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Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity K. Tanaka a,*, K. Matsuo a, T. Murakami a, D. Kawaguchi a, Y. Hiroshima a, K. Koda a, I. Endo b, Y. Ichikawa c, M. Taguri d, M. Tanabe e a Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan c Department of Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan d Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan e Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan b
Accepted 23 January 2015 Available online - - -
Abstract Background: We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease. Methods: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. Results: Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P ¼ 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 0.18) exceeded that in the classical 2-stage group (1.19 0.29, P ¼ 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). Conclusions: ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: ALPPS; Staged hepatectomy; Liver metastases; Colorectal cancer
Abbreviation: ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; CRC, colorectal cancer; CT, computed tomography; DIC, disseminated intravascular coagulation; DICOM, digital imaging and communication in medicine; FLR, future liver remnant; MDCT, multidetector CT; NET, neuroendocrine tumor; 99mTc-GSA, technetium-99m galactosyl human serum albumin; POD, postoperative day; PS, prediction score; PVE, portal vein embolization; SD, standard deviation; SPECT, single-photon emission computed tomography; TELV, total estimated liver volume. * Corresponding author. Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan. Tel.: þ81 436 62 1211; fax: þ81 436 61 3961. E-mail address: [email protected] (K. Tanaka). http://dx.doi.org/10.1016/j.ejso.2015.01.031 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Introduction Safe removal of extensive liver tumor burdens has been a main focus for hepatobiliary surgeons. Portal vein embolization (PVE) before hepatectomy and planned 2-stage hepatectomy have been studied as effective ways to completely remove diffuse bilobar colorectal cancer metastases from the liver, broadening indications for curative resection without risk of postoperative liver failure. Both hepatectomy with PVE and 2-stage hepatectomy rely greatly on regeneration of the remnant liver after the first procedure. Previous studies show that PVE enlarges the future liver remnant (FLR) between 7% and 27%, averaging 12% of total liver volume,1 or 20%e46% beyond the pre-PVE FLR volume,2e4 within 2e8 weeks. This enables surgeons to perform R0 resection in 58%e100% of selected patients.1 In 2-stage hepatectomy, the ratio of FLR hypertrophy to FLR prior to the first procedure was approximately 28% with 2-stage hepatectomy alone, while the ratio exceeded 50% in 2-stage hepatectomy including PVE.5 This 2-stage strategy has proven successful in 70%e80%6e8 of patients otherwise likely to have a poor outcome. Recently, a new 2-stage technique has been developed, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).9 ALPPS allowed an FLR growth of 40%e160% in only 6e9 days,9e11 so all patients then could complete second hepatectomy e representing a feasibility rate of 100%. The rapid regenerative response seems to offer significant advantages. Major tumor progression is unlikely during this short period, and rapid hypertrophy enables surgeons to proceed with second hepatectomy before development of troublesome adhesions. Additionally, the short surgical treatment period may allow faster patient recovery, possibly permitting earlier resumption of chemotherapy.12 Negative considerations include significantly increased morbidity and mortality reported with ALPPS.9,10,13e15 Further, despite sufficient increase of FLR volume, achievement of a sufficient functional increase within a short period remains uncertain. We therefore sought to clarify the impact of ALPPS in treating metastatic liver disease by comparing short-term outcomes, serial changes in FLR volume, functional FLR volume, and tumor growth activity during treatment between the ALPPS strategy and classical 2-stage hepatectomy. Patients and methods Between May 2013 and September 2014, we carried out the ALPPS technique in 10 patients with unresectable multiple liver metastases from colorectal cancer and 1 patient with unresectable multiple liver metastases after resection of pancreatic neuroendocrine tumor. For comparison, we analyzed data from 54 patients with colorectal liver metastases initially considered unresectable who were treated
with classical 2-stage hepatectomy between 1994 and April 2013. Short-term outcomes, sequential change of FLR volume and functional FLR volume assessed by technetium99m galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) scintigraphy, and tumor proliferative activity assessed by the Ki67 labeling index were compared between the 2 groups. Disease resectability and hepatectomy procedures Disease resectability or unresectability was established through multidisciplinary assessment by a team including surgeons and medical oncologists, usually based on insufficient remnant liver (less than 25%e30%) or excessive risk of surgery considering location and resected volume. Maximum resected liver volume for individual patients was calculated by a prediction score (PS) described below. Hepatectomy was not necessarily performed according to anatomic principles of resection. To determine whether or not a hepatectomy procedure was acceptably safe for a patient, we used a PS introduced by Yamanaka et al.16 The PS was calculated using the formula PS ¼ 84.6 þ 0.933a þ 1.11 b þ 0.999c, where a was the anticipated resection fraction (%) calculated from CT volumetry; b, indocyanine green retention rate at 15 min (%); and c, patient age in years. A PS less than 50 indicated that a given hepatectomy was acceptable. Patients with a PS of 50 or more were considered for a 2-stage approach with or without prehepatectomy PVE or ALPPS. In the classical 2-stage hepatectomy, most first procedures involved resecting metastases from the hemiliver planned to be the future liver remnant (“clean-up” resection)13,14 and performing PVE for the contralateral liver. Later, at the second operation, the embolized hemiliver was resected. While timing of the second resection depended on degree of liver hypertrophy or duration of chemotherapy, we generally measured volume by CT 3 weeks after first hepatectomy and performed second hepatectomy 4 weeks after initial hepatectomy with PVE. A second resection was performed only when it could be curative. In the ALPPS procedure, once the liver was mobilized, total liver partition to the level of the inferior vena cava was carried out at the main portal fissure, the left portal fissure, right portal fissure, or anterior fissure of the right liver depending on patient factors and local extent of disease, using the hanging maneuver method. Clean-up resection in the future liver remnant was performed next, after which the portal vein of the diseased hemiliver was ligated. Seven days after surgery, CT was performed to determine FRL volume. If this volume was considered sufficient and the patient was stable, completion surgery was performed. The Brisbane 2000 terminology of the International Hepato-Pancreato-Biliary Association was used to designate operative procedures.17
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Chemotherapy before hepatectomy
Perioperative factors analyzed
For all patients in both groups except 9 with classical 2stage hepatectomy, several regimens of chemotherapy were administered before and/or after first hepatectomy. Regimens usually were a combination of 5-fluorouracil, L-folinic acid, and oxaliplatin and/or irinotecan, with or without use of a monoclonal antibody.
