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Published online before print February 28, 2003, 10.1148/radiol.2271012010
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(Radiology 2003;227:251-260.)
© RSNA, 2003


Vascular and Interventional Radiology

Portal Vein Embolization with Polyvinyl Alcohol Particles and Coils in Preparation for Major Liver Resection for Hepatobiliary Malignancy: Safety and Effectiveness—Study in 26 Patients1

David C. Madoff, MD, Marshall E. Hicks, MD, Eddie K. Abdalla, MD, Jeffrey S. Morris, PhD and Jean-Nicolas Vauthey, MD

1 From the Departments of Diagnostic Imaging (D.C.M., M.E.H.), Surgical Oncology (E.K.A., J.N.V.), and Biostatistics (J.S.M.), University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 325, Houston, TX 77030-4009. Received December 7, 2001; revision requested February 22, 2002; final revision received July 29; accepted August 9. Address correspondence to M.E.H. (e-mail: mhicks@di.mdacc.tmc.edu).


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate whether preoperative portal vein embolization (PVE) with polyvinyl alcohol (PVA) particles and coils is safe and effective for inducing lobar hypertrophy in patients with hepatobiliary malignancy.

MATERIALS AND METHODS: PVE was performed in 26 patients. All patients had malignancy: metastases (n = 11), cholangiocarcinoma (n = 9), hepatocellular carcinoma (n = 5), and gallbladder carcinoma (n = 1). One patient had underlying liver disease caused by hepatitis. PVE was performed if the future liver remnant (FLR) was estimated to be less than 25% of the total liver volume. PVE was performed with a percutaneous transhepatic approach (right, 25 patients; left, one patient). PVA particles and coils were used to occlude the right portal system and veins supplying segment IV to promote FLR hypertrophy (segments I–III ± IV). FLR hypertrophy was assessed with comparison of computed tomographic scans obtained before and 2–4 weeks after PVE. Effectiveness evaluation was based on changes in absolute FLR size and ratio of FLR to total estimated liver volume (TELV). Safety of PVE and hepatic resection was determined with postprocedure complication rate and median hospital stay.

RESULTS: Sixteen patients underwent hepatic resection (right trisegmentectomy [n = 13], right lobectomy [n = 3]) without mortality. Ten patients did not undergo resection (complete remission after medical therapy [n = 1], lack of regeneration [n = 2], extrahepatic disease undetected prior to PVE [n = 7]). Six patients had biliary obstruction; five were treated percutaneously before PVE. No patient developed postembolization syndrome or signs of fulminant hepatic insufficiency after PVE or resection. Two patients had complications after PVE that did not preclude successful resection. Median hospital stays were 1 day (PVE) and 7 days (liver resection). Mean absolute FLR increased from 325.0 to 458.6 cm3 (increase, 41.1%). Mean TELV was 1,784.8 cm3. FLR/TELV ratio increase was 8%.

CONCLUSION: Preoperative PVE with PVA particles and coils is safe and effective for inducing lobar hypertrophy in patients with advanced hepatobiliary malignancy.

© RSNA, 2003

Index terms: Liver, regeneration • Liver, surgery • Liver neoplasms, chemotherapeutic embolization, 76.1264 • Portal vein, CT, 957.1291 • Portal vein, therapeutic embolization, 957.1264


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Transcatheter portal vein embolization (PVE) is gaining acceptance in the preoperative treatment of selected patients who are potential candidates for major hepatic resection (18). By inducing selective lobar hypertrophy of the nondiseased portion of the liver, PVE may reduce complications after major resection.

Findings in previous studies suggest that 25% of the total liver volume must be preserved to minimize the morbidity of surgical resection in patients with an otherwise normal liver, and 40% of this volume must be preserved in patients with a liver that is compromised by chronic liver disease or high-dose chemotherapy (4,911). Therefore, patients with a normal liver whose estimated future liver volume is less than 25% after resection may benefit from this procedure. PVE, performed in patients who at presentation were not considered eligible for surgical resection because of the lack of sufficient remaining normal parenchyma, may thus help these patients to become candidates for this potentially curative procedure.

