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Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function
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Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function Pim B. Olthof, MD, PhD,a Federico Tomassini, MD,b Pablo E. Huespe, MD,c Stephanie Truant, MD, PhD,d Franc¸ois-Ren e Pruvot, MD, PhD,d Roberto I. Troisi, MD, PhD,b Carlos Castro, MD,e Erik Schadde, MD, PhD,f,g,h Rimma Axelsson, MD, PhD,i Ernesto Sparrelid, MD, PhD,j Roelof J. Bennink, MD, PhD,k Rene Adam, MD, PhD,e Thomas M. van Gulik, MD, PhD,a and Eduardo de Santibanes, MD, PhD,c Amsterdam, the Netherlands, Ghent, Belgium, Buenos Aires, Argentina, Lille and Villejuif, France, Chicago, IL, Kanton Zurich and Zurich, Switzerland, and Stockholm, Sweden
Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces a rapid and extensive increase in liver volume. The functional quality of this hypertrophic response has been called into question because ALPPS is associated with a substantial incidence of liver failure and high perioperative mortality. This multicenter study aimed to evaluate functional liver regeneration in contrast to volumetric liver regeneration in ALPPS, using technetium-99m hepatobiliary scintigraphy and computed tomography volumetry, respectively. Methods. Patients who underwent ALPPS and hepatobiliary scintigraphy in 6 centers were included. Hepatobiliary scintigraphy data were analyzed centrally at the Academic Medical Center in Amsterdam according to established protocols. Increase in liver function as measured by hepatobiliary scintigraphy after stage 1 of ALPPS was compared with the increase in liver volume. In addition, we analyzed the impact of liver function and volume on postoperative outcomes including liver failure, morbidity, and mortality. Results. In 60 patients, future liver remnant volume increased by a median 78% (interquartile range 48–110) during a median 8 (interquartile range 6–14) days after stage 1, while function as measured by hepatobiliary scintigraphy increased by a median 29% (interquartile range 1–55) throughout 7 days (interquartile range 6–10) in the 27 patients with paired measurements. After stage 2 of ALPPS, liver failure occurred in 5/60 (8%) patients, severe complications in 24/60 (40%), and mortality occurred in 4/60 (7%). Conclusion. In ALPPS, volumetry overestimates liver function as measured by hepatobiliary scintigraphy and may be responsible for the high rate of liver failure. Quantitative liver function tests are highly recommended to avoid post hepatectomy liver failure. (Surgery 2017;j:j-j.) From the Department of Surgery,a Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of General,b HPB and Liver Transplantation Surgery, Ghent University Hospital Medical School, Ghent, Belgium; Department of Surgery,c Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Department of Digestive Surgery and Transplantation,d University of Lille Nord de France, Lille, France; Centre He pato-Biliaire,e H^o pital Paul Brousse, H^o pitaux de Paris Universite Paris-Sud, Villejuif, France; Department of Surgery,f Division of Transplantation, Rush University Medical Center, Chicago, IL; Cantonal Hospital Winterthur,g Kanton Zurich, Switzerland; Institute of Physiology,h Center for Integrative Accepted for publication May 26, 2017.
0039-6060/$ - see front matter
Reprint requests: Pim B. Olthof, MD, PhD, Department of Experimental Surgery, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. E-mail: pb.olthof@ amc.nl.
Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2017.05.022
SURGERY 1
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Human Physiology, University of Zurich, Zurich, Switzerland; Department of Clinical Science,i Intervention and Technology, Division of Radiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science,j Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; and Department of Nuclear Medicine, Academic Medical Center,k University of Amsterdam, Amsterdam, the Netherlands
ASSOCIATING LIVER PARTITION AND PORTAL VEIN LIGATION for staged hepatectomy (ALPPS) has redefined resectability in liver operation by induction of rapid and extensive hypertrophy in the remnant liver.1 The increase in liver volume exceeds established techniques such as portal vein embolization (PVE).2,3 Morbidity and mortality rates of ALPPS are unequivocally high and have led to an ongoing controversy in regards to the safety of the procedure.4-6 In the reports of the ALPPS registry, major complications are reported to occur in #27% of patients and the reported 90-day mortality rate is 9%.7,8 Liver failure, which ALPPS set out to avoid, remains common with an incidence of 14% and 30% after stages 1 and 2, respectively.8 Also, 75% of the mortalities after ALPPS were attributed to liver failure.8,9 These rates of liver failure are surprising, especially when considering the extensive hypertrophy observed using standard liver volume analysis. The discrepancy between sufficient volume prior to stage 2 and the high incidence of liver failure has called into question the relevance of the measured increase in liver volume and suggests functional immaturity of the rapid hypertrophied liver. Indeed, histologic assessment of the remnant liver from patients demonstrated that the hypertrophied hepatocytes after ALPPS ought to be classified as immature when compared to hepatocytes subjected to PVE.10 Because immature hepatocytes lack functional capacity, the accurate assessment of functional liver remnant has been thought by many to be the key to improve clinical outcomes by timing the second stage appropriately. Quantitative functional assessment of the liver remnant is gaining interest, and several techniques have been implemented, of which technetium-99m (99mTc) labeled mebrofenin hepatobiliary scintigraphy (HBS) is the most widely adopted.6,11-13 HBS had been shown to be a valuable tool to select patients for PVE by preoperatively predicting the risk of posthepatecomy liver failure.11 The aim of this study was to compare the increase in volume of the future liver remnant (FLR) with the increase in hepatic function in patients who underwent ALPPS using liver CT volumetry and HBS, respectively.
