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Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: Perioperative outcome and survival
Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: Perioperative outcome and survival Martin Palavecino, MD,a Yun S. Chun, MD,a David C. Madoff, MD,b Daria Zorzi, MD,a Yoji Kishi, MD,a Ahmed O. Kaseb, MD,c Steven A. Curley, MD,a Eddie K. Abdalla, MD,a and Jean-Nicolas Vauthey, MD,a Houston, TX
Background. Preoperative portal vein embolization (PVE) is performed to minimize perioperative risks of major hepatic resection for hepatocellular carcinoma (HCC), but its effects on tumor growth are ill defined. Perioperative outcome and survival after major hepatic resection for HCC, with and without PVE, were investigated. Methods. Patients that underwent major hepatic resection ($3 segments) for HCC between January 1998 and May 2007 were analyzed retrospectively. Preoperative PVE was performed when the remnant liver volume was predicted to be insufficient. Results. A total of 54 patients underwent major hepatic resection for HCC: 21 patients with PVE before resection (PVE group) and 33 patients without PVE (non-PVE group). PVE and non-PVE groups had similar rates of fibrosis or cirrhosis, hepatitis C virus, hepatitis B virus, American Joint Committee on Cancer stage, preoperative transarterial chemoembolization, overall postoperative complications, and positive margin (P = nonsignificant for all rates). There were no perioperative deaths in the PVE group and 6 (18%) deaths in the non-PVE group (P = .038). Median follow-up was 21 months. Excluding perioperative deaths, overall survival rates at 1, 3, and 5 years were 94%, 82%, and 72%, respectively, in the PVE group and 93%, 63%, and 54%, respectively, in the non-PVE group (P = .35). Similarly, disease-free survival (DFS) rates were not significantly different between the groups, with 1-, 3-, and 5-year DFS rates of 84%, 56%, and 56%, respectively, in the PVE group and 66%, 49%, and 49%, respectively, in the non-PVE group (P = .38). Conclusion. PVE before major hepatic resection for HCC is associated with improved perioperative outcome. Excluding perioperative mortality, overall survival and DFS rates were similar between patients with and without preoperative PVE. (Surgery 2009;145:399-405.) From the Departments of Surgical Oncology,a Interventional Radiology,b and Gastrointestinal Medical Oncology,c The University of Texas MD Anderson Cancer Center, Houston, TX
PREOPERATIVE PORTAL VEIN EMBOLIZATION (PVE) was originally reported by Makuuchi et al1 as a procedure to increase the resection rate in patients with inadequate future liver remnant (FLR) volumes. PVE reduces the risk of postoperative hepatic insufficiency by inducing atrophy of the embolized lobe with compensatory hypertrophy Presented at the 8th Annual Meeting of the American HepatoPancreato-Biliary Association, March 27--30, 2008, Ft. Lauderdale, FL. Accepted for publication October 16, 2008. Reprint requests: Jean-Nicolas Vauthey, MD, 1515 Holcombe Boulevard, Unit 444, Houston, TX 77030. E-mail: jvauthey@ mdanderson.org. 0039-6060/$ - see front matter Ó 2009 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2008.10.009
of the nonembolized FLR. The resultant increase in FLR volume has been associated with improved liver function and faster normalization of liver function tests after major hepatectomy.2,3 In patients with biliary cancer or liver metastases, comparable long-term survival rates have been reported between patients undergoing hepatic resection with and without preoperative PVE.4,5 The impact of PVE on long-term outcomes in patients with hepatocellular carcinoma (HCC) is limited to studies with small numbers of patients.6-8 There are controversies regarding the effects of PVE on hepatocellular tumor growth and distant metastases. Because HCC invades the portal venous system, PVE has been postulated as a strategy to suppress intrahepatic spread and improve prognosis after surgery.8 However, PVE has not been SURGERY 399
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shown to decrease HCC recurrence rates after hepatectomy. Rather, some reports have shown accelerated tumor growth in the liver after PVE, and an increased rate of distant metastases in patients undergoing hepatectomy after PVE.8,9 The aim of this study was to determine perioperative outcomes and survival after major hepatic resection for HCC with and without preoperative PVE. MATERIALS AND METHODS A total of 54 consecutive patients who underwent major hepatic resection ($3 segments) for HCC at The University of Texas MD Anderson Cancer Center between January 1998 and May 2007 were identified from a prospective hepatobiliary database, and their medical records were reviewed retrospectively. During the same time period, 9 patients underwent PVE in anticipation of major hepatectomy for HCC but were ineligible for surgery; their medical records were also reviewed. This study was approved by the institutional review board. Patients were evaluated preoperatively with a health history, physical examination, and laboratory tests (liver function and viral serology). Helical computed tomography (CT) with liver protocol (rapid injection of 150 mL of intravenous contrast with image reconstruction of 2.5--5 mm through the liver) was performed to assess the FLR volume. The total liver volume (TLV) was calculated using the body surface area (BSA) with a previously described formula: TLV = --794 + 1267.28 3 BSA.10 The standardized FLR (sFLR) was calculated using the previously described formula: sFLR = FLR volume/TLV.3 PVE was indicated if the sFLR was predicted to be insufficient (#20% in normal liver, #30% with significant fibrosis or steatosis, and #40% in cirrhosis).11 The technique used for PVE has been described previously.12 In summary, the right portal vein was accessed using an ipsilateral transhepatic approach. Anterior and posterior right portal veins (and segment 4 branches in patients undergoing extended right hepatectomy) were embolized using coils and polyvinyl alcohol particles or tris-acryl microspheres. CT was performed 3--4 weeks after PVE to assess hypertrophy of the nonembolized FLR (Fig 1). Transarterial chemoembolization (TACE) was indicated in patients who were considered unresectable or as a planned staged procedure before PVE to improve the hypertrophy of the FLR. TACE was performed by accessing the right common