The degree and rate of hypertrophy of the nonembolized hepatic segments are dependent on many variables, including underlying liver disease (cirrhosis, hepatitis C) (12) and systemic disease (diabetes mellitus) (1315). Various substances, including cyanoacrylate and ethiodized oil, absorbable gelatin (Gelfoam; Pharmacia and Upjohn, Kalamazoo, MI) and thrombin, coils, polyvinyl alcohol (PVA) particles, microspheres, and absolute alcohol (5,9,1520), have been used for PVE. A similar degree of hypertrophy results, regardless of the embolized substance (15). To our knowledge, to date, researchers in one study reported excellent liver hypertrophy with use of PVA and coils in swine (20). The purpose of our study was to evaluate whether preoperative PVE with PVA particles and coils is a safe effective method for inducing lobar hypertrophy in patients with hepatobiliary malignancy.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A retrospective review of data regarding patients in our hepatobiliary database was performed. From October 1998 to May 2001, 26 patients with advanced hepatobiliary malignancy were treated with preoperative PVE to induce selective hepatic hypertrophy. Twenty-one men and five women (mean age, 59 years) were examined. All patients had malignant disease (11 metastases, nine cholangiocarcinomas, five hepatocellular carcinomas, and one gallbladder carcinoma). One patient had underlying chronic liver disease (hepatitis B– and hepatitis C–induced cirrhosis). The patients were referred by a hepatobiliary surgeon (J.N.V.) after case discussion at a weekly multidisciplinary hepatobiliary tumor conference. A waiver for informed consent was granted by our institutional review board after the board approved this study.

Helical computed tomographic (CT) scans (including triple-phase hepatic imaging) of the abdomen and pelvis were evaluated for the extent of hepatobiliary disease, the presence or absence of extrahepatic and/or distant metastatic disease, the presence of normal or abnormal portal venous and hepatic arterial perfusion, the presence or absence of portal venous variants, and the presence of biliary obstruction. After formal interpretation of the CT scans (performed by one of several body imaging faculty), the CT scans were then evaluated by at least one interventional radiology faculty and the referring surgeon (J.N.V.). Patients with known extrahepatic metastatic disease and/or periportal lymphadenopathy indicative of metastatic disease were excluded because they were no longer considered candidates for surgery.

PVE was not performed in patients with portal venous occlusion or in patients with renal failure who were receiving dialysis. Patients receiving dialysis are not considered candidates for extensive hepatic resection. Liver enzyme levels, including total serum bilirubin, serum alkaline phosphatase, serum lactate dehydrogenase, serum aspartate aminotransferase, and serum alanine aminotransferase, were measured before and after PVE and after liver resection. Prothrombin time was also measured before and after resection as an indicator of potential liver failure. Except for true coagulopathy, there were no hepatic enzyme laboratory criteria that were used to completely exclude patients from undergoing PVE or surgical resection. However, if patients had increased bilirubin levels because of biliary obstruction, the biliary systems were drained before PVE was performed.

Procedure
Embolization procedures were performed by one of six vascular and interventional radiology faculty members. All faculty members were fellowship-trained in vascular and interventional radiology and had extensive experience with complex embolization procedures.

Before PVE, informed written consent was obtained from each patient. Patients received one dose, 1 g, of ceftriaxone sodium (Rocephin; Roche Laboratories, Nutley, NJ) administered intravenously immediately before the procedure. Conscious sedation (ie, induced with intravenously administered midazolam hydrochloride [ESI Lederle, Philadelphia, Pa] and fentanyl citrate [Abbott Laboratories, North Chicago, Ill]) and a local anesthetic (1% lidocaine hydrochloride [Astra USA, Westborough, Mass]) were used for pain control. Access was obtained with ultrasonographic guidance, fluoroscopic guidance, or both. In 25 patients, the portal venous system was accessed by using a right percutaneous transhepatic approach, and in one patient, it was accessed by using a left percutaneous transhepatic approach.