METHODS All patients who underwent ALPPS for any indication between June 2011 and August 2016 at 6 specialized centers were included; all patients underwent 99mTc-mebrofenin hepatobiliary scintigraphy after stage 1 of the ALPPS procedure to time the second stage. The participating centers were the Hospital Italiano de Buenos Aires, Karolinska University Hospital Stockholm, University of Lille Nord de France, Centre Hepato-Biliaire H^ opital Paul Brousse Paris, University Hospital Ghent, and the Academic Medical Center Amsterdam. Both partial-ALPPS and standard ALPPS procedures were included. The need for ethical approval was waived by the medical ethical committee of the Academic Medical Center in Amsterdam. In the participating centers, HBS was performed as part of standard practice before stage 2 of ALPPS. In addition, HBS also was performed at baseline before stage 1 as part of standard practice in Amsterdam, Lille, Stockholm, and Ghent. All original hepatobiliary scintigraphy data were transferred to Amsterdam and were analyzed by an experienced nuclear medicine physician (R.J.B.). All scans were processed according to a standardized protocol in order to ensure comparability of obtained results across centers. The methods of analysis of the scintigraphy data have been described in detail previously.14 Briefly, HBS was performed using a large field of view single photon emission computed tomography SPECT/CT camera (Siemens Symbia T16, Munich, Germany). After injection of 200 MBq of 99mTc-labeled (2,4,6 trimethyl-3-bromo) iminodiacetic acid (99mTc-mebrofenin), acquisition was started with a dynamic scan of 36 frames of 10 seconds, followed by a fast single photon emission computed tomography of 60 projections of 8 seconds each for the assessment of hepatic uptake function. Noncontrast CT was performed afterwards to correct for liver anatomy. All data were processed using a Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden). Hepatic mebrofenin uptake rate was calculated using the geometric mean data of the anterior and posterior detectors. Regions of interest were drawn around the liver, heart (serving as blood pool), and total field of view (indicative of total body activity). Generation of 3 different, time-activity curves was based on
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regions of interest of the liver, blood pool, and total field of view. With these 3 parameters, the liver uptake rate was calculated according to Ekman et al15 and expressed as percentage per minute (%/min) for 150 to 350 seconds after injection. Future liver remnant function (FLRF) was calculated by dividing the summed counts within the delineated FLR by the total liver counts and multiplying this factor by the total hepatic mebrofenin uptake rate. Correction for body surface area was not applied in the present analysis. Total liver function (TLF), FLR function, and the share of the FLR in TLF were analyzed before and after ALPPS stage 1. HBS data were compared with measurements of liver volume, which were performed usually on the same day or the day before or after HBS. FLR volume share was calculated according to the formula: ðFLR volume=total liver volumeÞ3100%. The increase in FLRV was calculated using the following formula: ððfuture liver remnant volume . ½FLRVafterstage1 FLRV baseline FLRV baseline 100%: The same formula was used to calculate the increase in FLRF. Study variables. Study variables included diagnosis, type of resection, serum bilirubin levels, and INR directly prior to stage 2. Parameters of liver volume were collected for all patients prior to both stages. Outcome parameters included morbidity and mortality after each stage, with complications of grade III or greater defined as major complications.16 Mortality was defined as death within 90 days after either stage. Other outcome parameters included intensive care unit stay, liver failure as defined and graded by the International Study Group of Liver Surgery with only grade B and C considered as clinically relevant liver failure.17 Statistical analysis. Data were expressed as median with interquartile range (IQR) unless stated otherwise. Differences in liver volume and function parameters over time were tested using Wilcoxon matched-pairs tests, signed-rank test, or Friedman tests. Differences between the liver volume and function parameters were tested using Mann-Whitney U tests. All statistical analyses were performed using GraphPad (GraphPad Prism, La Jolla, CA) or SPSS (IBM, Chicago, IL). RESULTS Patients. A total of 66 patients who underwent ALPPS and HBS in 6 centers were identified. Three patients were excluded because the heart was not captured sufficiently in the field of view, which hampers accurate correction for blood
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pool activity of mebrofenin and does not allow calculation of mebrofenin uptake. An additional 3 patients were excluded because these patients did not undergo stage 2 of ALPPS. One patient with perihilar cholangiocarcinoma (PHC) died shortly after stage 1 due to progressive multipleorgan failure secondary to ischemia and necrosis of segment IV, without any volume of function assessment after stage 1. One patient with CRLM never underwent stage 2 due to insufficient liver volume or function increase in liver function as measured by HBS. The third patient with CRLM had progression of extrahepatic disease after stage 1 and did not underwent stage 2 of ALPPS. The remaining 60 patients were included in the analyses. The indication for resection was CRLMs in majority of patients, 3 had hepatocellular carcinoma in a noncirrhotic liver, 2 had hepatic metastases from bladder cancer, 1 patient had liver metastases of melanoma, and 1 patient was diagnosed with intrahepatic cholangiocarcinoma. Baseline characteristics of the included patients are displayed in Table I. A total of 11 patients (18%) had undergone PVE with insufficient FLR hypertrophy before ALPPS. One patient had nonlethal liver failure after stage 1 (Table II). Five patients including the former patient suffered liver failure after stage 2, of whom 2 patients died within 90 days. Overall 90-day mortality was 7% (4 of 60). The other 2 patients died of respiratory complications and intestinal fistula, respectively. Quantification of the volume-hypertrophy response after ALPPS. Paired pre- and postoperative assessment of liver volume was available for all 60 patients. FLR volume increased in all patients with a median of 78% (IQR 48–110) throughout a median of 8 (IQR 6–14) days after stage 1 (Fig 1, B and E). The relative volume of the FLRV share increased from 22% (19–26) at baseline to 34% (29–41) after stage 1 (P < .01; Fig 1, A). Total liver volume increased from median 1,434 mL (IQR 1,133–1,643) prior to stage 1 to 1,619 mL (IQR 1,369–1,935) after stage 1 (P < .01). In the present study, the number of patients who developed posthepatectomy liver failure and 90-mortality events were insufficient to determine a cut-off value for FLRV share to perform the second stage safely (Fig 2, A to C). The area under the curve values representing the predictive value of FLRV% was 0.51 (95% CI, 0.26–0.76) for liver failure, 0.72 (0.45–0.99) for mortality, and 0.54 (95% CI, 0.38–0.70) for major morbidity.
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Table I. Patient and disease characteristics N = 60 Age, median, (IQR) 64 Male, n (%) 36 25.8 BMI, kg/m2, median, (IQR) Diagnosis, n (%) Colorectal liver metastases 53 Hepatocellular carcinoma 3 Bladder cancer liver 2 metastases Melanoma liver metastases 1 Intrahepatic 1 cholangiocarcinoma ASA classification, n (%) I 9 II 35 III 160 Indication for ALPPS, n (%) Bilateral extensive disease 37 Unexpected tumor extent 11 Failed PVE 11 Unknown 1 Previous liver resection, n (%) 9 Previous PVE, n (%) 11 1,434 Baseline TLV, mL, median (IQR) Baseline FLRV, mL, median 316 (IQR) Baseline FLRV share, mL%, 23.0 median (IQR) Baseline TLF, %/min, median 15.1 (IQR) Baseline FLRF, %/min, 3.7 median (IQR) Baseline FLRF share, %, 25.1 median (IQR)
(53–71) (60) (23.3–27.7) (88) (5) (3) (2) (2)
(15) (58) (27) (62) (18) (18) (2) (15) (18) (1,133–1,643) (257–416) (18.8–27.6) (12.7–17.5; n = 27) (3.2–5.0; n = 27) (21.1–33.7; n = 27)
Table II. Function, volume, and clinical outcomes N = 60 Interval stage 1 to volume 8 (6–14) assessment, median (IQR) TLV after stage 1, mL, median 1,619 (1,369–1,935) (IQR) FLRV after stage 1, mL, median 567 (463–661) (IQR) FLRV share after stage 1, %, 34.1 (29.1–40.6) median (IQR) Increase in FLRV, %, median 78 (48–110) (IQR) Interval stage 1 to function assessment, median (IQR) All patients 7 (6–9) Patients with paired 6 (6–10; n = 27) functionometry TLF after stage 1, median (IQR) 11.8 (9.6–14.1) FLRF after stage 1, %/min, 5.5 (4.3–6.3) median (IQR) FLRF share after stage 1, %, 43.6 (38.0–54.1) median (IQR) 29% (1–55; n = 27) Increase in FLRF, %, median (IQR) Resection, n (%) Right 13 (22) Extended right 47 (78) Liver failure, n (%) Stage 1 1 (2) Stage 2 5 (8) Severe morbidity, n (%) Stage 1 11 (18) Stage 2 18 (30) Overall 24 (40) ICU stay, yes, n (%) Stage 1 18 (30) Stage 2 29 (48) 90-day mortality, n (%) 4 (7)
BMI, Body mass index; ASA, American Society of Anesthesiologists; TLV, total liver volume.
PVE, Portal vein embolization; TLV, total liver volume; ICU, intensive care unit.