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femoral artery and advancing a 5- or 5.5-French catheter to the celiac trunk. A 3-French microcatheter was coaxially placed and advanced into the right and left hepatic artery. The origins of the arterial branches supplying the tumor(s) were supraselectively catheterized, and angiography was performed. Cisplatin, mitomycin, and doxorubicin mixed with ethiodized oil were then infused through the microcatheter, followed by infusion of embolic particles (300--700 micron) to ensure near stasis of arterial flow to the tumor(s). Hepatic resection was performed as described previously.13 In brief, a right subcostal incision was made with extension up the midline (hockey stick incision). Ultrasound was used to assess the tumor and its relation to vascular and biliary structures. Under low central venous pressure anesthesia, parenchymal transection was performed using a previously described technique with the saline-linked cautery (TissueLink Medical, Dover, NH) and the ultrasonic dissector (CUSA; ValleyLab, Boulder, CO).14 Intermittent portal triad clamping was used during parenchymal transection. For this study, patients were divided into 2 groups: patients who underwent PVE before major hepatic resection (PVE group) and patients who underwent major hepatic resection without PVE (non-PVE group). The following data were collected for analysis: sex, age, hepatitis C virus and hepatitis B virus infection, preoperative TACE, blood transfusions, American Joint Committee on Cancer (AJCC) stage,15 tumor number, size of the largest tumor, margins, vascular invasion, fibrosis, cirrhosis, perioperative course, and follow-up. All cases of HCC were confirmed histologically. Nontumorous liver parenchyma was examined for underlying liver disease. Fibrosis and cirrhosis were graded according to the scale proposed by Ishak et al.16 Complications were graded according to the classification reported by Dindo et al.17 Minor complications were defined as grades I or II and major complications as grades III or IV. Postoperative hepatic insufficiency was defined as a peak postoperative bilirubin of >7.0 mg/dL.18 Duration of stay was defined from the day of surgery to the day of discharge or death. Postoperative mortality was considered as any death occurring within 90 days after surgery. Statistical analysis was performed with SPSS statistical software (v.12.0; SPSS, Chicago, IL). Continuous data were expressed as median and range and compared with the Mann-Whitney U test. Categorical data were compared with the Chisquare test or the Fisher exact test, as appropriate. The overall survival and disease-free survival rates were estimated using the Kaplan-Meier method
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Fig 1. A 59-year-old male patient had a 16-cm hepatocellular carcinoma in the right liver without evidence of extrahepatic disease. (A) Computed tomography revealed that the standardized future liver remnant (sFLR) volume was 12%. (B) Right portal vein embolization (PVE) was performed. (C) Four weeks after PVE, the sFLR was 21%. (D) The patient had no evidence of disease 5 years post-resection.
and compared using the log-rank test. A P value < .05 was considered statistically significant. RESULTS Clinicopathologic characteristics of the 54 patients are summarized in Table I. A total of 40 (74%) patients were male, with a median age of 61 years (range, 23--83). A total of 46 patients (85%) underwent a right or extended right hepatectomy. There were 21 patients in the PVE group and 33 in the non-PVE group. The 2 groups had statistically similar rates of hepatitis C virus and hepatitis B virus infection, preoperative TACE, parenchymal fibrosis, cirrhosis, positive margins, and blood transfusion. AJCC stage was similar between the groups, with the highest number of patients staged IIIA. All patients with cirrhosis were classified as Child-Turcotte-Pugh class A. Patients in the PVE group were older, with a higher male/female ratio. In the PVE group, the median sFLR pre- and post-PVE were 23 (range, 12--44%) and 33.8% (range, 21--54%), respectively. Of the 33 patients in the non-PVE group, 2 underwent measurement of sFLR, which were 26 and 30%, respectively. The other patients did not
undergo FLR volume measurement because of surgeons’ estimation of sufficient FLR volume in patients with normal livers (n = 20), tumor-induced left liver hypertrophy in patients scheduled for right or extended right hepatectomy (n = 5), and portal vein thrombosis (n = 4). In addition, 2 of these patients enrolled early in the study period when FLR volumes were not routinely measured. Although not statistically significant, more HCC patients in the latter years of the study period underwent preoperative PVE and major hepatectomy (Fig 2). TACE was performed in 6 patients in the PVE group and 3 in the non-PVE group. Indications for TACE were initially unresectable tumors (n = 5), as planned sequential treatment before PVE in patients with cirrhosis or moderate steatosis (n = 3), and as a bridge to resection in a patient recovering from a cardiac procedure (n = 1). Notably, 8 of these 9 patients underwent TACE in the last 2 years of the study. During the same study period, 9 patients underwent PVE in anticipation of major hepatectomy for HCC but were ineligible for surgery due to inadequate FLR hypertrophy (n = 3), tumor progression (n = 3), worsening chronic liver disease
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Table I. Patient characteristics PVE group (n = 21) Sex, M:F Age, y (range) HCV, n (%) HBV, n (%) TACE, n (%) Stage, n (%) I II IIIA IIIB Vascular invasion, n (%) Fibrosis,* n (%) Grades 0--4 Grades 5--6 Median alpha-fetoprotein, ng/ml (range) Type of resection, n (%) Right hepatectomy Extended right Left hepatectomy Extended left Central hepatectomy Median no. of tumors (range) Median size of largest tumor, cm (range) Positive margin, n (%) Blood transfusion, n (%) Median duration of stay, d (range)
65 7 6 6
20:1 (43–77) (33) (29) (29)
8 (38) 2 (10) 11 (52) 0 11 (52) 18 (86) 3 (14) 24.1 (1.8–19,548) 11 (52) 10 (48) 0 0 0 1 (1–5) 7 (3.2–20) 2 (10) 4 (19) 7 (5–21)
Non-PVE group (n = 33)
P value
49 8 9 3
20:13 (23–83) (24) (27) (10)
.003 .05 .47 .92 .06
12 5 15 1 21
(36) (15) (46) (3) (64)
.78
29 (88) 4 (12) 26.5 (1.7–367,000) 17 8 2 5 1 1 9 3 8 7
(52) (24) (6) (15) (3) (1–4) (1.2–18) (10) (24) (4–65)
.41 .82
.60 .13
.08 .33 .96 .65 .90
*Fibrosis was graded according to the scale proposed by Ishak et al.16 HCV, Hepatitis C virus infection; HBV, hepatitis B virus infection.