A 22-gauge Chiba needle (Neff Percutaneous Access Set; Cook, Bloomington, Ind) was placed into a branch of the right portal venous system. The Seldinger technique was used to place a 6-F vascular sheath (Pinnacle Introducer Sheath; Boston Scientific/Medi-Tech, Natick, Mass) into the main right portal vein or a main portal branch. Flush portography was performed with a 5-F angiographic pigtail catheter (Royal Flush Plus; Cook) placed in the main portal vein. Anteroposterior (Fig 1), right and left anterior oblique, and craniocaudal projections were obtained to delineate the portal venous anatomy. Selective left and right portal vein injections also were performed.



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Figure 1. Normal anteroposterior flush portogram obtained before PVE by using a 6-F vascular sheath (white arrows) in the right portal vein branch and a 5-F pigtail catheter (large black arrow) in the superior mesenteric vein. An endoscopic plastic biliary endoprosthesis (small black arrow) was placed prior to evaluation for PVE. At CT before PVE, the patient had no biliary dilatation.

 
The hepatic segments were chosen for embolization on the basis of the hepatobiliary surgeon’s surgical plan. If a right hepatectomy was planned, segments V–VIII were embolized. If an extended right hepatectomy was planned, segments IVa and IVb were also embolized in an effort to embolize the entire tumor-bearing liver and to maximize future liver remnant (FLR) hypertrophy. In 26 PVE procedures, embolization of segment IV and segments V–VIII was performed in 21 patients. The remaining patients (n = 5) had no segment IV disease and underwent only right (segments V–VIII) PVE. No patient required a left hepatectomy or extended left hepatectomy, so left-sided embolizations were not performed.

Left portal vein segments (segments IVa and IVb) were embolized by using a microcatheter (Tracker; Target Therapeutics, Fremont, Calif) placed coaxially through a 5-F selective angiographic catheter. PVA particles (Contour; Boston Scientific/Target Vascular, Fremont, Calif) ranging from 300 to 500 µm (n = 21) and microcoils (Platinum Microcoils; Target Therapeutics) were used to embolize segments IVa and IVb. The particle size was chosen so as not to occlude the microcatheter. For right PVE (segments V–VIII), a 5-F reversed-curve catheter (Simmons 2; Cook) was used to deliver PVA particles ranging from 300 to 1,000 µm (n = 26) and 0.035- or 0.038-inch stainless steel embolization coils (Cook). The 5-F catheter was chosen for its ease of manipulation into the right portal branches, given the severe angulation of the right portal tree with the ipsilateral approach.

The smaller PVA particles were used first to occlude the distal smaller portal branches. The larger PVA particles were used later to help occlude the more proximal larger branches. Right hepatic lobe PVE was performed in all patients. Embolization was performed until stasis or near stasis was achieved. For segments V–VIII (right portal embolization), approximately four to six bottles (400–600 mg) of PVA particles were used to achieve near stasis. Approximately five to seven bottles (500–700 mg) were used to embolize segments IVa, IVb, and V–VIII. PVA particles were used to embolize third-order and smaller portal branches, whereas the coils were placed into the second-order portal branches. The number of coils varied from patient to patient, but the end point remained stasis or near stasis. Repeat portography was performed to evaluate embolization (Fig 2). The access track was embolized with 3-mm coils at the completion of the procedure. Before and after PVE, portal venous pressures were not obtained because no patient had a prior history of portal hypertension.



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Figure 2. Anteroposterior portogram obtained after right PVE demonstrates coils (large arrows) within branches of the right portal system and normal flow to left portal branches. Portal branches that supply segment IV are shown (small arrows).