Postoperative complications were evaluated according to the Dindo-Clavien classification.18 Post-hepatectomy liver failure was classified as grade A, B, or C according to International Study Group of Liver Surgery definitions.19
Liver volume evaluation CT images were obtained preoperatively and at 7 days after the first surgical procedure, using multidetector CT (MDCT) to determine FLR volume in both groups. In the classical 2-stage hepatectomy group, MDCT was performed again 3 weeks after the first procedure to guide planning of the second-stage resection. CT was performed on postoperative day 7 in the classical 2-stage group mainly to confirm interruption of portal flow within the embolized hemiliver as well as absence of a portal thrombus. Functional liver volume evaluation All patients except for 1 patient with postoperative mortality in the ALPPS group and recent 10 patients in the classical 2-stage group were able to undergo SPECT/ CT using a Symbia T16 scanner (Siemens, Munich, Germany). This instrument can perform SPECT and CT in an integrated, seamless manner. Dynamic scintigraphy and SPECT images were obtained with a low-energy, high-resolution collimator. CT images were obtained for revision location and attenuation correction. 99mTcDTPA-GSA (Nihon Medi-Physics, Tokyo, Japan; 185 MBq/3 mg) was administered as a bolus intravenously. SPECT data for the entire liver were obtained from 15 min to 30 min after dynamic scintigraphy. Contrastenhanced CT images were obtained during arterial, portal, and venous phases with the Aquilion 64 scanner (Toshiba Medical Systems, Tochigi, Japan). SPECT and contrastenhanced CT images were processed into Digital Imaging and Communication in Medicine (DICOM) data and transmitted to a 3-dimensional-image analysis system for fusion imaging (Synapse Vincent; Fujifilm Medical, Tokyo, Japan). Three-dimensional volume-rendering fused images for SPECT and contrast enhanced CT were produced manually. All patients underwent 99mTc-GSA scintigraphy SPECT/CT fusion before and 1 week after the first procedure in the ALPPS group or 3 weeks after the procedure in the classical 2-stage group. The % functional FLR volume was estimated using the calculation: total scinti-count for the FLR/total count for the whole liver. A correlation analysis was performed for the % FLR and % functional FLR before the procedure in both groups and 1 week after the first procedure in the ALPPS group vs. 3 weeks after the first procedure in the classical 2stage group.
Immunohistochemistry Tumor proliferative activity at first and second resection was compared between the ALPPS group and the classical 2-stage group. Mouse monoclonal antibodies used for immunohistochemistry included anti-Ki67 (Dako Cytomation, Kyoto, Japan). Normal liver tissue excised at resection, but at a distance from the tumor, was used as a control. Three high-power fields (400) were selected from throughout each section, and 500 cells per field were counted. The expression index for the proteins in each case was determined according to the formula: (number of positive tumor cells/total number of tumor cells) x 100%. The mean value of the index for the 3 high-power fields was used for analysis. Statistical analysis Statistical comparisons of baseline data were performed by the ManneWhitney U test, the c2 test, or Fisher’s exact test as appropriate. A difference was considered significant when the 2-sided P value was below 0.05. Results With respect to patient-related variables, maximum liver tumor diameter of patients treated with ALPPS was smaller than that of patients with classical 2-stage resection (P ¼ 0.001), probably because of differences in response to prehepatectomy chemotherapy. As for treatment-related variables, although frequency of prehepatectomy chemotherapy was not different between groups, total cycles of chemotherapy before hepatectomy in the ALPPS group was significantly greater than in the classical 2-stage group (P ¼ 0.002). All patients in the ALPPS group attained only R1 resection status, which indicates that a patient had a microscopically determined minimal tumor-free margin of only 0 mm, even though macroscopic complete removal of tumor tissue had been performed. Among 11 patients who could not undergo curative resection in the classical 2-stage hepatectomy group, curative hepatectomy could not be undertaken in 6 patients, while concomitant extrahepatic metastases precluded R0 resection in 5 other patients who had a curative liver resection (Table 1). Operative feasibility Total weight of resected liver was not different between groups. At first hepatectomy, both duration of operation and
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Table 1 Patient and tumor characteristics. Variables Patient-related Age, years Gender Male Female Primary disease CRC NET Liver-related Timing Synchronous Metachronous Recurrence Distribution Bilobar Number Maximum tumor size, mm Extrahepatic disease Present Prehepatectomy CEA, ng/mL Treatment-related Prehepatectomy CTx Performed Number of cycles Number of lines PVE/PVL Performed Local ablation adjunct to Hx Performed Curability R0/1 R2
ALPPS (n ¼ 11)
Staged (n ¼ 54)
P value
68 (50e78)
63 (35e76)
7 (64%) 4 (36%)
33 (61%) 21 (39%)