(n = 2), and poor performance status (n = 1). Among these 9 patients, 4 have died of disease, 3 are alive with disease, and 2 have undergone liver transplantation after median follow-up of 16 months (range, 1--53). Surgical results. Hepatic resection was performed at a median time of 30 days (range, 14--182) after PVE. Although the overall postoperative complication rates were comparable between the PVE and non-PVE groups (24 vs 36%, P = .33; Table II), there was a statistically higher rate of major complications in the non-PVE group (36 non-PVE vs 10% PVE group, P = .028). There were no postoperative deaths in the PVE group and 6 in the non-PVE group (P = .038). In the PVE group, 3 patients had minor complications, including ascites, wound infection, and self-limited bile leak (n = 1, each). Major complications occurred in 2 patients---1 required percutaneous drainage of a bile leak and the other required admission to the intensive care unit for respiratory distress. In the non-PVE group, 12 patients suffered major complications, including 6 postoperative deaths. Complications included bile leak requiring
Fig 2. Increasing number of patients undergoing preoperative portal vein embolization (PVE) and major hepatectomy in the past decade (P = .37).
percutaneous drainage (n = 1), mesenteric ischemia requiring reoperation in a patient with polycythemia vera (n = 1), respiratory distress requiring intensive care unit admission (n = 3), and nonfatal liver insufficiency (n = 1). Postoperative mortality in 5 patients was caused by liver insufficiency leading to multiorgan failure; 1 patient died of exacerbation of preexisting renal disease. The 2 patients in the non-PVE group who underwent preoperative liver volumetry did not have a postoperative complication.
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Table II. Postoperative complications Complication Minor complications, n (%) Self-limited bile leak Ascites Wound infection Total no. of patients Major complications, n (%) Bile leak Respiratory distress Mesenteric ischemia Nonfatal hepatic insufficiency Death Total no. of patients Total complications, n (%)
PVE group (n = 21) 1 1 1 3
Non-PVE group (n = 33)
P value
0 0 0 0
.206 .206 .206 .025
(3) (10) (3) (3) (18)* (36) (36)
.743 .554 .421 .421 .038 .028 .333
(5) (5) (5) (14)
1 (5) 1 (5) 0 0 0 2 (10) 5 (24)
1 3 1 1 6 12 12
*Five due to liver insufficiency and 1 from renal failure leading to multiorgan failure.
In the PVE group, 2 patients had bilobar HCC. In 1 patient, there was a suspicious lesion in segment 4. After right PVE, the lesion showed no change in size. The patient underwent a right hepatectomy and a wedge resection in segment 4; the lesion was confirmed as HCC. In another patient, a new lesion in the FLR was found during resection (nondetected in the pre- and post-PVE CT scans); the lesion was ablated. Survival and recurrence. After a median followup of 21 months (range, 0--114), the median overall survival for all 54 patients was 61 months. The overall survival rates at 1, 3, and 5 years was 94, 82, and 72%, respectively, in the PVE group and 93, 63, and 54%, respectively, in the non-PVE group, excluding the 6 postoperative deaths (P = .35; Fig 3). The recurrence rate in the PVE group was 38% (8 of 21 patients; 4 [19%] intrahepatic, 3 [14%] extrahepatic, and 1 [5%] intra- and extrahepatic). Excluding the 6 patients who died postoperatively, the recurrence rate in the non-PVE group was 48% (13 of 27 patients; 8 [30%] intrahepatic, 3 [11%] extrahepatic, and 2 [7%] intra- and extrahepatic). None of the 6 patients who underwent double embolization with TACE and PVE had disease recurrence. In the PVE group, disease-free survival rates at 1, 3, and 5 years was 84, 56, and 56%, respectively, compared with 66, 49, and 49%, respectively, in the non-PVE group (P = .38; Fig 4). DISCUSSION Hepatic resection remains the only potentially curative treatment for large HCC. Liver transplantation is not indicated in patients with large tumors or noncirrhotic livers. However, many patients with large HCC cannot undergo resection due to an
Fig 3. Overall survival after hepatectomy in patients with and without preoperative portal vein embolization (PVE), excluding postoperative deaths (P = .35).
inadequate FLR and/or impaired liver function. In the early 1980s, Makuuchi et al1 described using PVE to induce atrophy of the embolized lobe to be resected with compensatory hypertrophy of the nonembolized FLR. In the past 2 decades, PVE has been increasingly used to allow patients with initially inadequate FLR to undergo safe, curative hepatectomy; this technique has been used the most often in patients with colorectal liver metastases and cholangiocarcinoma.4,19 A recent metaanalysis by Abulkhir et al20 concluded that PVE is a safe and effective procedure to induce hypertrophy of the remnant liver and decrease postoperative liver failure rates. Although their study analyzed 75 publications on PVE that included 1,088 patients, less than 25% of the patients had HCC.20 The effects of PVE on HCC tumor growth and distant metastases remain ill-defined, with
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Fig 4. Disease-free survival in patients after hepatectomy with and without preoperative portal vein embolization (PVE), excluding 6 patients who died postoperatively (P = .38).