Quantification of the functional hypertrophy response as measured by HBS. Paired liver functionometry prior to stage 1 and prior to stage 2 using HBS measurements was available for 27 patients. In a median time of 7 days (IQR 6–10) after stage 1, liver function increased by a median 29% (IQR 1–55%), from a median 3.7%/min (IQR 3.2–5.0) before to a median 5.5%/min (IQR 4.9–6.2) after stage 1 (Fig 1, D). A decrease in future liver remnant function (FLRF) was seen in 6 of 27 patients, while the FLR volume relative to total liver volume and the FLR function relative to total liver function increased in all patients. Several centers used the increase in relative function to time the second stage of ALPPS. In the 27 patients, relative FLR function share increased in all patients
from a median of 25.1% (IQR 21.1–33.7) to 40.4% (IQR 35.2–49.8; P < .01), while total liver function decreased. Overall, total liver function decreased in these patients from a median 15.1%/min (IQR 12.7– 17.5) to 13.6% minutes (10.3–16.0) prior to stage 2 (P = .02), but when the 2 patients with a serum bilirubin level >50 mmol/L after stage 1 were excluded, TLF decreased slightly from a median 15.1%/min (IQR 13.2–17.4) to 14.1%/min (IQR 11.1–16.4; P = .05). The decrease in TLF may well be due to the competitive uptake of mebrofenin and bilirubin secondary to cholestasis rather than indicating an actual decrease in total liver function. FLRF prior to stage 2 was available in 60 patients at a median time of 7 (6–9) days after stage 1 and
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Fig 1. Comparison of the increase in liver volume and function after stage 1 of ALPPS. Increase in FLRV share (A) and FLRV (B) after stage 1 ALPPS (N = 60). Increase in FLRF share (C) and FLRF (D) after stage 1 of ALPPS (N = 27). Differences over time were analyzed using Wilcoxon signed-rank test. (E) Increase in future liver remnant volume after stage 1 compared with baseline values. Grey lines represent individual patients and the black line the median increase for all patients (N = 60). (F) Increase in future liver remnant function after stage 1 compared with baseline values. Grey lines represent individual patients and the black line the median increase for all patients (N = 27). (G) Comparison of the liver volume and function increase after stage 1 of ALPPS. Grey dots represent individual patients, and the black square the median of all patients overall (N = 27). Correlations were tested using Spearman’s correlation coefficient.
was 5.05%/min (3.84–5.67). These 60 patients do not provide this study with enough power to define a FLRF cut-off to perform stage 2 safely without liver failure or mortality (Fig 2, D to F). AUC values representing the predictive value of FLRF were 0.60 (95% CI, 0.30–0.90) for liver failure, 0.74 (0.50–0.98) for mortality, and 0.63 (0.49–0.78) for severe morbidity. Although the number of events was limited, the AUC value of FLRF for mortality does indicate some predictive value. In patients with a FLRF of at least 5.6%/min, no mortality occurred. In contrast, of the 32 patients with a lesser FLRF, only 4 died, indicating a low positive predictive value of 13%. Comparison of liver volume and function. The increase in liver volume was greater compared with the increase in liver function as measured by HBS in 23 of the 27 patients (85%) with paired data (Fig 1, C). The median increase in liver volume was 2.8-fold greater compared with liver function (median 75% [IQR 50–106] vs 29% [IQR 1–55];
P < .01), or expressed in another way, median function increase was only 42% of volumetric increase. There was no correlation between increases in volume and function (Spearman’s r = 0.10, P = .62). Previous PVE. A total of 11 patients had undergone previous PVE before being subjected to ALPPS in the present cohort. In these patients, the rate of increase in both volume and function was not different from patients who had not been subjected to previous PVE before ALPPS (Fig 3). The incidence of liver failure was comparable between PVE patients 2/11 (18%) and nonPVE patients 3/49 (6%; P = .24). Major morbidity after stage 1 occurred in 4/11 (36%) in PVE and 7/49 (14%) in nonPVE patients (P = .10), and major morbidity after stage 2 occurred in 6/11 (55%) in PVE patients and 12/49 in nonPVE patients (P = .07). Future larger studies should address outcomes of ALPPS in patients who have undergone PVE previously.
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Fig 2. Correlation of parameters of liver volume and function with outcomes. (A to C) shows the proportional volume of the FLR (as a percent of the total liver volume prior to stage 1) for patients experiencing posthepatectomy liver failure (A), complications >IIIA (B), or 90-day mortality (C). (D to F) shows the uptake function of the FLR (in % uptake per minute) for patients experiencing posthepatectomy liver failure (D), complications >IIIA (E), or 90-day mortality (F). The dotted lines represent the commonly accepted cut-offs for volume (40%) and function (3.0%/min).
Fig 3. Increase in liver volume and function after ALPPS after previous PVE. (A) Increase in FLRF after ALPPS in patients with and without previous PVE (N = 9–10). (B) Increase in FLRV after ALPPS in patients with and without previous PVE (N = 10–24). Differences between groups were analyzes using Mann-Whitney U tests.
DISCUSSION This multicenter study including 60 patients demonstrates that the increase in liver function as measured by HBS after stage 1 ALPPS is less than
the measured increase in liver volume. Rapid hypertrophy does not necessarily lead to a proportional increase in liver function as measured by HBS, but to a functionally immature liver. This
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study explains the conundrum of the high rates of liver failure despite the rapid volume growth induced by ALPPS. The study supports the recommendation that the timing of ALPPS stage 2 should likely be based on liver function metric data and not on volumetry data. The present mortality rate of 9% seen in ALPPS was attributable to posthepatectomy liver failure in #75% of patients.8 Liver failure defined according to the International Study Group of Liver Surgery criteria was observed in 14% of patients after stage 1 and in 30% after stage 2,8 despite the rapid increase in liver volume of 80% throughout 7 days.7 The discrepancy between rapid liver growth and the high incidence of liver failure is striking and questions the functional capacity of the rapidly increasing liver mass. Some preliminary reports on the use of HBS in ALPPS have suggested defective regeneration of functional liver parenchyma, but the data are limited.6,18 The histologic assessment of liver tissue in 8 patients after ALPPS stage 1 compared with liver tissue from patients undergoing PVE revealed that hepatocytes in ALPPS patients were morphologically immature compared with PVE.10 Morphologically immature hepatocytes are likely functionally immature, and assessment of liver volume probably overestimates actual functional liver regeneration.10 It was shown previously in the setting of PVE, that increase of functional liver regeneration measured by hepatobiliary scintigraphy actually exceeded the volume response after 21 days.19 This observation suggests that within 21 days after PVE, functional increase of the FLR has overtaken the volumetric increase. The histologic findings by Matsuo et al10 suggested otherwise, and the application of HBS in ALPPS in this study may add substance to their findings. Hepatobiliary scintigraphy may provide a valuable tool to time stage 2 in ALPPS, but the number of events of liver failure (5 patients) and 90-day mortality (4 patients) in the present series was insufficient to establish a cut-off for liver function to perform a safe second stage with any degree of certainty. Previous studies showed that clinical assessment of liver function by laboratory values or by the MELD score is superior to volumetry to determine the timing of stage 28 and proposed operational cut-offs based on a larger number of patients. The data presented in this study, but are strong enough to conclude with certainty that it is inappropriate to base timing of stage 2 solely on measurements of liver volume. Implementation of HBS would most likely often delay the second stage, which is essential to improve outcomes. A delayed second stage might result in a more