10 (91%) 1 (9%)
54 (100%) 0
0.169
10 (91%) 1 (9%) 0
45 (83%) 7 (13%) 2 (4%)
0.748
11 (100%) 14 (4e20) 22.0 (11e34)
54 (100%) 11 (2e46) 40.5 (9e185)
5 (45%) 16.7 (3.3e57.3)
15 (28%) 41.1 (1e10535.5)
0.292 0.130
11 (100%) 14 (8e46) 2 (1e8)
45 (83%) 6 (2e42) 1 (1e5)
0.337 0.002 0.086
11 (100%)
47 (87%)
0.592
0.100 >0.999
>0.999 0.371 0.001
complications, including 4 liver-related complications (biliary fistula in 1, refractory ascites in 1, grade B liver failure in 1, and other in 1); 7 infectious complications, and 11 other complications. Five complications occurred in 5 patients after secondstage hepatectomy in the ALPPS group, including liver failure in 4 (grade B in 2, and grade A and C in 1 each), and liver stump abscess in 1. For patients undergoing second resection in the classical 2-stage hepatectomy group, 21 patients (44%) experienced postoperative complications. Overall, 30 complications occurred in these patients, including 20 liver-related complications (biliary fistula in 4, grade A liver failure in 11, grade B liver failure in 3, and grade C liver failure in 2); 5 infectious complications, and 5 other complications. Severity according to DindoClavien classification was shown Table 3. Total hospital stay after both first and second hepatectomy was 27.0 days (range, 8e124) for the 2-stage group, and 11.0 days (range, 8e54) in the ALPPS group (P < 0.001; Table 2). One patient in each group died within 90 days of second hepatectomy (1/11 or 9.1% vs. 1/48 or 2.1%, P ¼ 0.341). The patient in the classical group died 81 days after second hepatectomy because of liver failure from insufficient remnant liver volume. For the patient who died in the ALPPS group, the patient developed septic shock and DIC 2 days after first hepatectomy and died of multiple organ failure 14 days after the second operation. Changes in morphologic and functional liver volume
0
4 (7%)
11 (100%) 0
43 (80%) 11 (20%)
>0.999 0.187
Values of continuous variables are medians. Ranges are shown in parentheses. CRC, colorectal cancer; NET, neuroendocrine tumor; CEA, carcinoembryonic antigen; Hx, hepatectomy; PVE, portal vein embolization; PVL, portal vein ligation; CTx, chemotherapy.
amount of intraoperative blood loss did not differ between groups. Among patients who could undergo second hepatectomy, median duration of operation and median intraoperative blood loss at second hepatectomy respectively were 225 min and 270 mL for the ALPPS group (n ¼ 11), and 440 min and 984 mL in the classical 2stage group (n ¼ 48; P < 0.001 and P < 0.001, respectively; Table 2). Details of hepatectomy procedures performed are shown by group in Table 2. Surgical deaths and postoperative complications Among patients undergoing initial liver resection, sepsis with disseminated intravascular coagulation (DIC) resulting in grade C liver failure and grade B liver failure occurred in 1 patient each in the ALPPS group (18%). In the classical 2-stage group, 18 patients (33%) had 22 postoperative
Serial changes of FLR volume, [the ratio of FLR volume to total estimated liver volume (TELV)] were determined using the following formula: [estimated FLR/(total liver volume-tumor volume)] 100%. The ratio of FLR hypertrophy to FLR before the first procedure was calculated from the formula: [(FLR volume after the procedure)/ (FLR volume before the procedure)]. In the classical 2stage group, the mean ratio (median, range) of FLR volume to TELV pre-procedure was 31.3% (30.9%, 10.4%e 50.7%), and mean volume (median, range) of FLR prior to first hepatectomy was 291.4 mL (277.5, 103.9e584.7). At 1 week after the procedure, ratio and volume of FLR respectively were 34.9% (32.9%, 20.8%e47.9%) and 355.8 mL (345.6, 218.6e586.1); these were 43.7% (44.2%, 21.1%e68.2%) and 381.9 mL (380.4, 170.6e700.1) at 3 weeks following the procedure. In the ALPPS group, the ratio of FLR before first procedure and volume were 33.9% (32.6%, 18.5%e47.3%) and 314.2 mL (327.9, 174.9e433). One week after the procedure, these were 46.3% (45.6%, 36.2%e55.8%; P ¼ 0.002 vs. the classical 2-stage group) and 480.2 mL (495.7, 301.2 to 674; P ¼ 0.014 vs. the classical 2-stage group). The mean hypertrophy ratio (median, range) with respect to liver volume corresponding to FLR after the first-stage procedure of classical 2-stage hepatectomy or ALPPS were 1.19 (1.22, 0.66e1.68) and 1.40 (1.30,
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Table 2 Operative feasibility and short-term outcome. Variables Operative feasibility Total resected liver weight, g Duration of operation, min First Hx Second Hx Blood loss, mL First Hx Second Hx Blood transfusion performed First Hx Second Hx Postoperative outcome Morbidity First Hx Second Hx Mortality (90 days) First Hx Second Hx Total length of hospital stay, days Total Hx procedure both with 1st and 2nd Hxs Monosegemnt þ partials 3 segments þ partials 2 sections þ partials Hemihepatectomy þ partials Extended hemihepatectomy þ partials Trisectionectomy Trisectionectomy þ partials
ALPPS (n ¼ 11)
Staged (n ¼ 54 (First Hx)) (n ¼ 48 (second Hx))
582.0 (414e890)
598.3 (120e1545)
453.0 (273e540) 225 (130e329)
403 (216e640) 440 (268e878)
0.201 0.999 0.341
11.0 (8e54)
27.0 (8e124)
) classical 2-stage hepatectomy, n ¼ 54. *, P < 0.01; #, P < 0.05.