studies describing both beneficial and adverse effects of PVE on patient outcome.6,21 In this series, overall and disease-free survival rates were similar between PVE and non-PVE groups, as shown by previous authors.6 HCC invades the portal vein at a relatively early stage and disseminates through the liver via the portal circulation.22 Therefore, researchers have postulated that PVE exerts an antitumor effect by preventing transportal dissemination of cancer cells. However, to our knowledge, no study to date has demonstrated decreased intrahepatic recurrence rates in patients who have undergone PVE before hepatectomy for HCC. Conversely, investigators have hypothesized that PVE may accelerate tumor growth because of growth factors and cytokines released in the regenerating liver.23 To circumvent this potential problem, we embolize all tumorbearing segments of the liver, including segment 4 branches, in patients who are candidates for extended right hepatectomy. Our study demonstrates comparable recurrence rates between PVE and non-PVE groups. Wakabayashi et al8 found an increased rate of extrahepatic recurrence after PVE, which they attributed to a diversion of blood flow after PVE from the portal to hepatic veins with resultant dissemination of tumor cells through the hepatic venous circulation during surgical manipulation. However, we did not find any difference in rate or site of recurrence between the PVE and non-PVE groups. Notably, none of the 6 patients in this series who underwent double embolization with TACE and PVE had disease recurrence. Because the main blood supply for HCC is the hepatic artery and
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PVE results in increased hepatic arterial flow, concerns have been raised about the potential for accelerated tumor growth after PVE.23,24 To avoid this possibility, TACE has been proposed as a complementary procedure to PVE in patients with HCC. TACE eliminates the arterial blood supply to the tumor and embolizes potential arterioportal shunts in cirrhotic livers that attenuate the effects of PVE.25,26 In our study, the number of patients who underwent TACE before PVE is too small to draw conclusions. Our results, however, support a study by Ogata et al25 in which patients who underwent TACE before PVE had improved disease-free survival and increased FLR hypertrophy than patients who underwent PVE alone. Our current recommendation for those patients with bilobar HCC and tumor nodules in the FLR is to perform TACE before PVE to avoid tumor growth in the FLR after PVE. In this study, postoperative mortality and major morbidity rates were significantly higher in the non-PVE than the PVE group. Of 6 cases of postoperative mortality, 5 were due to hepatic insufficiency. Although most patients in the nonPVE group did not undergo systematic measurement of FLR volumes, our results suggest that patients in the PVE group had lower rates of postoperative liver insufficiency because of higher FLR volumes. In addition, PVE allows improved selection of patients for hepatectomy. Other investigators have demonstrated that the rate of liver regeneration after PVE predicts outcome after resection.21,23,27 PVE provides a noninvasive test to assess the capacity of the liver to regenerate in patients with chronic liver disease, and data derived from PVE in normal liver indicate that patients whose FLR degree of hypertrophy is #5% are at high risk for complications.27 Taken together, our data suggest that PVE before major hepatectomy for HCC neither prevents nor accelerates tumor growth. Rather, PVE provides an opportunity for patients considered primarily as borderline resectable or unresectable due to an inadequate FLR to undergo potentially curative hepatectomy without impairing shortterm outcomes. In addition, PVE enables improved selection of patients with HCC for major hepatic resection. Accordingly, more patients in the latter period of this study underwent PVE and major hepatectomy for HCC. The limitations of this study include the retrospective nature of the analysis. However, we believe that a prospective randomized controlled trial would be unethical, considering the documented benefits of PVE.6,19 In addition, the small number
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of patients included in our study does not allow conclusions to be made about the benefits of TACE before PVE and the minimum FLR volume needed for major hepatectomy in patients with chronic liver disease. In conclusion, this study demonstrates that PVE before major hepatectomy for HCC is associated with improved perioperative outcomes. Excluding postoperative deaths, the overall and disease-free survival rates were similar between patients who underwent hepatectomy with and without PVE. Thus, PVE increases the safety of major hepatectomy in patients with HCC without compromising long-term oncologic outcomes. REFERENCES 1. Makuuchi M, Takayasu K, Takuma T, Yamazaki S, Hasegawa H, Nishiura S, et al. Preoperative transcatheter embolization of the portal venous branch for patients receiving extended lobectomy due to the bile duct carcinoma. J Jpn Soc Clin Surg 1984;45:1558. 2. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg 2001;88:165-75. 3. Vauthey JN, Chaoui A, Do KA, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 2000;127:512-9. 4. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;243: 364-72. 5. Elias D, Ouellet JF, De Baere T, Lasser P, Roche A. Preoperative selective portal vein embolization before hepatectomy for liver metastases: long-term results and impact on survival. Surgery 2002;131:294-9. 6. Azoulay D, Castaing D, Krissat J, Smail A, Hargreaves GM, Lemoine A, et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg 2000; 232:665-72. 7. Tanaka H, Hirohashi K, Kubo S, Shuto T, Higaki I, Kinoshita H. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000; 87:879-82. 8. Wakabayashi H, Ishimura K, Okano K, Izuishi K, Karasawa Y, Goda F, et al. Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma? Cancer 2001;92:2384-90. 9. Hayashi S, Baba Y, Ueno K, Nakajo M, Kubo F, Ueno S, et al. Acceleration of primary liver tumor growth rate in embolized hepatic lobe after portal vein embolization. Acta Radiol 2007;48:721-7. 10. Vauthey JN, Abdalla EK, Doherty DA, Gertsch P, Fenstermacher MJ, Loyer EM, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002;8:233-40.
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11. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1271-80. 12. Madoff DC, Abdalla EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care. J Vasc Interv Radiol 2005;16: 779-90. 13. Vauthey JN, Pawlik TM, Abdalla EK, Arens JF, Nemr RA, Wei SH, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 2004;239:722-30; discussion 730-2. 14. Aloia TA, Zorzi D, Abdalla EK, Vauthey JN. Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection. Ann Surg 2005;242:172-7. 15. Vauthey JN, Sobin LH. On the uniform use of the AJCC/ UICC staging system for hepatocellular carcinoma. Surgery 2000;128:870. 16. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9. 17. 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. 18. Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, et al. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg 2007;204:854-62; discussion 862-4. 19. Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 2002;137:675-80; discussion 680-1. 20. Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008;247:49-57. 21. Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;237:208-17. 22. Kinoshita H, Sakai K, Hirohashi K, Igawa S, Yamasaki O, Kubo S. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986;10:803-8. 23. Kokudo N, Tada K, Seki M, Ohta H, Azekura K, Ueno M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology 2001;34:267-72. 24. Nagino M, Nimura Y, Kamiya J, Kanai M, Hayakawa N, Yamamoto H. Immediate increase in arterial blood flow in embolized hepatic segments after portal vein embolization: CT demonstration. AJR Am J Roentgenol 1998; 171:1037-9. 25. Ogata S, Belghiti J, Farges O, Varma D, Sibert A, Vilgrain V. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 2006;93:1091-8. 26. Aoki T, Imamura H, Hasegawa K, Matsukura A, Sano K, Sugawara Y, et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004;139:766-74. 27. Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg 2007;94:1386-94.