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complicated procedure due to adhesions and interstage complications. Nevertheless, liver volume is inaccurate to time the second stage, while assessment of liver function provides a crucial parameter. The overestimation of liver function by liver volume in ALPPS is unique because this was not observed after PVE.19 In the present report, 11 patients underwent PVE before ALPPS, with insufficient hypertrophy to proceed to standard resection. It was shown previously that the increase in liver volume after ALPPS was not affected by previous PVE,20 and in the present report, increases in liver function as measured by HBS was not different between patients with or without previous PVE (Fig 3). These results suggest that the performance of PVE in patients did not affect the regenerative response after ALPPS. Therefore, it might be safer to perform PVE first in patients scheduled for major liver resection with insufficient FLR and only proceed to ALPPS when the hypertrophy is insufficient rather than proceeding directly with ALPPS. Hepatobiliary scintigraphy quantitatively assesses regional mebrofenin uptake as an indirect measure of liver function and provides information on both total and FLR function. Some centers use the proportion of FLRF compared with TLF to time the second stage. Although an increase in FLR share might be of value when TLF does not change over time, using the proportion alone without assessing TLF in absolute terms may lead to misinterpretation. For instance, one patient in the present report had a FLR function share of 42%, which seems adequate for a safe stage 2, but the TLF was severely impaired at an uptake function of 2.9%/min leading to an absolute FLR function of 0.7%/min, and this patient died from posthepatectomy liver failure. Therefore, using the FLR share as measure of liver function and timing of stage 2 should be discouraged while segmental uptake function expressed as %/min is advised for clinical decisions, as we have demonstrated in multiple reports. The present study has some limitations. Not every patient in the study underwent HBS before and after stage 1 of ALPPS. Therefore, function metrics were not available for all patients. When we compared volumetrics and function metrics in only the 27 patients in which paired liver function was available, we found the same differences in growth of volume and function. Second, the number of events of post hepatectomy liver failure and mortality events were limited in the present cohort, and accurate cut-off values for liver function allowing for a safe second stage of
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ALPPS could not be determined. We cannot exclude that the limited number of events of posthepatectomy failure in this cohort due to the clinical application of HBS in the management of these patients. Accordingly, rates of both mortality and liver failure in the present report were less compared with the rates reported in literature. If ALPPS is being used to expand the limits of resectability safely, a future large, global collaboration between centers will be necessary to determine safe cut-off values liver function for timing of stage 2 in ALPPS. Also, it remains to be established whether these results in a cohort with majority of CRLM patients will apply to other tumor types. It has been reported that ALPPS currently is most likely not suitable for biliary neoplasms.21,22 At any rate, the power of the present study is insufficient to reliably determine a critical or accurate cut-off value for liver function. In conclusion, the present study demonstrates that the gain in liver volume after stage 1 in ALPPS is greater compared with liver function as measured by HBS. Liver volume overestimated liver function, and the timing of stage 2 most likely is better addressed by assessment of liver function using HBS or some other accurate marker of parenchymal liver function. The present study warrants implementation of a quantitative liver function test such as HBS in the ALPPS procedure to improve outcomes, which would most likely result in a delayed stage 2. Future collaborative studies and data analysis should make it possible to generate sufficient patient numbers to identify a cut-off value of liver function to safely undertake stage 2 of ALPPS.
REFERENCES 1. Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA, 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;255:40514. 2. Croome KP, Hernandez-Alejandro R, Parker M, Heimbach J, Rosen C, Nagorney DM. Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. HPB (Oxford) 2015;17:477-84. 3. Shindoh J, Vauthey JN, Zimmitti G, Curley SA, Huang SY, Mahvash A, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg 2013;217:126-33; discussion 33-34. 4. Aloia TA, Vauthey JN. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is
Surgery j 2017
5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
gained and what is lost? Ann Surg 2012;256:e9; author reply e16-e19. Dokmak S, Belghiti J. Which limits to the “ALPPS” approach? Ann Surg 2012;256:e6; author reply e16-e17. Truant S, Baillet C, Deshorgue AC, Leteurtre E, Hebbar M, Ernst O, et al. Drop of total liver function in the interstages of the new associating liver partition and portal vein ligation for staged hepatectomy technique: analysis of the “auxiliary liver” by HIDA scintigraphy. Ann Surg 2016;263:e33-4. Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014;260:829-36; discussion 36-38. Schadde E, Raptis DA, Schnitzbauer AA, Ardiles V, Tschuor C, Lesurtel M, et al. Prediction of mortality after ALPPS stage-1: an analysis of 320 patients from the international ALPPS registry. Ann Surg 2015;262:780-5; discussion 5-6. Truant S, Scatton O, Dokmak S, Regimbeau JM, Lucidi V, Laurent A, 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 2015;41:674-82. Matsuo K, Murakami T, Kawaguchi D, Hiroshima Y, Koda K, Yamazaki K, et al. Histologic features after surgery associating liver partition and portal vein ligation for staged hepatectomy versus those after hepatectomy with portal vein embolization. Surgery 2016;159:1289-98. de Graaf W, van Lienden KP, Dinant S, Roelofs JJ, Busch OR, Gouma DJ, et al. Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection. J Gastrointest Surg 2010;14:369-78. Chapelle T, Op De Beeck B, Huyghe I, Francque S, Driessen A, Roeyen G, et al. Future remnant liver function estimated by combining liver volumetry on magnetic resonance imaging with total liver function on (99m)Tc-mebrofenin hepatobiliary scintigraphy: can this tool predict post-hepatectomy liver failure? HPB (Oxford) 2016;18:494-503. de Santibanes M, Alvarez FA, de Santibanes E. Hepatobiliary scintigraphy in associating liver partition and portal vein ligation for staged hepatectomy: all that glitters is not gold. Ann Surg 2016 [Epub ahead of print]. de Graaf W, van Lienden KP, van Gulik TM, Bennink RJ. (99m)Tc-mebrofenin hepatobiliary scintigraphy with SPECT for the assessment of hepatic function and liver functional volume before partial hepatectomy. J Nucl Med 2010;51:229-36. Ekman M, Fjalling M, Holmberg S, Person H. IODIDA clearance rate: a method for measuring hepatocyte uptake function. Transplant Proc 1992;24:387-8. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery 2011;149:713-24. Cieslak KP, Olthof PB, van Lienden KP, Besselink MG, Busch OR, van Gulik TM, et al. Assessment of liver function using (99m)Tc-mebrofenin hepatobiliary scintigraphy in ALPPS (associating liver partition and portal vein ligation for staged hepatectomy). Case Rep Gastroenterol 2015;9: 353-60.
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19. de Graaf W, van Lienden KP, van den Esschert JW, Bennink RJ, van Gulik TM. Increase in future remnant liver function after preoperative portal vein embolization. Br J Surg 2011;98:825-34. 20. Tschuor C, Croome KP, Sergeant G, Cano V, Schadde E, Ardiles V, et al. Salvage parenchymal liver transection for patients with insufficient volume increase after portal vein occlusion---an extension of the ALPPS approach. Eur J Surg Oncol 2013;39:1230-5.
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21. Olthof PB, Coelen RJ, Wiggers JK, Groot Koerkamp B, Malago M, Hernandez-Alejandro R, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB (Oxford) 2017;19:381-7. 22. Serenari M, Zanello M, Schadde E, Toschi E, Ratti F, Gringeri E, et al. Importance of primary indication and liver function between stages: results of a multicenter Italian audit of ALPPS 2012–2014. HPB (Oxford) 2016;18:419-27.
Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function Pim B. Olthof, MD, PhD,a Federico Tomassini, MD,b Pablo E. Huespe, MD,c Stephanie Truant, MD, PhD,d Franc¸ois-Ren e Pruvot, MD, PhD,d Roberto I. Troisi, MD, PhD,b Carlos Castro, MD,e Erik Schadde, MD, PhD,f,g,h Rimma Axelsson, MD, PhD,i Ernesto Sparrelid, MD, PhD,j Roelof J. Bennink, MD, PhD,k Rene Adam, MD, PhD,e Thomas M. van Gulik, MD, PhD,a and Eduardo de Santibanes, MD, PhD,c Amsterdam, the Netherlands, Ghent, Belgium, Buenos Aires, Argentina, Lille and Villejuif, France, Chicago, IL, Kanton Zurich and Zurich, Switzerland, and Stockholm, Sweden
Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces a rapid and extensive increase in liver volume. The functional quality of this hypertrophic response has been called into question because ALPPS is associated with a substantial incidence of liver failure and high perioperative mortality. This multicenter study aimed to evaluate functional liver regeneration in contrast to volumetric liver regeneration in ALPPS, using technetium-99m hepatobiliary scintigraphy and computed tomography volumetry, respectively. Methods. Patients who underwent ALPPS and hepatobiliary scintigraphy in 6 centers were included. Hepatobiliary scintigraphy data were analyzed centrally at the Academic Medical Center in Amsterdam according to established protocols. Increase in liver function as measured by hepatobiliary scintigraphy after stage 1 of ALPPS was compared with the increase in liver volume. In addition, we analyzed the impact of liver function and volume on postoperative outcomes including liver failure, morbidity, and mortality. Results. In 60 patients, future liver remnant volume increased by a median 78% (interquartile range 48–110) during a median 8 (interquartile range 6–14) days after stage 1, while function as measured by hepatobiliary scintigraphy increased by a median 29% (interquartile range 1–55) throughout 7 days (interquartile range 6–10) in the 27 patients with paired measurements. After stage 2 of ALPPS, liver failure occurred in 5/60 (8%) patients, severe complications in 24/60 (40%), and mortality occurred in 4/60 (7%). Conclusion. In ALPPS, volumetry overestimates liver function as measured by hepatobiliary scintigraphy and may be responsible for the high rate of liver failure. Quantitative liver function tests are highly recommended to avoid post hepatectomy liver failure. (Surgery 2017;j:j-j.) From the Department of Surgery,a Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of General,b HPB and Liver Transplantation Surgery, Ghent University Hospital Medical School, Ghent, Belgium; Department of Surgery,c Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Department of Digestive Surgery and Transplantation,d University of Lille Nord de France, Lille, France; Centre He pato-Biliaire,e H^o pital Paul Brousse, H^o pitaux de Paris Universite Paris-Sud, Villejuif, France; Department of Surgery,f Division of Transplantation, Rush University Medical Center, Chicago, IL; Cantonal Hospital Winterthur,g Kanton Zurich, Switzerland; Institute of Physiology,h Center for Integrative Accepted for publication May 26, 2017.
0039-6060/$ - see front matter
Reprint requests: Pim B. Olthof, MD, PhD, Department of Experimental Surgery, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. E-mail: pb.olthof@ amc.nl.
Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2017.05.022
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Human Physiology, University of Zurich, Zurich, Switzerland; Department of Clinical Science,i Intervention and Technology, Division of Radiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science,j Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; and Department of Nuclear Medicine, Academic Medical Center,k University of Amsterdam, Amsterdam, the Netherlands
ASSOCIATING LIVER PARTITION AND PORTAL VEIN LIGATION for staged hepatectomy (ALPPS) has redefined resectability in liver operation by induction of rapid and extensive hypertrophy in the remnant liver.1 The increase in liver volume exceeds established techniques such as portal vein embolization (PVE).2,3 Morbidity and mortality rates of ALPPS are unequivocally high and have led to an ongoing controversy in regards to the safety of the procedure.4-6 In the reports of the ALPPS registry, major complications are reported to occur in #27% of patients and the reported 90-day mortality rate is 9%.7,8 Liver failure, which ALPPS set out to avoid, remains common with an incidence of 14% and 30% after stages 1 and 2, respectively.8 Also, 75% of the mortalities after ALPPS were attributed to liver failure.8,9 These rates of liver failure are surprising, especially when considering the extensive hypertrophy observed using standard liver volume analysis. The discrepancy between sufficient volume prior to stage 2 and the high incidence of liver failure has called into question the relevance of the measured increase in liver volume and suggests functional immaturity of the rapid hypertrophied liver. Indeed, histologic assessment of the remnant liver from patients demonstrated that the hypertrophied hepatocytes after ALPPS ought to be classified as immature when compared to hepatocytes subjected to PVE.10 Because immature hepatocytes lack functional capacity, the accurate assessment of functional liver remnant has been thought by many to be the key to improve clinical outcomes by timing the second stage appropriately. Quantitative functional assessment of the liver remnant is gaining interest, and several techniques have been implemented, of which technetium-99m (99mTc) labeled mebrofenin hepatobiliary scintigraphy (HBS) is the most widely adopted.6,11-13 HBS had been shown to be a valuable tool to select patients for PVE by preoperatively predicting the risk of posthepatecomy liver failure.11 The aim of this study was to compare the increase in volume of the future liver remnant (FLR) with the increase in hepatic function in patients who underwent ALPPS using liver CT volumetry and HBS, respectively.