 
Between October 1998 and May 2001, a total of 26 patients underwent PVE at our institution. All of the patients were included in the data presented. Embolization was not performed with other embolic agents either prior to or during the present study. The technique was slightly modified during the series. In the first patient, access was achieved by using the left medial segment (contralateral approach), but this proved technically difficult. In addition, with the contralateral approach, there is risk of injury to the FLR and the portal veins of segments II and III. Also, craniocaudal views were obtained in addition to the routine anteroposterior views because there was improved visualization of the veins of segment IV. No patients were excluded because of excessive tumor burden (size or number), but attempts were made to avoid access through tumors.

Patient Follow-up Examination
Evaluation of postembolization syndrome or hepatic insufficiency included review of patient symptoms and clinical signs and laboratory data, such as an increased white blood cell count, increasing serum aspartate aminotransferase and serum alanine aminotransferase levels, or increasing prothrombin time. Patients were discharged when they were clinically stable and had no complaints. Only oral analgesics or no analgesics were administered to the patients after embolization.

Cross-sectional imaging was performed before and approximately 2–4 weeks after PVE to determine the degree of hypertrophy. The range of CT follow-up varied because the majority of patients did not live in close proximity to the medical center (specialty cancer center) and underwent imaging at their convenience. Evaluation of the preoperative FLR was performed by one member of the interventional radiology faculty and the referring surgeon (J.N.V.) and was determined by calculation of the total estimated liver volume (TELV) and measurement of the FLR (segments I–III ± IV) at cross-sectional imaging.

The FLR/TELV ratio was calculated before and after embolization (21). PVE was performed if the preembolization FLR/TELV ratio was 25% or less in patients without chronic underlying liver disease or 40% or less in patients with a compromised liver (15). The TELV was calculated on the basis of an equation as follows: total liver volume = 706.2 x body surface area + 2.4. The equation was derived from the close association between the total liver volume and the body surface area, as previously described (21,22). Paired t tests were used to determine whether any changes in FLR or FLR/TELV ratio demonstrated a statistically significant difference.

Selection of patients for surgical treatment was determined on the basis of CT volumetric analysis, with new FLR measurements determined immediately before surgery. Resection was performed in patients in whom an increase in FLR was noted (two patients without regeneration were excluded from undergoing resection).

Surgical resection was performed by a hepatobiliary surgeon (J.N.V.). The type of surgical resection was determined after review of the patient’s clinical status and radiologic study findings. When possible, an extended right hepatectomy (right trisegmentectomy) or right lobectomy was performed. If evidence of extrahepatic spread (nodal or distant metastasis) was found before or at laparotomy, resection was not performed. Postresection monitoring was performed by the surgical staff and included daily evaluation of clinical and laboratory data. Hospital discharge was at the discretion of the surgical staff when clinically appropriate.

Safety and Effectiveness
The safety and effectiveness of PVE was determined by calculation of the median hospital stay (in days) after PVE and surgical resection. A hospital stay of less than 1 day was considered as an inpatient hospitalization of 23 hours or less. The mean absolute FLR (in cubic centimeters) and the FLR/TELV ratio were calculated before and after embolization to determine the degree of hypertrophy. From a review of the literature, the embolic materials used in our study were then compared with those used in other studies on the basis of the degrees of hypertrophy achieved. Complications after PVE and surgery were recorded.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PVE was attempted in 26 patients and was technically successful in all patients. Sixteen patients underwent successful hepatic resection. In 13 patients, an extended right hepatectomy (right trisegmentectomy) was performed, and in three patients, a right lobectomy was performed. Ten patients did not undergo resection. In seven patients who had adequate hypertrophy, resection was not performed because of progression of disease documented at immediate preoperative imaging or at laparotomy. Two patients did not undergo resection because of insufficient liver regeneration necessary to achieve a safe FLR/TELV ratio; one of these two patients had diabetes mellitus. There was no CT evidence of portal vein recanalization in either patient. At 1-month follow-up CT, one patient with hepatocellular carcinoma had complete remission after treatment with three cycles of fluorouracil (Adrucil; Pharmacia and Upjohn) and interferon-alfa-2b (Intron A; Schering-Plough, Madison, NJ) and therefore did not undergo resection.