51.7 35.6% in the classical 2-stage group (P ¼ 0.09). At second hepatectomy, expression was 20.5 24.7% in the ALPPS group and 54.5 26.9% in the classical 2-stage group (P ¼ 0.01). No difference of Ki67 expression in liver
tumor cells was seen at first hepatectomy, but expression at second hepatectomy was greater in the classical group than the ALPPS group. Discussion
Figure 2. Serial changes in morphologic liver volume and functional liver volume: (,) morphologic and (-) functional volume in the ALPPS group, n ¼ 10; (>) morphologic and (A) functional volume in classical 2-stage hepatectomy, n ¼ 10.
The ALPPS procedure clearly induces a much stronger stimulus leading to rapid and marked liver hypertrophy, since this procedure prevents formation of vascular collaterals between the 2 parts of the liver by completely transecting the parenchyma. ALPPS also produces a completely devascularized area, such as segment IV in right trisectionectomy, resulting in early shrinkage of that area with compensatory FLR hypertrophy.9 After the first resection, size of the area with inflammatory injury also is considered a reason for intense stimulation of liver regeneration.12 Unfortunately, a diseased liver region rendered ischemic by complete devascularization after the first surgery could become the origin of severe sepsis, as in our patient with septic shock and DIC resulting in postoperative mortality. Further, the impact of systemic inflammatory stress responses provoked by the first procedure upon patients at the second stage of resection is still unclear, although the frequency of infectious complications at the first procedure did not differ between the ALPPS group (1/11 or 9%) and the classical 2-stage group (7/54 or 13%), and frequency of liver failure after completion of the second procedure in the ALPPS group (4/11 or 36%)
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was similar to frequencies in the classical 2 stage group (16/48 or 33%) in this study. As outlined above, the increase in volume of FLR and the FLR hypertrophy ratio from the ratio before treatment in the ALPPS group were greater than in the classical staged hepatectomy group 1 week after the first procedure. While the FLR/ TELV ratio of 46.3% in our ALPPS group 1 week after the first procedure was significantly greater than the ratio of 34.9% observed in the classical group, some previous reports claimed a greater increase in FLR (40%e160%) obtained by ALPPS in only 6e9 days.9e11 Our present volume increase in the ALPPS group probably was smaller than in some previous reports because of relatively large FLR volume or liver parenchyma heavily pretreated by chemotherapy, resulting in less capacity for regeneration. In fact, the functional increase was greater after the first procedure in the classical 2-stage group than in our ALPPS group. Although up to 60% of total liver function shifted to the FLR 3 weeks after first hepatectomy according to the GSA-SPECT/CT in our classical 2-stage group, less shift of function to the FLR was obtained in our ALPPS group, being essentially the same before and after the first procedure. The functional increase within a short period previously has been unclear, but we found the functional increase of the FLR with ALPPS to be less than with classical 2-stage hepatectomy despite a sufficient increase of FLR volume. This also was confirmed by propensity-score matching analysis with the aim of resolving differences in patients’ background characteristics such as maximum liver tumor size and the number of cycles of prehepatectomy chemotherapy. As compared to classical 2-stage hepatectomy, tumor progression in the ALPPS procedure is reported to be unlikely because of the short treatment period.12 In the present study, Ki67 expression in resected liver tumors at both first and second procedures was lower in the ALPPS group than in the classical 2-stage group, probably because more cycles and more lines of prehepatectomy chemotherapy were used for the ALPPS group. However, our finding of less Ki67 expression in resected liver tumors at second hepatectomy in the ALPPS group than in the classical 2-stage group still may support an oncologic benefit from ALPPS, with the short period between the 2 interventions helping to avoid risk of tumor progression. In conclusion, ALPPS can permit complete resection in patients with advanced liver disease previously declared unresectable. ALPPS induces a rapid liver volume increase while avoiding remnant tumor progression, also offering completion of the treatment in a relatively short period. However, the functional increase in FLR with ALPPS is poorer than with classical 2-stage hepatectomy. ALPPS still is largely untried; further basic and clinical research will be needed to define its role. Conflict of interest statement The authors declare that they have no conflicts of interest.
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Acknowledgments The authors declare that they have no disclosure of financial interests.