METHODS All patients who underwent ALPPS for any indication between June 2011 and August 2016 at 6 specialized centers were included; all patients underwent 99mTc-mebrofenin hepatobiliary scintigraphy after stage 1 of the ALPPS procedure to time the second stage. The participating centers were the Hospital Italiano de Buenos Aires, Karolinska University Hospital Stockholm, University of Lille Nord de France, Centre Hepato-Biliaire H^ opital Paul Brousse Paris, University Hospital Ghent, and the Academic Medical Center Amsterdam. Both partial-ALPPS and standard ALPPS procedures were included. The need for ethical approval was waived by the medical ethical committee of the Academic Medical Center in Amsterdam. In the participating centers, HBS was performed as part of standard practice before stage 2 of ALPPS. In addition, HBS also was performed at baseline before stage 1 as part of standard practice in Amsterdam, Lille, Stockholm, and Ghent. All original hepatobiliary scintigraphy data were transferred to Amsterdam and were analyzed by an experienced nuclear medicine physician (R.J.B.). All scans were processed according to a standardized protocol in order to ensure comparability of obtained results across centers. The methods of analysis of the scintigraphy data have been described in detail previously.14 Briefly, HBS was performed using a large field of view single photon emission computed tomography SPECT/CT camera (Siemens Symbia T16, Munich, Germany). After injection of 200 MBq of 99mTc-labeled (2,4,6 trimethyl-3-bromo) iminodiacetic acid (99mTc-mebrofenin), acquisition was started with a dynamic scan of 36 frames of 10 seconds, followed by a fast single photon emission computed tomography of 60 projections of 8 seconds each for the assessment of hepatic uptake function. Noncontrast CT was performed afterwards to correct for liver anatomy. All data were processed using a Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden). Hepatic mebrofenin uptake rate was calculated using the geometric mean data of the anterior and posterior detectors. Regions of interest were drawn around the liver, heart (serving as blood pool), and total field of view (indicative of total body activity). Generation of 3 different, time-activity curves was based on
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regions of interest of the liver, blood pool, and total field of view. With these 3 parameters, the liver uptake rate was calculated according to Ekman et al15 and expressed as percentage per minute (%/min) for 150 to 350 seconds after injection. Future liver remnant function (FLRF) was calculated by dividing the summed counts within the delineated FLR by the total liver counts and multiplying this factor by the total hepatic mebrofenin uptake rate. Correction for body surface area was not applied in the present analysis. Total liver function (TLF), FLR function, and the share of the FLR in TLF were analyzed before and after ALPPS stage 1. HBS data were compared with measurements of liver volume, which were performed usually on the same day or the day before or after HBS. FLR volume share was calculated according to the formula: ðFLR volume=total liver volumeÞ3100%. The increase in FLRV was calculated using the following formula: ððfuture liver remnant volume . ½FLRVafterstage1 FLRV baseline FLRV baseline 100%: The same formula was used to calculate the increase in FLRF. Study variables. Study variables included diagnosis, type of resection, serum bilirubin levels, and INR directly prior to stage 2. Parameters of liver volume were collected for all patients prior to both stages. Outcome parameters included morbidity and mortality after each stage, with complications of grade III or greater defined as major complications.16 Mortality was defined as death within 90 days after either stage. Other outcome parameters included intensive care unit stay, liver failure as defined and graded by the International Study Group of Liver Surgery with only grade B and C considered as clinically relevant liver failure.17 Statistical analysis. Data were expressed as median with interquartile range (IQR) unless stated otherwise. Differences in liver volume and function parameters over time were tested using Wilcoxon matched-pairs tests, signed-rank test, or Friedman tests. Differences between the liver volume and function parameters were tested using Mann-Whitney U tests. All statistical analyses were performed using GraphPad (GraphPad Prism, La Jolla, CA) or SPSS (IBM, Chicago, IL). RESULTS Patients. A total of 66 patients who underwent ALPPS and HBS in 6 centers were identified. Three patients were excluded because the heart was not captured sufficiently in the field of view, which hampers accurate correction for blood
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pool activity of mebrofenin and does not allow calculation of mebrofenin uptake. An additional 3 patients were excluded because these patients did not undergo stage 2 of ALPPS. One patient with perihilar cholangiocarcinoma (PHC) died shortly after stage 1 due to progressive multipleorgan failure secondary to ischemia and necrosis of segment IV, without any volume of function assessment after stage 1. One patient with CRLM never underwent stage 2 due to insufficient liver volume or function increase in liver function as measured by HBS. The third patient with CRLM had progression of extrahepatic disease after stage 1 and did not underwent stage 2 of ALPPS. The remaining 60 patients were included in the analyses. The indication for resection was CRLMs in majority of patients, 3 had hepatocellular carcinoma in a noncirrhotic liver, 2 had hepatic metastases from bladder cancer, 1 patient had liver metastases of melanoma, and 1 patient was diagnosed with intrahepatic cholangiocarcinoma. Baseline characteristics of the included patients are displayed in Table I. A total of 11 patients (18%) had undergone PVE with insufficient FLR hypertrophy before ALPPS. One patient had nonlethal liver failure after stage 1 (Table II). Five patients including the former patient suffered liver failure after stage 2, of whom 2 patients died within 90 days. Overall 90-day mortality was 7% (4 of 60). The other 2 patients died of respiratory complications and intestinal fistula, respectively. Quantification of the volume-hypertrophy response after ALPPS. Paired pre- and postoperative assessment of liver volume was available for all 60 patients. FLR volume increased in all patients with a median of 78% (IQR 48–110) throughout a median of 8 (IQR 6–14) days after stage 1 (Fig 1, B and E). The relative volume of the FLRV share increased from 22% (19–26) at baseline to 34% (29–41) after stage 1 (P < .01; Fig 1, A). Total liver volume increased from median 1,434 mL (IQR 1,133–1,643) prior to stage 1 to 1,619 mL (IQR 1,369–1,935) after stage 1 (P < .01). In the present study, the number of patients who developed posthepatectomy liver failure and 90-mortality events were insufficient to determine a cut-off value for FLRV share to perform the second stage safely (Fig 2, A to C). The area under the curve values representing the predictive value of FLRV% was 0.51 (95% CI, 0.26–0.76) for liver failure, 0.72 (0.45–0.99) for mortality, and 0.54 (95% CI, 0.38–0.70) for major morbidity.
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Table I. Patient and disease characteristics N = 60 Age, median, (IQR) 64 Male, n (%) 36 25.8 BMI, kg/m2, median, (IQR) Diagnosis, n (%) Colorectal liver metastases 53 Hepatocellular carcinoma 3 Bladder cancer liver 2 metastases Melanoma liver metastases 1 Intrahepatic 1 cholangiocarcinoma ASA classification, n (%) I 9 II 35 III 160 Indication for ALPPS, n (%) Bilateral extensive disease 37 Unexpected tumor extent 11 Failed PVE 11 Unknown 1 Previous liver resection, n (%) 9 Previous PVE, n (%) 11 1,434 Baseline TLV, mL, median (IQR) Baseline FLRV, mL, median 316 (IQR) Baseline FLRV share, mL%, 23.0 median (IQR) Baseline TLF, %/min, median 15.1 (IQR) Baseline FLRF, %/min, 3.7 median (IQR) Baseline FLRF share, %, 25.1 median (IQR)
(53–71) (60) (23.3–27.7) (88) (5) (3) (2) (2)
(15) (58) (27) (62) (18) (18) (2) (15) (18) (1,133–1,643) (257–416) (18.8–27.6) (12.7–17.5; n = 27) (3.2–5.0; n = 27) (21.1–33.7; n = 27)
Table II. Function, volume, and clinical outcomes N = 60 Interval stage 1 to volume 8 (6–14) assessment, median (IQR) TLV after stage 1, mL, median 1,619 (1,369–1,935) (IQR) FLRV after stage 1, mL, median 567 (463–661) (IQR) FLRV share after stage 1, %, 34.1 (29.1–40.6) median (IQR) Increase in FLRV, %, median 78 (48–110) (IQR) Interval stage 1 to function assessment, median (IQR) All patients 7 (6–9) Patients with paired 6 (6–10; n = 27) functionometry TLF after stage 1, median (IQR) 11.8 (9.6–14.1) FLRF after stage 1, %/min, 5.5 (4.3–6.3) median (IQR) FLRF share after stage 1, %, 43.6 (38.0–54.1) median (IQR) 29% (1–55; n = 27) Increase in FLRF, %, median (IQR) Resection, n (%) Right 13 (22) Extended right 47 (78) Liver failure, n (%) Stage 1 1 (2) Stage 2 5 (8) Severe morbidity, n (%) Stage 1 11 (18) Stage 2 18 (30) Overall 24 (40) ICU stay, yes, n (%) Stage 1 18 (30) Stage 2 29 (48) 90-day mortality, n (%) 4 (7)
BMI, Body mass index; ASA, American Society of Anesthesiologists; TLV, total liver volume.
PVE, Portal vein embolization; TLV, total liver volume; ICU, intensive care unit.