Six patients had biliary obstruction before PVE as determined at cross-sectional imaging and with increased liver function test values. Five of these patients were treated successfully with percutaneous biliary drainage before PVE. No patient developed postembolization syndrome after PVE or signs of fulminant liver insufficiency after PVE or resection. Although three patients were discharged on the same day on which PVE was performed, postprocedure (ie, PVE) management included overnight hospital admission for observation in most patients. Longer hospitalization was required for patients with additional medical concerns, such as fever or pain.

Average CT volumetric data were calculated in the 24 of 26 patients. Table 1 provides these data and clinical and demographic information. The two patients who were not included underwent PVE early in the study, and the data were not available. However, the patients continued to undergo clinical assessment and follow-up. The mean TELV was 1,784.8 cm3. The mean absolute FLR increased from 325.0 to 458.6 cm3 (ie, an increase of 41.1%). This increase was statistically significant (P < .001, paired t test). Before PVE, the FLR/TELV ratio was 18.1%. After PVE, the FLR/TELV ratio was 25.8%. The mean FLR/TELV ratio increase after PVE was 7.7%, and this increase also was statistically significant (P < .001). The FLR/TELV ratio with the PVA particle and coil combination embolic agent was compared with the ratios obtained in other studies in which investigators evaluated different embolic agents (Table 2).


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TABLE 1. Demographic and Liver Volume Data before and after PVE

 

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TABLE 2. Multistudy Comparison of the FLR/TELV Ratio Increase after PVE with Different Embolic Agents

 
Images obtained in selected patients (Figs 35) demonstrate substantial hypertrophy of the FLR after PVE. There are an insufficient number of patients with only right PVE in this study to enable a meaningful analysis of added effect of segment IV embolization to right lobe PVE with regard to the extent of contralateral hypertrophy. Median hospital stays were less than 2 days (range, 1–8 days) for PVE and less than 8 days (range, 7–17 days) for liver resection.



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Figure 3a. (a) Transverse CT scan obtained in a 63-year-old man with hepatocellular carcinoma shows a 5-cm necrotic mass (arrow) in segments VI and VII. The TELV was 1,783 cm3. The FLRs for segments I-III and IV (arrowheads) were 398 and 676 cm3 before and after PVE, respectively. The FLR/TELV ratio before PVE was 22.3%. (b) Transverse CT scan obtained after PVE shows substantial increase in the size of the FLR (arrowheads). The FLR/TELV ratio was 37.9%, which represented an increase of 15.6%. The patient subsequently underwent successful right hepatic hepatectomy and pancreaticoduodenectomy.

 


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Figure 3b. (a) Transverse CT scan obtained in a 63-year-old man with hepatocellular carcinoma shows a 5-cm necrotic mass (arrow) in segments VI and VII. The TELV was 1,783 cm3. The FLRs for segments I-III and IV (arrowheads) were 398 and 676 cm3 before and after PVE, respectively. The FLR/TELV ratio before PVE was 22.3%. (b) Transverse CT scan obtained after PVE shows substantial increase in the size of the FLR (arrowheads). The FLR/TELV ratio was 37.9%, which represented an increase of 15.6%. The patient subsequently underwent successful right hepatic hepatectomy and pancreaticoduodenectomy.

 


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Figure 4a. (a) Transverse CT scan obtained in a 55-year-old man with cholangiocarcinoma shows tumor within the proximal common hepatic duct, just inferior to this CT section. The FLRs for segments I-III (arrowheads) were 301 and 463 cm3 before and after PVE, respectively. The TELV was 2,007 cm3. The FLR/TELV ratio before PVE was 17.0%. (b) Transverse CT scan obtained after PVE demonstrates hypertrophy. The FLR/TELV ratio was 25.1%, which represented an increase of 8.1%. The FLRs for segments I-III (arrowheads) are shown. The patient subsequently underwent successful right trisegmentectomy. (c) Transverse CT scan obtained after resection shows a massive liver remnant (arrows).