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Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity K. Tanaka a,*, K. Matsuo a, T. Murakami a, D. Kawaguchi a, Y. Hiroshima a, K. Koda a, I. Endo b, Y. Ichikawa c, M. Taguri d, M. Tanabe e a Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan c Department of Clinical Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan d Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan e Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan b
Accepted 23 January 2015 Available online - - -
Abstract Background: We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease. Methods: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. Results: Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P ¼ 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 0.18) exceeded that in the classical 2-stage group (1.19 0.29, P ¼ 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). Conclusions: ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: ALPPS; Staged hepatectomy; Liver metastases; Colorectal cancer
Abbreviation: ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; CRC, colorectal cancer; CT, computed tomography; DIC, disseminated intravascular coagulation; DICOM, digital imaging and communication in medicine; FLR, future liver remnant; MDCT, multidetector CT; NET, neuroendocrine tumor; 99mTc-GSA, technetium-99m galactosyl human serum albumin; POD, postoperative day; PS, prediction score; PVE, portal vein embolization; SD, standard deviation; SPECT, single-photon emission computed tomography; TELV, total estimated liver volume. * Corresponding author. Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan. Tel.: þ81 436 62 1211; fax: þ81 436 61 3961. E-mail address: [email protected] (K. Tanaka). http://dx.doi.org/10.1016/j.ejso.2015.01.031 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Introduction Safe removal of extensive liver tumor burdens has been a main focus for hepatobiliary surgeons. Portal vein embolization (PVE) before hepatectomy and planned 2-stage hepatectomy have been studied as effective ways to completely remove diffuse bilobar colorectal cancer metastases from the liver, broadening indications for curative resection without risk of postoperative liver failure. Both hepatectomy with PVE and 2-stage hepatectomy rely greatly on regeneration of the remnant liver after the first procedure. Previous studies show that PVE enlarges the future liver remnant (FLR) between 7% and 27%, averaging 12% of total liver volume,1 or 20%e46% beyond the pre-PVE FLR volume,2e4 within 2e8 weeks. This enables surgeons to perform R0 resection in 58%e100% of selected patients.1 In 2-stage hepatectomy, the ratio of FLR hypertrophy to FLR prior to the first procedure was approximately 28% with 2-stage hepatectomy alone, while the ratio exceeded 50% in 2-stage hepatectomy including PVE.5 This 2-stage strategy has proven successful in 70%e80%6e8 of patients otherwise likely to have a poor outcome. Recently, a new 2-stage technique has been developed, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).9 ALPPS allowed an FLR growth of 40%e160% in only 6e9 days,9e11 so all patients then could complete second hepatectomy e representing a feasibility rate of 100%. The rapid regenerative response seems to offer significant advantages. Major tumor progression is unlikely during this short period, and rapid hypertrophy enables surgeons to proceed with second hepatectomy before development of troublesome adhesions. Additionally, the short surgical treatment period may allow faster patient recovery, possibly permitting earlier resumption of chemotherapy.12 Negative considerations include significantly increased morbidity and mortality reported with ALPPS.9,10,13e15 Further, despite sufficient increase of FLR volume, achievement of a sufficient functional increase within a short period remains uncertain. We therefore sought to clarify the impact of ALPPS in treating metastatic liver disease by comparing short-term outcomes, serial changes in FLR volume, functional FLR volume, and tumor growth activity during treatment between the ALPPS strategy and classical 2-stage hepatectomy. Patients and methods Between May 2013 and September 2014, we carried out the ALPPS technique in 10 patients with unresectable multiple liver metastases from colorectal cancer and 1 patient with unresectable multiple liver metastases after resection of pancreatic neuroendocrine tumor. For comparison, we analyzed data from 54 patients with colorectal liver metastases initially considered unresectable who were treated
with classical 2-stage hepatectomy between 1994 and April 2013. Short-term outcomes, sequential change of FLR volume and functional FLR volume assessed by technetium99m galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) scintigraphy, and tumor proliferative activity assessed by the Ki67 labeling index were compared between the 2 groups. Disease resectability and hepatectomy procedures Disease resectability or unresectability was established through multidisciplinary assessment by a team including surgeons and medical oncologists, usually based on insufficient remnant liver (less than 25%e30%) or excessive risk of surgery considering location and resected volume. Maximum resected liver volume for individual patients was calculated by a prediction score (PS) described below. Hepatectomy was not necessarily performed according to anatomic principles of resection. To determine whether or not a hepatectomy procedure was acceptably safe for a patient, we used a PS introduced by Yamanaka et al.16 The PS was calculated using the formula PS ¼ 84.6 þ 0.933a þ 1.11 b þ 0.999c, where a was the anticipated resection fraction (%) calculated from CT volumetry; b, indocyanine green retention rate at 15 min (%); and c, patient age in years. A PS less than 50 indicated that a given hepatectomy was acceptable. Patients with a PS of 50 or more were considered for a 2-stage approach with or without prehepatectomy PVE or ALPPS. In the classical 2-stage hepatectomy, most first procedures involved resecting metastases from the hemiliver planned to be the future liver remnant (“clean-up” resection)13,14 and performing PVE for the contralateral liver. Later, at the second operation, the embolized hemiliver was resected. While timing of the second resection depended on degree of liver hypertrophy or duration of chemotherapy, we generally measured volume by CT 3 weeks after first hepatectomy and performed second hepatectomy 4 weeks after initial hepatectomy with PVE. A second resection was performed only when it could be curative. In the ALPPS procedure, once the liver was mobilized, total liver partition to the level of the inferior vena cava was carried out at the main portal fissure, the left portal fissure, right portal fissure, or anterior fissure of the right liver depending on patient factors and local extent of disease, using the hanging maneuver method. Clean-up resection in the future liver remnant was performed next, after which the portal vein of the diseased hemiliver was ligated. Seven days after surgery, CT was performed to determine FRL volume. If this volume was considered sufficient and the patient was stable, completion surgery was performed. The Brisbane 2000 terminology of the International Hepato-Pancreato-Biliary Association was used to designate operative procedures.17
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Chemotherapy before hepatectomy
Perioperative factors analyzed
For all patients in both groups except 9 with classical 2stage hepatectomy, several regimens of chemotherapy were administered before and/or after first hepatectomy. Regimens usually were a combination of 5-fluorouracil, L-folinic acid, and oxaliplatin and/or irinotecan, with or without use of a monoclonal antibody.
