure (PHLF) after ALPPS still ranges between 7 and 30%, representing the main cause of 90-day mortality.5,10,14– 20 The occurrence of PHLF despite apparently adequate FLR has been explained by the absence of reciprocity between increase in volume and function.15,21 For this reason the functional assessment of the FLR using hepato-biliary-scintigraphy (HBS) has been introduced in the preoperative work-up.15,22–24 In this context, HBS based on administration of 99mTcmebrofenin is seen as a valuable method to predict liver function in extended hepatectomy. De Graaf et al. identified a mebrofenin uptake inferior to 2.69%/min/m2 as predictive of PHLF after major liver resection.25,26 However, this evaluation was based on a single center experience regarding 55 patients, which did not include two-stage procedures. As compared with indocyanine green, the advantage of HBS is represented by the possibility to obtain quantitative information on the segmental liver function, providing visual information about liver segments with inferior function, crucial to the riskassessment before major or two stage hepatectomies.27 The present study has been particularly designed to identify and evaluate the role of HBS in predicting PHLF after ALPPS, with the attempt to define a safe cut-off value for HBS. Liver volumetry, functional assessment with HBS and analysis of the kinetic growth rate (KGR) were therefore evaluated and compared in a cohort of patients undergoing ALPPS in centers who had routinely adopted HBS and were contributing to the ALPPS Registry.
Methods An investigator-driven multicenter study involving 9 highly specialized European hepatobiliary units evaluating the liver function through HBS was approved by the ALPPS Registry (www.alpps.net). The Internal Review Board of the principal investigators from the Ghent University Hospital approved this study (BE670201421317).
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Patients’ selection and data collection All patients selected for an ALPPS procedure or undergoing a rescue-ALPPS (ALPPS performed after failed portal vein embolization or ligation) between 2012 and 2018, were retrospectively evaluated. Patients were selected on an “intention-totreat” basis, including also those who failed to complete the planned two-stage procedure. Patients included were evaluated by liver volumetric and functional assessment by HBS. Every participating center decided independently to perform an ALPPS following its own local policy. Pre-stage-1 and inter-stage HBS evaluation were considered; in the case of a patient received multiple HBS over time, the one right before ALPPS-2 was considered. Demographic data, indications for ALPPS, operative and post-operative data were recorded and retrospectively analysed. Data collection was finalized on May 2018. Final assessment following reading of the DICOM files containing dynamic data acquisition was completed by January 2019. This acquisition was needed in order to make a uniform assessment of the HBS, avoiding center variation in calculations. Liver volumetry Liver volumetric analysis was based on an Angio-CT volumetry. For Rescue ALPPS, the CT volumetry performed before ALPPS-1 was recorded. Total liver volume (TLV) and FLR volumes were calculated, as well as the ratio between FLR and body weight (FLR/BW) and the FLR/TLV. Variations of the FLR volume after ALPPS-1 were expressed as absolute difference (FLRinterstage − FLRbaseline) and percentage increase, calculated as: (FLRinterstage − FLRbaseline)/FLRbaseline. The kinetic growth rate of the FLR (KGRFLR) was calculated as the mean daily volumetric increase, expressed as volume percentage increase/day (%/day) from ALPPS-1 (even for rescue-ALPPS), or from PVE when performed post-operatively, to pre-ALPPS-2 radiological assesment. Standard Total liver volume (sTLV) was calculated using the Vauthey formula.28 Centralization of the HBS data and analysis All HBS data coming from each center were sent to the Department of Nuclear Medicine of the Ghent University Hospital and analysed by one of the authors (YD), who was blinded to clinical outcomes, accordingly with the aim to standardize the methodology eventually minimizing bias of interpretation across institutions. Image processing was performed on Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden). Geometric mean images were calculated and region of interest were drawn on the liver and heart. Time activity curves were obtained for liver, blood pool (based on the heart region) and total activity within the field of view. Time activity curves were then used to calculate liver uptake rate (expressed as %/min) between 150 and 350 s after the injection, according to Ekman et al.29 Liver uptake rate was corrected for the body surface area, generating corrected uptake rates in %/min/m2. Finally, function
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Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010