Background. Preoperative portal vein embolization (PVE) is performed to minimize perioperative risks of major hepatic resection for hepatocellular carcinoma (HCC), but its effects on tumor growth are ill defined. Perioperative outcome and survival after major hepatic resection for HCC, with and without PVE, were investigated. Methods. Patients that underwent major hepatic resection ($3 segments) for HCC between January 1998 and May 2007 were analyzed retrospectively. Preoperative PVE was performed when the remnant liver volume was predicted to be insufficient. Results. A total of 54 patients underwent major hepatic resection for HCC: 21 patients with PVE before resection (PVE group) and 33 patients without PVE (non-PVE group). PVE and non-PVE groups had similar rates of fibrosis or cirrhosis, hepatitis C virus, hepatitis B virus, American Joint Committee on Cancer stage, preoperative transarterial chemoembolization, overall postoperative complications, and positive margin (P = nonsignificant for all rates). There were no perioperative deaths in the PVE group and 6 (18%) deaths in the non-PVE group (P = .038). Median follow-up was 21 months. Excluding perioperative deaths, overall survival rates at 1, 3, and 5 years were 94%, 82%, and 72%, respectively, in the PVE group and 93%, 63%, and 54%, respectively, in the non-PVE group (P = .35). Similarly, disease-free survival (DFS) rates were not significantly different between the groups, with 1-, 3-, and 5-year DFS rates of 84%, 56%, and 56%, respectively, in the PVE group and 66%, 49%, and 49%, respectively, in the non-PVE group (P = .38). Conclusion. PVE before major hepatic resection for HCC is associated with improved perioperative outcome. Excluding perioperative mortality, overall survival and DFS rates were similar between patients with and without preoperative PVE. (Surgery 2009;145:399-405.) From the Departments of Surgical Oncology,a Interventional Radiology,b and Gastrointestinal Medical Oncology,c The University of Texas MD Anderson Cancer Center, Houston, TX
PREOPERATIVE PORTAL VEIN EMBOLIZATION (PVE) was originally reported by Makuuchi et al1 as a procedure to increase the resection rate in patients with inadequate future liver remnant (FLR) volumes. PVE reduces the risk of postoperative hepatic insufficiency by inducing atrophy of the embolized lobe with compensatory hypertrophy Presented at the 8th Annual Meeting of the American HepatoPancreato-Biliary Association, March 27--30, 2008, Ft. Lauderdale, FL. Accepted for publication October 16, 2008. Reprint requests: Jean-Nicolas Vauthey, MD, 1515 Holcombe Boulevard, Unit 444, Houston, TX 77030. E-mail: jvauthey@ mdanderson.org. 0039-6060/$ - see front matter Ó 2009 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2008.10.009
of the nonembolized FLR. The resultant increase in FLR volume has been associated with improved liver function and faster normalization of liver function tests after major hepatectomy.2,3 In patients with biliary cancer or liver metastases, comparable long-term survival rates have been reported between patients undergoing hepatic resection with and without preoperative PVE.4,5 The impact of PVE on long-term outcomes in patients with hepatocellular carcinoma (HCC) is limited to studies with small numbers of patients.6-8 There are controversies regarding the effects of PVE on hepatocellular tumor growth and distant metastases. Because HCC invades the portal venous system, PVE has been postulated as a strategy to suppress intrahepatic spread and improve prognosis after surgery.8 However, PVE has not been SURGERY 399
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shown to decrease HCC recurrence rates after hepatectomy. Rather, some reports have shown accelerated tumor growth in the liver after PVE, and an increased rate of distant metastases in patients undergoing hepatectomy after PVE.8,9 The aim of this study was to determine perioperative outcomes and survival after major hepatic resection for HCC with and without preoperative PVE. MATERIALS AND METHODS A total of 54 consecutive patients who underwent major hepatic resection ($3 segments) for HCC at The University of Texas MD Anderson Cancer Center between January 1998 and May 2007 were identified from a prospective hepatobiliary database, and their medical records were reviewed retrospectively. During the same time period, 9 patients underwent PVE in anticipation of major hepatectomy for HCC but were ineligible for surgery; their medical records were also reviewed. This study was approved by the institutional review board. Patients were evaluated preoperatively with a health history, physical examination, and laboratory tests (liver function and viral serology). Helical computed tomography (CT) with liver protocol (rapid injection of 150 mL of intravenous contrast with image reconstruction of 2.5--5 mm through the liver) was performed to assess the FLR volume. The total liver volume (TLV) was calculated using the body surface area (BSA) with a previously described formula: TLV = --794 + 1267.28 3 BSA.10 The standardized FLR (sFLR) was calculated using the previously described formula: sFLR = FLR volume/TLV.3 PVE was indicated if the sFLR was predicted to be insufficient (#20% in normal liver, #30% with significant fibrosis or steatosis, and #40% in cirrhosis).11 The technique used for PVE has been described previously.12 In summary, the right portal vein was accessed using an ipsilateral transhepatic approach. Anterior and posterior right portal veins (and segment 4 branches in patients undergoing extended right hepatectomy) were embolized using coils and polyvinyl alcohol particles or tris-acryl microspheres. CT was performed 3--4 weeks after PVE to assess hypertrophy of the nonembolized FLR (Fig 1). Transarterial chemoembolization (TACE) was indicated in patients who were considered unresectable or as a planned staged procedure before PVE to improve the hypertrophy of the FLR. TACE was performed by accessing the right common