Postoperative complications were evaluated according to the Dindo-Clavien classification.18 Post-hepatectomy liver failure was classified as grade A, B, or C according to International Study Group of Liver Surgery definitions.19
Liver volume evaluation CT images were obtained preoperatively and at 7 days after the first surgical procedure, using multidetector CT (MDCT) to determine FLR volume in both groups. In the classical 2-stage hepatectomy group, MDCT was performed again 3 weeks after the first procedure to guide planning of the second-stage resection. CT was performed on postoperative day 7 in the classical 2-stage group mainly to confirm interruption of portal flow within the embolized hemiliver as well as absence of a portal thrombus. Functional liver volume evaluation All patients except for 1 patient with postoperative mortality in the ALPPS group and recent 10 patients in the classical 2-stage group were able to undergo SPECT/ CT using a Symbia T16 scanner (Siemens, Munich, Germany). This instrument can perform SPECT and CT in an integrated, seamless manner. Dynamic scintigraphy and SPECT images were obtained with a low-energy, high-resolution collimator. CT images were obtained for revision location and attenuation correction. 99mTcDTPA-GSA (Nihon Medi-Physics, Tokyo, Japan; 185 MBq/3 mg) was administered as a bolus intravenously. SPECT data for the entire liver were obtained from 15 min to 30 min after dynamic scintigraphy. Contrastenhanced CT images were obtained during arterial, portal, and venous phases with the Aquilion 64 scanner (Toshiba Medical Systems, Tochigi, Japan). SPECT and contrastenhanced CT images were processed into Digital Imaging and Communication in Medicine (DICOM) data and transmitted to a 3-dimensional-image analysis system for fusion imaging (Synapse Vincent; Fujifilm Medical, Tokyo, Japan). Three-dimensional volume-rendering fused images for SPECT and contrast enhanced CT were produced manually. All patients underwent 99mTc-GSA scintigraphy SPECT/CT fusion before and 1 week after the first procedure in the ALPPS group or 3 weeks after the procedure in the classical 2-stage group. The % functional FLR volume was estimated using the calculation: total scinti-count for the FLR/total count for the whole liver. A correlation analysis was performed for the % FLR and % functional FLR before the procedure in both groups and 1 week after the first procedure in the ALPPS group vs. 3 weeks after the first procedure in the classical 2stage group.
Immunohistochemistry Tumor proliferative activity at first and second resection was compared between the ALPPS group and the classical 2-stage group. Mouse monoclonal antibodies used for immunohistochemistry included anti-Ki67 (Dako Cytomation, Kyoto, Japan). Normal liver tissue excised at resection, but at a distance from the tumor, was used as a control. Three high-power fields (400) were selected from throughout each section, and 500 cells per field were counted. The expression index for the proteins in each case was determined according to the formula: (number of positive tumor cells/total number of tumor cells) x 100%. The mean value of the index for the 3 high-power fields was used for analysis. Statistical analysis Statistical comparisons of baseline data were performed by the ManneWhitney U test, the c2 test, or Fisher’s exact test as appropriate. A difference was considered significant when the 2-sided P value was below 0.05. Results With respect to patient-related variables, maximum liver tumor diameter of patients treated with ALPPS was smaller than that of patients with classical 2-stage resection (P ¼ 0.001), probably because of differences in response to prehepatectomy chemotherapy. As for treatment-related variables, although frequency of prehepatectomy chemotherapy was not different between groups, total cycles of chemotherapy before hepatectomy in the ALPPS group was significantly greater than in the classical 2-stage group (P ¼ 0.002). All patients in the ALPPS group attained only R1 resection status, which indicates that a patient had a microscopically determined minimal tumor-free margin of only 0 mm, even though macroscopic complete removal of tumor tissue had been performed. Among 11 patients who could not undergo curative resection in the classical 2-stage hepatectomy group, curative hepatectomy could not be undertaken in 6 patients, while concomitant extrahepatic metastases precluded R0 resection in 5 other patients who had a curative liver resection (Table 1). Operative feasibility Total weight of resected liver was not different between groups. At first hepatectomy, both duration of operation and
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Table 1 Patient and tumor characteristics. Variables Patient-related Age, years Gender Male Female Primary disease CRC NET Liver-related Timing Synchronous Metachronous Recurrence Distribution Bilobar Number Maximum tumor size, mm Extrahepatic disease Present Prehepatectomy CEA, ng/mL Treatment-related Prehepatectomy CTx Performed Number of cycles Number of lines PVE/PVL Performed Local ablation adjunct to Hx Performed Curability R0/1 R2
ALPPS (n ¼ 11)
Staged (n ¼ 54)
P value
68 (50e78)
63 (35e76)
7 (64%) 4 (36%)
33 (61%) 21 (39%)
10 (91%) 1 (9%)
54 (100%) 0
0.169
10 (91%) 1 (9%) 0
45 (83%) 7 (13%) 2 (4%)
0.748
11 (100%) 14 (4e20) 22.0 (11e34)
54 (100%) 11 (2e46) 40.5 (9e185)