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of the FLR was calculated as a fraction of the corrected uptake of the remaining segments. The HBS of the total liver volume and of the FLR were analysed.30 Variations of the HBSFLR were expressed as absolute difference (HBSinterstage − HBSbaseline) or percentage increase [(HBSinterstage − HBSbaseline)/HBSbaseline] after ALPPS-1. Peri-operative outcomes Data on intraoperative and 90-day morbidity and mortality were recorded. Complications were classified according to the Clavien-Dindo classification.31 PHLF was reported according to the definition of the International Study Group of Liver Surgery.32 PHLF grade B or C were considered as clinically significant.33
inadequate regeneration and left hepatic vein thrombosis with PHLF after ALPPS-1. Moreover two PHLF Grade B were observed after ALPPS-2. Patients’ characteristics are depicted in Table 1. All patients affected by CRLM received upfront chemotherapy. ALPPS was performed as first choice procedure in 75 patients (76%), with PVE-ALPPS performed in five patients. The remaining 23 patients (23%) underwent rescue ALPPS after failed portal vein embolization or ligation. Before ALPPS-1, the median FLR/TLV was 24% (19–29), FLR/sTLV was 26% (19–29) and the FLR/BW was 0.5 (0.4–0.6). The median FLR function (HBSFLR) was of 2.1%/min/m2 (1.7–2.7). Additional volumetric and functional data are shown in Table 2. Table 1 Age, BMI, operative time and estimated blood losses are
Statistical analysis Numerical variables were synthesized using median and interquartile range. Categorical variables were described as frequency and percentage. Pearson’s correlation coefficient r was used to measure the correlation between numerical variables. Wilcoxon’s and Mann–Whitney’s test were used for assessing within and between group differences. The area under a Receiving Operator Characteristics (ROC) curve (AUC) was used to estimate the accuracy of variables in discriminating PHLF Grade B/C. The optimal cut-off values were chosen by maximizing the Youden’s index. Univariable analyses were performed considering the defined cut-offs and other risk factors for PHLF, as gender, age, ASA Score and CRLM. Multivariable logistic model was finally built by including, as explicative factors, those significantly associated with outcome in univariate analysis. However, due to the small numbers of observed events, the multivariable model should not be intended as a clinical prediction model but was built to confirm the independent association between KGRFLR, HBSFLR and PHLF. For the same reason, interactions between independent variables were not tested in the multivariable model. Fagan’s nomograms were elaborated to show how positive or negative test change the probability of developing PHLF after ALPSS-2.34 The pre-test probability of developing PHLF corresponds with the prevalence of PHLF within the study (14%). A p-value .05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Mac (Version 20.0. Armonk, NY: IBM Corp.). STATA Statistical software (StataCorp. 2017. Release 15. College Station, TX: StataCorp LLC) was used for Fagan’s nomograms.
presented as median (interquartile range)
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n (%)
Age (years)
62 (55–69)
Sex Male
59 (60)
Female a
39 (40) 2
BMI (kg/m )
26 (22–28)
ASA scoreb I/II
76 (78)
III
22 (22)
Indication for ALPPSc Colorectal liver metastases
80 (82)
Hepatocellular carcinoma
7 (7)
Intra-hepatic cholangiocarcinoma
3 (3)
Hilar cholangiocarcinoma
3 (3)
Other
5 (5)
Intraoperative characteristics Operative time (min) ALPPS 1
337 (269–410)
ALPPS 2
230 (100–300)
Estimated blood losses (ml) ALPPS 1
500 (300–900)
ALPPS 2
400 (200–725)
Associated procedures on the FLR (%) Wedge resection + Microwave ablation
Results Patients’ characteristics and ALPPS stage-1 A total of 130 patients receiving ALPPS were collected and evaluated. Centralization of the HBS was feasible in 98 patients that were included in the analysis, while the remaining 32 were excluded due to incomplete HBS data. In these excluded patients ALPPS-2 was performed in all but two, due to respectively
Patients’ characteristics (n [ 98)
25 (25) 8 (8)
Multiple wedge resection
5 (5)
+ Microwave ablation
1 (1)
Radiofrequency ablation
1 (1)
Microwave ablation
2 (2)
Caudatectomy
1 (1)
a
Body Mass Index. American Society of Anesthesiologists Score. c Associating Liver Partition and Portal vein ligation for Staged hepatectomy. b
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Table 2 Volumetric and functional variation observed between
ALPPS-1 and -2 Before ALPPS-1
Before ALPPS-2
p
1637 (1472–1865)
1774 (1548–2192)
<.001
FLR (ml)
396 (300–474)
593 (503–708)
<.001
FLR/TLV (%)
24 (19–29)
32 (27–38)
<.001
FLR/sTLV (%)
26 (19–29)
35 (31–43)
<.001
TLV (ml)
FLR/BW
0.5 (0.4–0.6)
0.8 (0.6–0.9)
<.001
HBSTLV (%/min/m2)
8.8 (7–10)
9.0 (7–11)
.512
HBSFLR (%/min/m2)
2.1 (1.7–2.7)
2.7 (2–4)
<.001
Values are presented as median (interquartile range). p-value .05 statistically significant (in bold).