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femoral artery and advancing a 5- or 5.5-French catheter to the celiac trunk. A 3-French microcatheter was coaxially placed and advanced into the right and left hepatic artery. The origins of the arterial branches supplying the tumor(s) were supraselectively catheterized, and angiography was performed. Cisplatin, mitomycin, and doxorubicin mixed with ethiodized oil were then infused through the microcatheter, followed by infusion of embolic particles (300--700 micron) to ensure near stasis of arterial flow to the tumor(s). Hepatic resection was performed as described previously.13 In brief, a right subcostal incision was made with extension up the midline (hockey stick incision). Ultrasound was used to assess the tumor and its relation to vascular and biliary structures. Under low central venous pressure anesthesia, parenchymal transection was performed using a previously described technique with the saline-linked cautery (TissueLink Medical, Dover, NH) and the ultrasonic dissector (CUSA; ValleyLab, Boulder, CO).14 Intermittent portal triad clamping was used during parenchymal transection. For this study, patients were divided into 2 groups: patients who underwent PVE before major hepatic resection (PVE group) and patients who underwent major hepatic resection without PVE (non-PVE group). The following data were collected for analysis: sex, age, hepatitis C virus and hepatitis B virus infection, preoperative TACE, blood transfusions, American Joint Committee on Cancer (AJCC) stage,15 tumor number, size of the largest tumor, margins, vascular invasion, fibrosis, cirrhosis, perioperative course, and follow-up. All cases of HCC were confirmed histologically. Nontumorous liver parenchyma was examined for underlying liver disease. Fibrosis and cirrhosis were graded according to the scale proposed by Ishak et al.16 Complications were graded according to the classification reported by Dindo et al.17 Minor complications were defined as grades I or II and major complications as grades III or IV. Postoperative hepatic insufficiency was defined as a peak postoperative bilirubin of >7.0 mg/dL.18 Duration of stay was defined from the day of surgery to the day of discharge or death. Postoperative mortality was considered as any death occurring within 90 days after surgery. Statistical analysis was performed with SPSS statistical software (v.12.0; SPSS, Chicago, IL). Continuous data were expressed as median and range and compared with the Mann-Whitney U test. Categorical data were compared with the Chisquare test or the Fisher exact test, as appropriate. The overall survival and disease-free survival rates were estimated using the Kaplan-Meier method
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Fig 1. A 59-year-old male patient had a 16-cm hepatocellular carcinoma in the right liver without evidence of extrahepatic disease. (A) Computed tomography revealed that the standardized future liver remnant (sFLR) volume was 12%. (B) Right portal vein embolization (PVE) was performed. (C) Four weeks after PVE, the sFLR was 21%. (D) The patient had no evidence of disease 5 years post-resection.
and compared using the log-rank test. A P value < .05 was considered statistically significant. RESULTS Clinicopathologic characteristics of the 54 patients are summarized in Table I. A total of 40 (74%) patients were male, with a median age of 61 years (range, 23--83). A total of 46 patients (85%) underwent a right or extended right hepatectomy. There were 21 patients in the PVE group and 33 in the non-PVE group. The 2 groups had statistically similar rates of hepatitis C virus and hepatitis B virus infection, preoperative TACE, parenchymal fibrosis, cirrhosis, positive margins, and blood transfusion. AJCC stage was similar between the groups, with the highest number of patients staged IIIA. All patients with cirrhosis were classified as Child-Turcotte-Pugh class A. Patients in the PVE group were older, with a higher male/female ratio. In the PVE group, the median sFLR pre- and post-PVE were 23 (range, 12--44%) and 33.8% (range, 21--54%), respectively. Of the 33 patients in the non-PVE group, 2 underwent measurement of sFLR, which were 26 and 30%, respectively. The other patients did not
undergo FLR volume measurement because of surgeons’ estimation of sufficient FLR volume in patients with normal livers (n = 20), tumor-induced left liver hypertrophy in patients scheduled for right or extended right hepatectomy (n = 5), and portal vein thrombosis (n = 4). In addition, 2 of these patients enrolled early in the study period when FLR volumes were not routinely measured. Although not statistically significant, more HCC patients in the latter years of the study period underwent preoperative PVE and major hepatectomy (Fig 2). TACE was performed in 6 patients in the PVE group and 3 in the non-PVE group. Indications for TACE were initially unresectable tumors (n = 5), as planned sequential treatment before PVE in patients with cirrhosis or moderate steatosis (n = 3), and as a bridge to resection in a patient recovering from a cardiac procedure (n = 1). Notably, 8 of these 9 patients underwent TACE in the last 2 years of the study. During the same study period, 9 patients underwent PVE in anticipation of major hepatectomy for HCC but were ineligible for surgery due to inadequate FLR hypertrophy (n = 3), tumor progression (n = 3), worsening chronic liver disease
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Table I. Patient characteristics PVE group (n = 21) Sex, M:F Age, y (range) HCV, n (%) HBV, n (%) TACE, n (%) Stage, n (%) I II IIIA IIIB Vascular invasion, n (%) Fibrosis,* n (%) Grades 0--4 Grades 5--6 Median alpha-fetoprotein, ng/ml (range) Type of resection, n (%) Right hepatectomy Extended right Left hepatectomy Extended left Central hepatectomy Median no. of tumors (range) Median size of largest tumor, cm (range) Positive margin, n (%) Blood transfusion, n (%) Median duration of stay, d (range)
65 7 6 6
20:1 (43–77) (33) (29) (29)
8 (38) 2 (10) 11 (52) 0 11 (52) 18 (86) 3 (14) 24.1 (1.8–19,548) 11 (52) 10 (48) 0 0 0 1 (1–5) 7 (3.2–20) 2 (10) 4 (19) 7 (5–21)
Non-PVE group (n = 33)
P value
49 8 9 3
20:13 (23–83) (24) (27) (10)
.003 .05 .47 .92 .06
12 5 15 1 21
(36) (15) (46) (3) (64)
.78
29 (88) 4 (12) 26.5 (1.7–367,000) 17 8 2 5 1 1 9 3 8 7
(52) (24) (6) (15) (3) (1–4) (1.2–18) (10) (24) (4–65)
.41 .82
.60 .13
.08 .33 .96 .65 .90
*Fibrosis was graded according to the scale proposed by Ishak et al.16 HCV, Hepatitis C virus infection; HBV, hepatitis B virus infection.