5 (45%) 16.7 (3.3e57.3)
15 (28%) 41.1 (1e10535.5)
0.292 0.130
11 (100%) 14 (8e46) 2 (1e8)
45 (83%) 6 (2e42) 1 (1e5)
0.337 0.002 0.086
11 (100%)
47 (87%)
0.592
0.100 >0.999
>0.999 0.371 0.001
complications, including 4 liver-related complications (biliary fistula in 1, refractory ascites in 1, grade B liver failure in 1, and other in 1); 7 infectious complications, and 11 other complications. Five complications occurred in 5 patients after secondstage hepatectomy in the ALPPS group, including liver failure in 4 (grade B in 2, and grade A and C in 1 each), and liver stump abscess in 1. For patients undergoing second resection in the classical 2-stage hepatectomy group, 21 patients (44%) experienced postoperative complications. Overall, 30 complications occurred in these patients, including 20 liver-related complications (biliary fistula in 4, grade A liver failure in 11, grade B liver failure in 3, and grade C liver failure in 2); 5 infectious complications, and 5 other complications. Severity according to DindoClavien classification was shown Table 3. Total hospital stay after both first and second hepatectomy was 27.0 days (range, 8e124) for the 2-stage group, and 11.0 days (range, 8e54) in the ALPPS group (P < 0.001; Table 2). One patient in each group died within 90 days of second hepatectomy (1/11 or 9.1% vs. 1/48 or 2.1%, P ¼ 0.341). The patient in the classical group died 81 days after second hepatectomy because of liver failure from insufficient remnant liver volume. For the patient who died in the ALPPS group, the patient developed septic shock and DIC 2 days after first hepatectomy and died of multiple organ failure 14 days after the second operation. Changes in morphologic and functional liver volume
0
4 (7%)
11 (100%) 0
43 (80%) 11 (20%)
>0.999 0.187
Values of continuous variables are medians. Ranges are shown in parentheses. CRC, colorectal cancer; NET, neuroendocrine tumor; CEA, carcinoembryonic antigen; Hx, hepatectomy; PVE, portal vein embolization; PVL, portal vein ligation; CTx, chemotherapy.
amount of intraoperative blood loss did not differ between groups. Among patients who could undergo second hepatectomy, median duration of operation and median intraoperative blood loss at second hepatectomy respectively were 225 min and 270 mL for the ALPPS group (n ¼ 11), and 440 min and 984 mL in the classical 2stage group (n ¼ 48; P < 0.001 and P < 0.001, respectively; Table 2). Details of hepatectomy procedures performed are shown by group in Table 2. Surgical deaths and postoperative complications Among patients undergoing initial liver resection, sepsis with disseminated intravascular coagulation (DIC) resulting in grade C liver failure and grade B liver failure occurred in 1 patient each in the ALPPS group (18%). In the classical 2-stage group, 18 patients (33%) had 22 postoperative
Serial changes of FLR volume, [the ratio of FLR volume to total estimated liver volume (TELV)] were determined using the following formula: [estimated FLR/(total liver volume-tumor volume)] 100%. The ratio of FLR hypertrophy to FLR before the first procedure was calculated from the formula: [(FLR volume after the procedure)/ (FLR volume before the procedure)]. In the classical 2stage group, the mean ratio (median, range) of FLR volume to TELV pre-procedure was 31.3% (30.9%, 10.4%e 50.7%), and mean volume (median, range) of FLR prior to first hepatectomy was 291.4 mL (277.5, 103.9e584.7). At 1 week after the procedure, ratio and volume of FLR respectively were 34.9% (32.9%, 20.8%e47.9%) and 355.8 mL (345.6, 218.6e586.1); these were 43.7% (44.2%, 21.1%e68.2%) and 381.9 mL (380.4, 170.6e700.1) at 3 weeks following the procedure. In the ALPPS group, the ratio of FLR before first procedure and volume were 33.9% (32.6%, 18.5%e47.3%) and 314.2 mL (327.9, 174.9e433). One week after the procedure, these were 46.3% (45.6%, 36.2%e55.8%; P ¼ 0.002 vs. the classical 2-stage group) and 480.2 mL (495.7, 301.2 to 674; P ¼ 0.014 vs. the classical 2-stage group). The mean hypertrophy ratio (median, range) with respect to liver volume corresponding to FLR after the first-stage procedure of classical 2-stage hepatectomy or ALPPS were 1.19 (1.22, 0.66e1.68) and 1.40 (1.30,
Please cite this article in press as: Tanaka K, et al., Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): Short-term outcome, functional changes in the future liver remnant, and tumor growth activity, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.031
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Table 2 Operative feasibility and short-term outcome. Variables Operative feasibility Total resected liver weight, g Duration of operation, min First Hx Second Hx Blood loss, mL First Hx Second Hx Blood transfusion performed First Hx Second Hx Postoperative outcome Morbidity First Hx Second Hx Mortality (90 days) First Hx Second Hx Total length of hospital stay, days Total Hx procedure both with 1st and 2nd Hxs Monosegemnt þ partials 3 segments þ partials 2 sections þ partials Hemihepatectomy þ partials Extended hemihepatectomy þ partials Trisectionectomy Trisectionectomy þ partials
ALPPS (n ¼ 11)
Staged (n ¼ 54 (First Hx)) (n ¼ 48 (second Hx))
582.0 (414e890)
598.3 (120e1545)
453.0 (273e540) 225 (130e329)
403 (216e640) 440 (268e878)
0.201 0.999 0.341
11.0 (8e54)
27.0 (8e124)
) classical 2-stage hepatectomy, n ¼ 54. *, P < 0.01; #, P < 0.05.