Quantification of the functional hypertrophy response as measured by HBS. Paired liver functionometry prior to stage 1 and prior to stage 2 using HBS measurements was available for 27 patients. In a median time of 7 days (IQR 6–10) after stage 1, liver function increased by a median 29% (IQR 1–55%), from a median 3.7%/min (IQR 3.2–5.0) before to a median 5.5%/min (IQR 4.9–6.2) after stage 1 (Fig 1, D). A decrease in future liver remnant function (FLRF) was seen in 6 of 27 patients, while the FLR volume relative to total liver volume and the FLR function relative to total liver function increased in all patients. Several centers used the increase in relative function to time the second stage of ALPPS. In the 27 patients, relative FLR function share increased in all patients
from a median of 25.1% (IQR 21.1–33.7) to 40.4% (IQR 35.2–49.8; P < .01), while total liver function decreased. Overall, total liver function decreased in these patients from a median 15.1%/min (IQR 12.7– 17.5) to 13.6% minutes (10.3–16.0) prior to stage 2 (P = .02), but when the 2 patients with a serum bilirubin level >50 mmol/L after stage 1 were excluded, TLF decreased slightly from a median 15.1%/min (IQR 13.2–17.4) to 14.1%/min (IQR 11.1–16.4; P = .05). The decrease in TLF may well be due to the competitive uptake of mebrofenin and bilirubin secondary to cholestasis rather than indicating an actual decrease in total liver function. FLRF prior to stage 2 was available in 60 patients at a median time of 7 (6–9) days after stage 1 and
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Fig 1. Comparison of the increase in liver volume and function after stage 1 of ALPPS. Increase in FLRV share (A) and FLRV (B) after stage 1 ALPPS (N = 60). Increase in FLRF share (C) and FLRF (D) after stage 1 of ALPPS (N = 27). Differences over time were analyzed using Wilcoxon signed-rank test. (E) Increase in future liver remnant volume after stage 1 compared with baseline values. Grey lines represent individual patients and the black line the median increase for all patients (N = 60). (F) Increase in future liver remnant function after stage 1 compared with baseline values. Grey lines represent individual patients and the black line the median increase for all patients (N = 27). (G) Comparison of the liver volume and function increase after stage 1 of ALPPS. Grey dots represent individual patients, and the black square the median of all patients overall (N = 27). Correlations were tested using Spearman’s correlation coefficient.
was 5.05%/min (3.84–5.67). These 60 patients do not provide this study with enough power to define a FLRF cut-off to perform stage 2 safely without liver failure or mortality (Fig 2, D to F). AUC values representing the predictive value of FLRF were 0.60 (95% CI, 0.30–0.90) for liver failure, 0.74 (0.50–0.98) for mortality, and 0.63 (0.49–0.78) for severe morbidity. Although the number of events was limited, the AUC value of FLRF for mortality does indicate some predictive value. In patients with a FLRF of at least 5.6%/min, no mortality occurred. In contrast, of the 32 patients with a lesser FLRF, only 4 died, indicating a low positive predictive value of 13%. Comparison of liver volume and function. The increase in liver volume was greater compared with the increase in liver function as measured by HBS in 23 of the 27 patients (85%) with paired data (Fig 1, C). The median increase in liver volume was 2.8-fold greater compared with liver function (median 75% [IQR 50–106] vs 29% [IQR 1–55];
P < .01), or expressed in another way, median function increase was only 42% of volumetric increase. There was no correlation between increases in volume and function (Spearman’s r = 0.10, P = .62). Previous PVE. A total of 11 patients had undergone previous PVE before being subjected to ALPPS in the present cohort. In these patients, the rate of increase in both volume and function was not different from patients who had not been subjected to previous PVE before ALPPS (Fig 3). The incidence of liver failure was comparable between PVE patients 2/11 (18%) and nonPVE patients 3/49 (6%; P = .24). Major morbidity after stage 1 occurred in 4/11 (36%) in PVE and 7/49 (14%) in nonPVE patients (P = .10), and major morbidity after stage 2 occurred in 6/11 (55%) in PVE patients and 12/49 in nonPVE patients (P = .07). Future larger studies should address outcomes of ALPPS in patients who have undergone PVE previously.
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Fig 2. Correlation of parameters of liver volume and function with outcomes. (A to C) shows the proportional volume of the FLR (as a percent of the total liver volume prior to stage 1) for patients experiencing posthepatectomy liver failure (A), complications >IIIA (B), or 90-day mortality (C). (D to F) shows the uptake function of the FLR (in % uptake per minute) for patients experiencing posthepatectomy liver failure (D), complications >IIIA (E), or 90-day mortality (F). The dotted lines represent the commonly accepted cut-offs for volume (40%) and function (3.0%/min).
Fig 3. Increase in liver volume and function after ALPPS after previous PVE. (A) Increase in FLRF after ALPPS in patients with and without previous PVE (N = 9–10). (B) Increase in FLRV after ALPPS in patients with and without previous PVE (N = 10–24). Differences between groups were analyzes using Mann-Whitney U tests.
DISCUSSION This multicenter study including 60 patients demonstrates that the increase in liver function as measured by HBS after stage 1 ALPPS is less than
the measured increase in liver volume. Rapid hypertrophy does not necessarily lead to a proportional increase in liver function as measured by HBS, but to a functionally immature liver. This
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study explains the conundrum of the high rates of liver failure despite the rapid volume growth induced by ALPPS. The study supports the recommendation that the timing of ALPPS stage 2 should likely be based on liver function metric data and not on volumetry data. The present mortality rate of 9% seen in ALPPS was attributable to posthepatectomy liver failure in #75% of patients.8 Liver failure defined according to the International Study Group of Liver Surgery criteria was observed in 14% of patients after stage 1 and in 30% after stage 2,8 despite the rapid increase in liver volume of 80% throughout 7 days.7 The discrepancy between rapid liver growth and the high incidence of liver failure is striking and questions the functional capacity of the rapidly increasing liver mass. Some preliminary reports on the use of HBS in ALPPS have suggested defective regeneration of functional liver parenchyma, but the data are limited.6,18 The histologic assessment of liver tissue in 8 patients after ALPPS stage 1 compared with liver tissue from patients undergoing PVE revealed that hepatocytes in ALPPS patients were morphologically immature compared with PVE.10 Morphologically immature hepatocytes are likely functionally immature, and assessment of liver volume probably overestimates actual functional liver regeneration.10 It was shown previously in the setting of PVE, that increase of functional liver regeneration measured by hepatobiliary scintigraphy actually exceeded the volume response after 21 days.19 This observation suggests that within 21 days after PVE, functional increase of the FLR has overtaken the volumetric increase. The histologic findings by Matsuo et al10 suggested otherwise, and the application of HBS in ALPPS in this study may add substance to their findings. Hepatobiliary scintigraphy may provide a valuable tool to time stage 2 in ALPPS, but the number of events of liver failure (5 patients) and 90-day mortality (4 patients) in the present series was insufficient to establish a cut-off for liver function to perform a safe second stage with any degree of certainty. Previous studies showed that clinical assessment of liver function by laboratory values or by the MELD score is superior to volumetry to determine the timing of stage 28 and proposed operational cut-offs based on a larger number of patients. The data presented in this study, but are strong enough to conclude with certainty that it is inappropriate to base timing of stage 2 solely on measurements of liver volume. Implementation of HBS would most likely often delay the second stage, which is essential to improve outcomes. A delayed second stage might result in a more