(n = 2), and poor performance status (n = 1). Among these 9 patients, 4 have died of disease, 3 are alive with disease, and 2 have undergone liver transplantation after median follow-up of 16 months (range, 1--53). Surgical results. Hepatic resection was performed at a median time of 30 days (range, 14--182) after PVE. Although the overall postoperative complication rates were comparable between the PVE and non-PVE groups (24 vs 36%, P = .33; Table II), there was a statistically higher rate of major complications in the non-PVE group (36 non-PVE vs 10% PVE group, P = .028). There were no postoperative deaths in the PVE group and 6 in the non-PVE group (P = .038). In the PVE group, 3 patients had minor complications, including ascites, wound infection, and self-limited bile leak (n = 1, each). Major complications occurred in 2 patients---1 required percutaneous drainage of a bile leak and the other required admission to the intensive care unit for respiratory distress. In the non-PVE group, 12 patients suffered major complications, including 6 postoperative deaths. Complications included bile leak requiring
Fig 2. Increasing number of patients undergoing preoperative portal vein embolization (PVE) and major hepatectomy in the past decade (P = .37).
percutaneous drainage (n = 1), mesenteric ischemia requiring reoperation in a patient with polycythemia vera (n = 1), respiratory distress requiring intensive care unit admission (n = 3), and nonfatal liver insufficiency (n = 1). Postoperative mortality in 5 patients was caused by liver insufficiency leading to multiorgan failure; 1 patient died of exacerbation of preexisting renal disease. The 2 patients in the non-PVE group who underwent preoperative liver volumetry did not have a postoperative complication.
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Table II. Postoperative complications Complication Minor complications, n (%) Self-limited bile leak Ascites Wound infection Total no. of patients Major complications, n (%) Bile leak Respiratory distress Mesenteric ischemia Nonfatal hepatic insufficiency Death Total no. of patients Total complications, n (%)
PVE group (n = 21) 1 1 1 3
Non-PVE group (n = 33)
P value
0 0 0 0
.206 .206 .206 .025
(3) (10) (3) (3) (18)* (36) (36)
.743 .554 .421 .421 .038 .028 .333
(5) (5) (5) (14)
1 (5) 1 (5) 0 0 0 2 (10) 5 (24)
1 3 1 1 6 12 12
*Five due to liver insufficiency and 1 from renal failure leading to multiorgan failure.
In the PVE group, 2 patients had bilobar HCC. In 1 patient, there was a suspicious lesion in segment 4. After right PVE, the lesion showed no change in size. The patient underwent a right hepatectomy and a wedge resection in segment 4; the lesion was confirmed as HCC. In another patient, a new lesion in the FLR was found during resection (nondetected in the pre- and post-PVE CT scans); the lesion was ablated. Survival and recurrence. After a median followup of 21 months (range, 0--114), the median overall survival for all 54 patients was 61 months. The overall survival rates at 1, 3, and 5 years was 94, 82, and 72%, respectively, in the PVE group and 93, 63, and 54%, respectively, in the non-PVE group, excluding the 6 postoperative deaths (P = .35; Fig 3). The recurrence rate in the PVE group was 38% (8 of 21 patients; 4 [19%] intrahepatic, 3 [14%] extrahepatic, and 1 [5%] intra- and extrahepatic). Excluding the 6 patients who died postoperatively, the recurrence rate in the non-PVE group was 48% (13 of 27 patients; 8 [30%] intrahepatic, 3 [11%] extrahepatic, and 2 [7%] intra- and extrahepatic). None of the 6 patients who underwent double embolization with TACE and PVE had disease recurrence. In the PVE group, disease-free survival rates at 1, 3, and 5 years was 84, 56, and 56%, respectively, compared with 66, 49, and 49%, respectively, in the non-PVE group (P = .38; Fig 4). DISCUSSION Hepatic resection remains the only potentially curative treatment for large HCC. Liver transplantation is not indicated in patients with large tumors or noncirrhotic livers. However, many patients with large HCC cannot undergo resection due to an
Fig 3. Overall survival after hepatectomy in patients with and without preoperative portal vein embolization (PVE), excluding postoperative deaths (P = .35).
inadequate FLR and/or impaired liver function. In the early 1980s, Makuuchi et al1 described using PVE to induce atrophy of the embolized lobe to be resected with compensatory hypertrophy of the nonembolized FLR. In the past 2 decades, PVE has been increasingly used to allow patients with initially inadequate FLR to undergo safe, curative hepatectomy; this technique has been used the most often in patients with colorectal liver metastases and cholangiocarcinoma.4,19 A recent metaanalysis by Abulkhir et al20 concluded that PVE is a safe and effective procedure to induce hypertrophy of the remnant liver and decrease postoperative liver failure rates. Although their study analyzed 75 publications on PVE that included 1,088 patients, less than 25% of the patients had HCC.20 The effects of PVE on HCC tumor growth and distant metastases remain ill-defined, with
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Fig 4. Disease-free survival in patients after hepatectomy with and without preoperative portal vein embolization (PVE), excluding 6 patients who died postoperatively (P = .38).