51.7 35.6% in the classical 2-stage group (P ¼ 0.09). At second hepatectomy, expression was 20.5 24.7% in the ALPPS group and 54.5 26.9% in the classical 2-stage group (P ¼ 0.01). No difference of Ki67 expression in liver
tumor cells was seen at first hepatectomy, but expression at second hepatectomy was greater in the classical group than the ALPPS group. Discussion
Figure 2. Serial changes in morphologic liver volume and functional liver volume: (,) morphologic and (-) functional volume in the ALPPS group, n ¼ 10; (>) morphologic and (A) functional volume in classical 2-stage hepatectomy, n ¼ 10.
The ALPPS procedure clearly induces a much stronger stimulus leading to rapid and marked liver hypertrophy, since this procedure prevents formation of vascular collaterals between the 2 parts of the liver by completely transecting the parenchyma. ALPPS also produces a completely devascularized area, such as segment IV in right trisectionectomy, resulting in early shrinkage of that area with compensatory FLR hypertrophy.9 After the first resection, size of the area with inflammatory injury also is considered a reason for intense stimulation of liver regeneration.12 Unfortunately, a diseased liver region rendered ischemic by complete devascularization after the first surgery could become the origin of severe sepsis, as in our patient with septic shock and DIC resulting in postoperative mortality. Further, the impact of systemic inflammatory stress responses provoked by the first procedure upon patients at the second stage of resection is still unclear, although the frequency of infectious complications at the first procedure did not differ between the ALPPS group (1/11 or 9%) and the classical 2-stage group (7/54 or 13%), and frequency of liver failure after completion of the second procedure in the ALPPS group (4/11 or 36%)
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was similar to frequencies in the classical 2 stage group (16/48 or 33%) in this study. As outlined above, the increase in volume of FLR and the FLR hypertrophy ratio from the ratio before treatment in the ALPPS group were greater than in the classical staged hepatectomy group 1 week after the first procedure. While the FLR/ TELV ratio of 46.3% in our ALPPS group 1 week after the first procedure was significantly greater than the ratio of 34.9% observed in the classical group, some previous reports claimed a greater increase in FLR (40%e160%) obtained by ALPPS in only 6e9 days.9e11 Our present volume increase in the ALPPS group probably was smaller than in some previous reports because of relatively large FLR volume or liver parenchyma heavily pretreated by chemotherapy, resulting in less capacity for regeneration. In fact, the functional increase was greater after the first procedure in the classical 2-stage group than in our ALPPS group. Although up to 60% of total liver function shifted to the FLR 3 weeks after first hepatectomy according to the GSA-SPECT/CT in our classical 2-stage group, less shift of function to the FLR was obtained in our ALPPS group, being essentially the same before and after the first procedure. The functional increase within a short period previously has been unclear, but we found the functional increase of the FLR with ALPPS to be less than with classical 2-stage hepatectomy despite a sufficient increase of FLR volume. This also was confirmed by propensity-score matching analysis with the aim of resolving differences in patients’ background characteristics such as maximum liver tumor size and the number of cycles of prehepatectomy chemotherapy. As compared to classical 2-stage hepatectomy, tumor progression in the ALPPS procedure is reported to be unlikely because of the short treatment period.12 In the present study, Ki67 expression in resected liver tumors at both first and second procedures was lower in the ALPPS group than in the classical 2-stage group, probably because more cycles and more lines of prehepatectomy chemotherapy were used for the ALPPS group. However, our finding of less Ki67 expression in resected liver tumors at second hepatectomy in the ALPPS group than in the classical 2-stage group still may support an oncologic benefit from ALPPS, with the short period between the 2 interventions helping to avoid risk of tumor progression. In conclusion, ALPPS can permit complete resection in patients with advanced liver disease previously declared unresectable. ALPPS induces a rapid liver volume increase while avoiding remnant tumor progression, also offering completion of the treatment in a relatively short period. However, the functional increase in FLR with ALPPS is poorer than with classical 2-stage hepatectomy. ALPPS still is largely untried; further basic and clinical research will be needed to define its role. Conflict of interest statement The authors declare that they have no conflicts of interest.
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Acknowledgments The authors declare that they have no disclosure of financial interests.
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