A total of 54 (55%) patients underwent a right trisectionectomy. Other liver resections planned were: right hepatectomy (n = 40, 41%), left trisectionectomy (n = 3, 3%) and one left hepatectomy. After ALPPS-1, 52 patients (53%) experienced complications. According to Clavien-Dindo classification, 13 patients (13%) had a grade 3a complication. Two patients (2%) developed PHLF grade C after ALPPS-1. One died after 7 days (pre-operative HBSFLR of 1.3%/min/m2). In the second patient, ALPPS-2 was performed after 55 days, but the patient required urgent liver transplantation after 6 days. Volumetric and functional variations between ALPPS stage-1 and stage-2 CT-volumetry before ALPPS-2 was performed after a median of 7 days (6–13) while HBS after a median of 8 days (6–13). In five patients incomplete data regarding pre-ALPPS-1 volumetry were collected, while the pre-ALPPS-2 total liver volume was missing in 3 patients. Changes in liver volume and function following ALPPS-1 are shown in Table 2. The FLR volume increased by 52% (26–79), with a KGRFLR of 5.9%/day (3–11). The FLR function increased by 22% (1–51), with a median HBSFLR of 2.7%/min/m2 (2–4). The increase in volume after ALPPS-1 showed a correlation with the increase in function (r = 0.4, p < .001, R2 = 0.15). Moreover, smaller baseline FLR (ml) presented faster regeneration (r = −0.5, p < .001, R2 = 0.25). Liver fibrosis and/or chemotherapy injury of the FLR was observed in 26 patients (24%) presenting a median HBSFLR of 2.9%/min/m2 (2–4) with no significant difference from patients without histological anomalies (2.8%/min/m2 (2–3); p = .534). Outcomes after ALPPS stage-2 The second stage was performed in 92 patients (94%) after a median period of 10 days (7–15) from ALPPS-1; 2 days (1–4) from the CT-volumetry and 1 (1–4) from HBS. Six patients (6%) failed to proceed to the second stage due to post-stage-1 death (n = 1), insufficient FLR growth (n = 3), and tumour progression (n = 2).
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Postoperative hospital stay was of 15 days (8–23). Fifty-five patients (60%) had postoperative complications, with 31 patients (34%) developing severe complications (ClavienDindo 3a). PHLF grade B occurred in 6 patients (7%), while 7 developed PHLF grade C (8%). In patients underwent ALPPS-2 the minimum FLR/sTLV was of 20%, while the minimum HBSFLR of 0.6%/min/m2 was recorded in a patient experienced PHLF grade C and received liver transplantation, still alive at 36 months follow-up. Ten patients (11%) died within 90-days, due to PHLF grade C (n = 6), tumour progression (n = 3), and sepsis from an intestinal fistula (n = 1). Predictors of liver failure after ALPPS stage-2 Thirteen patients (14%) developed clinically significant PHLF after ALPPS-2. At pre-ALPPS-2 evaluation, these patients had lower FLR function (HBSFLR, p = .004) and slower FLR regeneration (KGRFLR, p = .041) than patients without clinically significant PHLF. On the contrary, there was no significant difference in FLR volume (FLR/TLV, FLR/sTLV and FLR/BW) between these groups of patients (Table 3). Receiver Operating Characteristic (ROC) curve analysis confirmed the prognostic role of FLR function in discriminating clinically significant PHLF (AUC = 0.75; 95% CI: 0.61–0.88) with a cut-off value of 2.7%/min/m2 (sensitivity 0.85 and specificity 0.55 – Fig. 1a). KGRFLR showed a slight lower discriminatory accuracy with an AUC equal to 0.68 (95% CI: 0.50–0.85), with a cut-off value of 4.1%/day (sensitivity 0.62 and specificity 0.73 – Fig. 1a). The subgroup analysis of the KGRFLR excluding rescue ALPPS confirmed a slower regeneration in patients developed clinically significant PHLF (5.5 vs 2.1%/day, p = .023) with the ROC curve analysis pointing out the same cut-off value of 4.1%/day (AUC = 0.75; 95% CI: 0.62–0.91, sensitivity 0.75 and specificity 0.69). Table 3 Volumetric and functional differences observed in patients
experienced PHLF Grade B and C after ALPPS-2 p
PHLF None–Grade A Grade B–C FLR (ml)
602 (505–705)
653 (496–769)
.520
FLR/TLV (%)
33 (28–39)
31 (24–43)
.508
FLR/sTLV (%)
35 (32–43)
39 (31–44)
.692
FLR/BW
0.78 (0.65–0.94) 0.82 (0.64–0.94) .779
FLR increase (ml)
198 (134–299)
FLR increase (%)
54 (34–80)
43 (6–81)
.378
KGRFLR (Volume gain/day) (%)
6.4 (3–11)
2.2 (1–7)
.041
2.8 (2.3–3.6)
2 (1.4–2.6)
.004
HBSFLR (%/min/m2) 2
170 (33–350)
.564
HBSFLR increase (%/min/m ) 0.4 (0.1–1.2)
0.1 (−0.1 to 0.8) .231
HBSFLR increase (%)
5 (−11 to 32)
24 (2–51)
.192
Values are presented as median (interquartile range). p-value .05 statistically significant (in bold).