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complicated procedure due to adhesions and interstage complications. Nevertheless, liver volume is inaccurate to time the second stage, while assessment of liver function provides a crucial parameter. The overestimation of liver function by liver volume in ALPPS is unique because this was not observed after PVE.19 In the present report, 11 patients underwent PVE before ALPPS, with insufficient hypertrophy to proceed to standard resection. It was shown previously that the increase in liver volume after ALPPS was not affected by previous PVE,20 and in the present report, increases in liver function as measured by HBS was not different between patients with or without previous PVE (Fig 3). These results suggest that the performance of PVE in patients did not affect the regenerative response after ALPPS. Therefore, it might be safer to perform PVE first in patients scheduled for major liver resection with insufficient FLR and only proceed to ALPPS when the hypertrophy is insufficient rather than proceeding directly with ALPPS. Hepatobiliary scintigraphy quantitatively assesses regional mebrofenin uptake as an indirect measure of liver function and provides information on both total and FLR function. Some centers use the proportion of FLRF compared with TLF to time the second stage. Although an increase in FLR share might be of value when TLF does not change over time, using the proportion alone without assessing TLF in absolute terms may lead to misinterpretation. For instance, one patient in the present report had a FLR function share of 42%, which seems adequate for a safe stage 2, but the TLF was severely impaired at an uptake function of 2.9%/min leading to an absolute FLR function of 0.7%/min, and this patient died from posthepatectomy liver failure. Therefore, using the FLR share as measure of liver function and timing of stage 2 should be discouraged while segmental uptake function expressed as %/min is advised for clinical decisions, as we have demonstrated in multiple reports. The present study has some limitations. Not every patient in the study underwent HBS before and after stage 1 of ALPPS. Therefore, function metrics were not available for all patients. When we compared volumetrics and function metrics in only the 27 patients in which paired liver function was available, we found the same differences in growth of volume and function. Second, the number of events of post hepatectomy liver failure and mortality events were limited in the present cohort, and accurate cut-off values for liver function allowing for a safe second stage of
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ALPPS could not be determined. We cannot exclude that the limited number of events of posthepatectomy failure in this cohort due to the clinical application of HBS in the management of these patients. Accordingly, rates of both mortality and liver failure in the present report were less compared with the rates reported in literature. If ALPPS is being used to expand the limits of resectability safely, a future large, global collaboration between centers will be necessary to determine safe cut-off values liver function for timing of stage 2 in ALPPS. Also, it remains to be established whether these results in a cohort with majority of CRLM patients will apply to other tumor types. It has been reported that ALPPS currently is most likely not suitable for biliary neoplasms.21,22 At any rate, the power of the present study is insufficient to reliably determine a critical or accurate cut-off value for liver function. In conclusion, the present study demonstrates that the gain in liver volume after stage 1 in ALPPS is greater compared with liver function as measured by HBS. Liver volume overestimated liver function, and the timing of stage 2 most likely is better addressed by assessment of liver function using HBS or some other accurate marker of parenchymal liver function. The present study warrants implementation of a quantitative liver function test such as HBS in the ALPPS procedure to improve outcomes, which would most likely result in a delayed stage 2. Future collaborative studies and data analysis should make it possible to generate sufficient patient numbers to identify a cut-off value of liver function to safely undertake stage 2 of ALPPS.
REFERENCES 1. Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA, 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;255:40514. 2. Croome KP, Hernandez-Alejandro R, Parker M, Heimbach J, Rosen C, Nagorney DM. Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. HPB (Oxford) 2015;17:477-84. 3. Shindoh J, Vauthey JN, Zimmitti G, Curley SA, Huang SY, Mahvash A, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg 2013;217:126-33; discussion 33-34. 4. Aloia TA, Vauthey JN. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is
Surgery j 2017
5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
gained and what is lost? Ann Surg 2012;256:e9; author reply e16-e19. Dokmak S, Belghiti J. Which limits to the “ALPPS” approach? Ann Surg 2012;256:e6; author reply e16-e17. Truant S, Baillet C, Deshorgue AC, Leteurtre E, Hebbar M, Ernst O, et al. Drop of total liver function in the interstages of the new associating liver partition and portal vein ligation for staged hepatectomy technique: analysis of the “auxiliary liver” by HIDA scintigraphy. Ann Surg 2016;263:e33-4. Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014;260:829-36; discussion 36-38. Schadde E, Raptis DA, Schnitzbauer AA, Ardiles V, Tschuor C, Lesurtel M, et al. Prediction of mortality after ALPPS stage-1: an analysis of 320 patients from the international ALPPS registry. Ann Surg 2015;262:780-5; discussion 5-6. Truant S, Scatton O, Dokmak S, Regimbeau JM, Lucidi V, Laurent A, 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 2015;41:674-82. Matsuo K, Murakami T, Kawaguchi D, Hiroshima Y, Koda K, Yamazaki K, et al. Histologic features after surgery associating liver partition and portal vein ligation for staged hepatectomy versus those after hepatectomy with portal vein embolization. Surgery 2016;159:1289-98. de Graaf W, van Lienden KP, Dinant S, Roelofs JJ, Busch OR, Gouma DJ, et al. Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection. J Gastrointest Surg 2010;14:369-78. Chapelle T, Op De Beeck B, Huyghe I, Francque S, Driessen A, Roeyen G, et al. Future remnant liver function estimated by combining liver volumetry on magnetic resonance imaging with total liver function on (99m)Tc-mebrofenin hepatobiliary scintigraphy: can this tool predict post-hepatectomy liver failure? HPB (Oxford) 2016;18:494-503. de Santibanes M, Alvarez FA, de Santibanes E. Hepatobiliary scintigraphy in associating liver partition and portal vein ligation for staged hepatectomy: all that glitters is not gold. Ann Surg 2016 [Epub ahead of print]. de Graaf W, van Lienden KP, van Gulik TM, Bennink RJ. (99m)Tc-mebrofenin hepatobiliary scintigraphy with SPECT for the assessment of hepatic function and liver functional volume before partial hepatectomy. J Nucl Med 2010;51:229-36. Ekman M, Fjalling M, Holmberg S, Person H. IODIDA clearance rate: a method for measuring hepatocyte uptake function. Transplant Proc 1992;24:387-8. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery 2011;149:713-24. Cieslak KP, Olthof PB, van Lienden KP, Besselink MG, Busch OR, van Gulik TM, et al. Assessment of liver function using (99m)Tc-mebrofenin hepatobiliary scintigraphy in ALPPS (associating liver partition and portal vein ligation for staged hepatectomy). Case Rep Gastroenterol 2015;9: 353-60.
ARTICLE IN PRESS Surgery Volume j, Number j
19. de Graaf W, van Lienden KP, van den Esschert JW, Bennink RJ, van Gulik TM. Increase in future remnant liver function after preoperative portal vein embolization. Br J Surg 2011;98:825-34. 20. Tschuor C, Croome KP, Sergeant G, Cano V, Schadde E, Ardiles V, et al. Salvage parenchymal liver transection for patients with insufficient volume increase after portal vein occlusion---an extension of the ALPPS approach. Eur J Surg Oncol 2013;39:1230-5.
Olthof et al 9
21. Olthof PB, Coelen RJ, Wiggers JK, Groot Koerkamp B, Malago M, Hernandez-Alejandro R, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB (Oxford) 2017;19:381-7. 22. Serenari M, Zanello M, Schadde E, Toschi E, Ratti F, Gringeri E, et al. Importance of primary indication and liver function between stages: results of a multicenter Italian audit of ALPPS 2012–2014. HPB (Oxford) 2016;18:419-27.