studies describing both beneficial and adverse effects of PVE on patient outcome.6,21 In this series, overall and disease-free survival rates were similar between PVE and non-PVE groups, as shown by previous authors.6 HCC invades the portal vein at a relatively early stage and disseminates through the liver via the portal circulation.22 Therefore, researchers have postulated that PVE exerts an antitumor effect by preventing transportal dissemination of cancer cells. However, to our knowledge, no study to date has demonstrated decreased intrahepatic recurrence rates in patients who have undergone PVE before hepatectomy for HCC. Conversely, investigators have hypothesized that PVE may accelerate tumor growth because of growth factors and cytokines released in the regenerating liver.23 To circumvent this potential problem, we embolize all tumorbearing segments of the liver, including segment 4 branches, in patients who are candidates for extended right hepatectomy. Our study demonstrates comparable recurrence rates between PVE and non-PVE groups. Wakabayashi et al8 found an increased rate of extrahepatic recurrence after PVE, which they attributed to a diversion of blood flow after PVE from the portal to hepatic veins with resultant dissemination of tumor cells through the hepatic venous circulation during surgical manipulation. However, we did not find any difference in rate or site of recurrence between the PVE and non-PVE groups. Notably, none of the 6 patients in this series who underwent double embolization with TACE and PVE had disease recurrence. Because the main blood supply for HCC is the hepatic artery and
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PVE results in increased hepatic arterial flow, concerns have been raised about the potential for accelerated tumor growth after PVE.23,24 To avoid this possibility, TACE has been proposed as a complementary procedure to PVE in patients with HCC. TACE eliminates the arterial blood supply to the tumor and embolizes potential arterioportal shunts in cirrhotic livers that attenuate the effects of PVE.25,26 In our study, the number of patients who underwent TACE before PVE is too small to draw conclusions. Our results, however, support a study by Ogata et al25 in which patients who underwent TACE before PVE had improved disease-free survival and increased FLR hypertrophy than patients who underwent PVE alone. Our current recommendation for those patients with bilobar HCC and tumor nodules in the FLR is to perform TACE before PVE to avoid tumor growth in the FLR after PVE. In this study, postoperative mortality and major morbidity rates were significantly higher in the non-PVE than the PVE group. Of 6 cases of postoperative mortality, 5 were due to hepatic insufficiency. Although most patients in the nonPVE group did not undergo systematic measurement of FLR volumes, our results suggest that patients in the PVE group had lower rates of postoperative liver insufficiency because of higher FLR volumes. In addition, PVE allows improved selection of patients for hepatectomy. Other investigators have demonstrated that the rate of liver regeneration after PVE predicts outcome after resection.21,23,27 PVE provides a noninvasive test to assess the capacity of the liver to regenerate in patients with chronic liver disease, and data derived from PVE in normal liver indicate that patients whose FLR degree of hypertrophy is #5% are at high risk for complications.27 Taken together, our data suggest that PVE before major hepatectomy for HCC neither prevents nor accelerates tumor growth. Rather, PVE provides an opportunity for patients considered primarily as borderline resectable or unresectable due to an inadequate FLR to undergo potentially curative hepatectomy without impairing shortterm outcomes. In addition, PVE enables improved selection of patients with HCC for major hepatic resection. Accordingly, more patients in the latter period of this study underwent PVE and major hepatectomy for HCC. The limitations of this study include the retrospective nature of the analysis. However, we believe that a prospective randomized controlled trial would be unethical, considering the documented benefits of PVE.6,19 In addition, the small number
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of patients included in our study does not allow conclusions to be made about the benefits of TACE before PVE and the minimum FLR volume needed for major hepatectomy in patients with chronic liver disease. In conclusion, this study demonstrates that PVE before major hepatectomy for HCC is associated with improved perioperative outcomes. Excluding postoperative deaths, the overall and disease-free survival rates were similar between patients who underwent hepatectomy with and without PVE. Thus, PVE increases the safety of major hepatectomy in patients with HCC without compromising long-term oncologic outcomes. REFERENCES 1. Makuuchi M, Takayasu K, Takuma T, Yamazaki S, Hasegawa H, Nishiura S, et al. Preoperative transcatheter embolization of the portal venous branch for patients receiving extended lobectomy due to the bile duct carcinoma. J Jpn Soc Clin Surg 1984;45:1558. 2. Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg 2001;88:165-75. 3. Vauthey JN, Chaoui A, Do KA, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 2000;127:512-9. 4. Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y. Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;243: 364-72. 5. Elias D, Ouellet JF, De Baere T, Lasser P, Roche A. Preoperative selective portal vein embolization before hepatectomy for liver metastases: long-term results and impact on survival. Surgery 2002;131:294-9. 6. Azoulay D, Castaing D, Krissat J, Smail A, Hargreaves GM, Lemoine A, et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg 2000; 232:665-72. 7. Tanaka H, Hirohashi K, Kubo S, Shuto T, Higaki I, Kinoshita H. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000; 87:879-82. 8. Wakabayashi H, Ishimura K, Okano K, Izuishi K, Karasawa Y, Goda F, et al. Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma? Cancer 2001;92:2384-90. 9. Hayashi S, Baba Y, Ueno K, Nakajo M, Kubo F, Ueno S, et al. Acceleration of primary liver tumor growth rate in embolized hepatic lobe after portal vein embolization. Acta Radiol 2007;48:721-7. 10. Vauthey JN, Abdalla EK, Doherty DA, Gertsch P, Fenstermacher MJ, Loyer EM, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002;8:233-40.
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11. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13:1271-80. 12. Madoff DC, Abdalla EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care. J Vasc Interv Radiol 2005;16: 779-90. 13. Vauthey JN, Pawlik TM, Abdalla EK, Arens JF, Nemr RA, Wei SH, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 2004;239:722-30; discussion 730-2. 14. Aloia TA, Zorzi D, Abdalla EK, Vauthey JN. Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection. Ann Surg 2005;242:172-7. 15. Vauthey JN, Sobin LH. On the uniform use of the AJCC/ UICC staging system for hepatocellular carcinoma. Surgery 2000;128:870. 16. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9. 17. 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. 18. Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, et al. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg 2007;204:854-62; discussion 862-4. 19. Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 2002;137:675-80; discussion 680-1. 20. Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008;247:49-57. 21. Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;237:208-17. 22. Kinoshita H, Sakai K, Hirohashi K, Igawa S, Yamasaki O, Kubo S. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986;10:803-8. 23. Kokudo N, Tada K, Seki M, Ohta H, Azekura K, Ueno M, et al. Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization. Hepatology 2001;34:267-72. 24. Nagino M, Nimura Y, Kamiya J, Kanai M, Hayakawa N, Yamamoto H. Immediate increase in arterial blood flow in embolized hepatic segments after portal vein embolization: CT demonstration. AJR Am J Roentgenol 1998; 171:1037-9. 25. Ogata S, Belghiti J, Farges O, Varma D, Sibert A, Vilgrain V. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma. Br J Surg 2006;93:1091-8. 26. Aoki T, Imamura H, Hasegawa K, Matsukura A, Sano K, Sugawara Y, et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma. Arch Surg 2004;139:766-74. 27. Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg 2007;94:1386-94.