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Figure 1 a: ROC curve of factors influencing PHLF after ALPPS-2. b: Association between the defined cut-off for HBSFLR and daily volume gain
in predicting PHLF. c: Fagan’s nomograms showing as negative (A) or positive (B) tests change the probability of a developing liver failure following ALPPS 2
The association between KGRFLR and HBSFLR and the occurrence of PHFL grade B/C is shown in Fig. 1b. Among 14 patients showing both low function (HBSFLR < 2.7%/min/m2) and slow regeneration (KGRFLR < 4.1%/day) clinically significant PHLF was observed in 7. Moreover, the majority (7/13) of patients developing clinically significant PHLF showed both low function and regeneration. Only one patient with PHLF was observed in the higher function and growth quadrant (1/29, p < .001). This 58 y.o. male, defined as ASA III and affected by CRLM, received a challenging right trisectionectomy with an EBL of 5600 ml during ALPPS-1. Following ALPPS-2, performed one week from the first stage with a HBSFLR of 2.9%/min/m2 and a KGRFLR of 9.4%/day (CT volumetry performed at 6 days), the patient developed pulmonary embolism and subsequent PHLF Grade B with discharge after 25 days. Fagan’s nomograms show how the probability of a developing liver failure following ALPPS-2 changes after positive or negative tests (Fig. 1c). At multivariate analysis, in addition to the low function and slow regeneration of the FLR, indication for surgery other than CRLM was associated with the occurrence of clinically significant PHLF (Table 4).
Discussion This study found HBS to be more accurate than liver volumetry in predicting PHLF following ALPPS stage 2. Additionally, the KGRFLR has been found to be indicative of the risk of PHLF. The importance of performing functional evaluation of the liver through HBS before extended hepatectomy, has been highlighted by several studies.15,24,35–37 The result of the ROC curve regarding HBS confirmed the cut-off value of 2.7%/min/m2 pointed out by Graaf et al. on a cohort of patients undergoing major hepatectomy.25 Moreover, a similar HBS cut-off value of 2.3%/min/m2 was previously identified as an accurate selecting tool to predict PHLF grade B/C after PVE.38,39 Of note, in the present study, the increase in volume of the FLR correlated with its increase in function. Nevertheless, the current
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results do not show that volume and function are equivalent parameters. Indeed, despite a correlation showing that in most patients the volumetric increase corresponds to some increase in function, the low R2 indicates that a high variability of data exists, with patients having a considerable increase in the FLR volume but only a modest increase in function, and vice versa. This observation confirms that liver volume is not a reliable predictor of liver function, supporting the necessity of a functional assessment as recently reported in a multicenter study.15 Moreover, in this series, liver fibrosis and/or chemotherapy injury of the FLR didn’t affect the functional regeneration process. The present study also points out the importance of the velocity of growth of the FLR during ALPPS. Shindoh et al. first focused on the KGRFLR after portal vein embolization, identifying it as a more accurate predictor of PHLF than liver volume. In particular, a KGRFLR >2%/week was associated to a lower risk of PHLF.40 On this background, the current study focused on the KGRFLR. As ALPPS triggers faster regeneration than portal vein embolization, volume gain was calculated per day, rather than per week.41 The results show that patients with slower volumetric regeneration (<4.1%/day), presented higher incidence of PHLF after ALPPS-2. This result confirms the importance of KGRFLR in the ALPPS setting, suggesting the paradigm that “faster regeneration” could be synonymous of “better regeneration”. Kambakamba et al. also focused on KGRFLR in ALPPS. In this study conducted on 36 patients, the incidence of PHLF was 0% in those having a FLR/TLV >30% and a KGR 6%/day.41 These results were based on a single center experience where volumetric assessment was routinely performed within one week after ALPPS-1. However, kinetic growth of the liver is not linear and the time interval assessed for calculation is crucial. In the current multicenter study, volumetry was performed after a median of 7 days presenting anticipated centres’ variations. This lack of standardization is certainly a limit, making difficult the comparison with different cut-offs described in literature. Additional studies focusing on KGRFLR are necessary to standardize the definition of the time interval to use for calculation.
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Table 4 Logistic regression analysis of the predictive variables of PHLF Grade B and C
Variables
PHLF B and C
Univariate analysis
n
p
OR
95% CI
.186
0.37
0.85–1.65
.480
0.62
0.17–2.29
.456
0.62
0.17–2.18
.006
5.91
1.6–21
.335
0.55
0.16–1.83
.427
0.61
0.18–2.03
.041
4.3
1.1–17.09
.713
0.6
0.06–6.22
.235
0.4
0.1–1.5
.013
0.14
.020
0.2
Age (y.o.) 73
10/81
>73
3/11
ASA score I/II
9/71
III
4/21
Gender Male
9/55
Female
4/37
CRLM Yes
7/76
No
6/16
FLR/BW <0.8
5/47
0.8
8/45
Multivariate analysis p
OR
95% CI
.021
6.4
1.4–30
.110
0.2
0.05–1.3
0.03–0.6
.023
0.13
0.02–0.75
0.7–8
.015
0.15
0.03–0.66
Complications ‡3a after ALPPS-1 Yes
3/10
No
10/82
FLR/TLV (%) <25
4/11
25
9/78
FLR/sTLV (%) <25
1/5
25
12/87
Rescue-ALPPS Yes
5/22
No
8/70 2
HBSFLR (%/min/m ) <2.7
11/45
2.7
2/47
KGRFLR (%) <4.1
8/28
4.1
5/59
p-value .05 statistically significant (in bold).
In line with the current findings, Chiba et al. recently showed that KGRFLR after ALPPS-1 was inversely correlated to initial FLR volumes, with smaller FLR growing more rapidly.22 This paradigm has been described by the authors’ previous experience evaluating hemodynamic stress in ALPPS: smaller FLR result in better volume regeneration, possibly related to the higher portal perfusion recorded at the end of stage-1.6 Therefore, in patients with very small FLR volume before ALPPS-1, a functional assessment with HBS could help in identifying those that will significantly respond to surgical interventions of volume enhancement. HPB xxxx, xxx, xxx
In the present study, both HBSFLR and KGRFLR predicted with good accuracy PHLF and is therefore necessary to understand if these two tests are complementary and they must be performed both. This question is of value, as data on KGRFLR are immediately available at the time of volumetric assessment, while HBS requires specific expertise and logistics, eventually leading to additional costs. As observed in Fig. 1b, using the abovediscussed cut-offs for HBSFLR and KGRFLR different groups of patients at risk of PHLF were selected (those on the left and below the vertical and horizontal lines, respectively). However, in both groups, a number of false positive examinations (patients
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who will not develop PHLF) do exist. Using both criteria (i.e. slow regeneration and low function) allows identifying a group of patients (left-bottom part of the scatter plot) in whom the incidence of PHLF becomes very high. The Fagan’s nomograms confirm the highest probability of developing PHLF after ALPPS2 in this group of patients with a clear graphic expression. As consequence, HBSFLR and KGRFLR analysis work in synergistic way, by enhancing the specificity of the other. On this background, patients having both slow regeneration and low function of the FLR at the inter-stage assessment, should be thoroughly scrutinized and their stage-2 eventually postponed after reevaluated a second time. Other risk factors were analysed at the univariate analysis, as advanced age, gender, ASA score, FLR/BW <0.8, FLR/sTLV <25%, rescue ALPPS and complications defined as 3a after ALPPS-1, but were not found to be predictive factors for PHLF Grade B/C after ALPPS-2. However TLV/FLR <25%, calculated by CT-volumetry before ALPPS-2, was indicated as risk factor for PHLF at the univariate analysis but was not confirmed at the multivariate. Indication for ALPPS other than CRLM was confirmed as risk factor for PHLF.7 As shown in the first report of the International ALPPS Registry, treatment of CRLM is associated with the lowest morbidity and mortality rates compared with other malignancies.2 ALPPS has clearly expanded the treatment options and resectability for patients with CLRM once defined as unresectable (bilobar diffusion and small FLR), representing nowadays a safe and valid chance for cure. This study has some limitations. Due to the retrospective fashion of the study, the decision to proceed or not to ALPPS-2 according to the calculated FLR, liver function and/or other different parameters (as FLR/BW, FLR/TLV, FLR/sTLV and patients’ clinical condition) was taken independently by every participating center. Moreover, volumetric analysis was not centralized, but performed in each participating center according to local protocols. Hence, some inter-center variations in volumetric calculations exist, due to the use of different softwares and protocols. The KGRFLR as risk factor for PHLF is an important additional finding, which confirms previous studies. However, in the present study no patients were effectively managed according to the KGRFLR value, which was not used to decide whether or not to proceed to ALPPS-2. Moreover, the heterogeneity of the study population with both PVE-ALPPS and rescue ALPPS included, represents another limit due to the difficulties to define the time interval for KGRFLR calculation. Therefore, while this parameter is very promising, further studies are needed to confirm its value prior to take clinical decisions based on it. Finally, the small number of PHLF B or C, prevented us from developing a clinical prediction model to assess the predictive performance of both KGRFLR and HBSFLR. In conclusion, during ALPPS inter-stage, analysis of the kinetic growth rate and function of the FLR are more accurate than liver volume alone in predicting the risk of PHLF. Two cut-offs for both analyses were identified. In particular, lower incidence of PHLF
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was observed in patients with HBSFLR 2.7%/min/m2 (4.3%, n = 2/47) while in KGRFLR 4.1%/day the incidence was of 8.5% (n = 5/59). Moreover, considering the two parameters together, patients presenting slow growth (<4.1%/day) and limited function of the FLR, calculated as an HBS uptake <2.7%/min/m2, have to be considered at high risk (50%) of PHLF and should be rediscussed and wait to proceed to ALPPS-2. These two analyses, especially HBS, should be considered in the decisional work-up during ALPPS being an useful tool to define the preoperative functional liver assessment before major hepatectomy. Author’s contributions FT: acquisition of data, writing the manuscript. MCG: data collection, statistical analysis. YD: centralisation of HBS DICOM data and analysis. DB: Statistical analysis. MCG, ML, CCB, ST, RA, PO, RM, LC, TC, VL, ES, RA, TVG, RFP, PAC, KG: critical revision and data interpretation. RIT: study conception and design, critical revision, supervision. Funding The authors received no funding for this research and no competing financial interest. Conflicts of interest None to declare. References 1. Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA et al. (2012) Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2staged extended right hepatic resection in small-for-size settings. Ann Surg 255:405–414. 2. Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R et al. (2014) Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 260:829–836. discussion 36–8. 3. Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore SJ, Edinburgh Liver S et al. (2005) The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 54:289–296. 4. Hammond JS, Guha IN, Beckingham IJ, Lobo DN. (2011) Prediction, prevention and management of postresection liver failure. Br J Surg 98: 1188–1200. 5. Linecker M, Stavrou GA, Oldhafer KJ, Jenner RM, Seifert B, Lurje G et al. (2016) The ALPPS risk score: avoiding futile use of ALPPS. Ann Surg 264:763–771. 6. Tomassini F, D’Asseler Y, Giglio MC, Lecluyse C, Lambert B, SainzBarriga M et al. (2019) Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study. HPB 21: 557–565. 7. Lang H, de Santibanes E, Schlitt HJ, Malago M, van Gulik T, Machado MA et al. (2019) 10th anniversary of ALPPS-lessons learned and quo vadis. Ann Surg 269:114–119. 8. Huiskens J, Schadde E, Lang H, Malago M, Petrowsky H, de Santibanes E et al. (2019 Jul) Avoiding postoperative mortality after
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© 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Tomassini F et al., Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study, HPB, https://doi.org/10.1016/j.hpb.2020.01.010