 


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Figure 4b. (a) Transverse CT scan obtained in a 55-year-old man with cholangiocarcinoma shows tumor within the proximal common hepatic duct, just inferior to this CT section. The FLRs for segments I-III (arrowheads) were 301 and 463 cm3 before and after PVE, respectively. The TELV was 2,007 cm3. The FLR/TELV ratio before PVE was 17.0%. (b) Transverse CT scan obtained after PVE demonstrates hypertrophy. The FLR/TELV ratio was 25.1%, which represented an increase of 8.1%. The FLRs for segments I-III (arrowheads) are shown. The patient subsequently underwent successful right trisegmentectomy. (c) Transverse CT scan obtained after resection shows a massive liver remnant (arrows).

 


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Figure 4c. (a) Transverse CT scan obtained in a 55-year-old man with cholangiocarcinoma shows tumor within the proximal common hepatic duct, just inferior to this CT section. The FLRs for segments I-III (arrowheads) were 301 and 463 cm3 before and after PVE, respectively. The TELV was 2,007 cm3. The FLR/TELV ratio before PVE was 17.0%. (b) Transverse CT scan obtained after PVE demonstrates hypertrophy. The FLR/TELV ratio was 25.1%, which represented an increase of 8.1%. The FLRs for segments I-III (arrowheads) are shown. The patient subsequently underwent successful right trisegmentectomy. (c) Transverse CT scan obtained after resection shows a massive liver remnant (arrows).

 


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Figure 5a. (a) Transverse CT scan obtained in a 66-year-old man with colon carcinoma and liver metastases (arrow). The FLRs for segments I-III (arrowheads) were 214 and 475 cm3 before and after PVE, respectively. The TELV was 1,982 cm3. The FLR/TELV ratio before PVE was 10.8%. (b) Transverse CT scan obtained after PVE demonstrates hypertrophy. The FLR/TELV ratio was 24.0%, which represented an increase of 13.2%. The FLRs for segments I-III (arrowheads) are shown. The patient subsequently underwent successful right trisegmentectomy.

 


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Figure 5b. (a) Transverse CT scan obtained in a 66-year-old man with colon carcinoma and liver metastases (arrow). The FLRs for segments I-III (arrowheads) were 214 and 475 cm3 before and after PVE, respectively. The TELV was 1,982 cm3. The FLR/TELV ratio before PVE was 10.8%. (b) Transverse CT scan obtained after PVE demonstrates hypertrophy. The FLR/TELV ratio was 24.0%, which represented an increase of 13.2%. The FLRs for segments I-III (arrowheads) are shown. The patient subsequently underwent successful right trisegmentectomy.

 
Two (8%) of 26 patients developed complications after PVE, but no complication precluded successful resection. One patient developed main and left portal vein thrombosis after PVE, which was diagnosed on the basis of findings at routine follow-up CT to evaluate FLR hypertrophy. The patient reported low-grade fevers but was otherwise asymptomatic. The portal vein thrombosis was subsequently treated successfully with a 30-hour infusion of recombinant tissue plasminogen activator (Activase; Genentech, South San Francisco, Calif), at a dose of 0.4 mg/h administered through the left portal vein and at a dose of 0.6 mg/h administered through the main portal vein, and mechanical thrombolysis (Angiojet; Possis, Minneapolis, Minn). This patient had a patent aberrant left gastric vein, which was crucial in maintaining blood supply to the left lateral segment but also may have facilitated portal vein thrombosis by providing competing flow.

Findings at follow-up CT performed 2 weeks after thrombolysis demonstrated patency of the main and left portal veins. The patient underwent subsequent successful resection, and a CT scan obtained at that time showed that the portal veins were patent. After surgery, the portal veins reoccluded, as was documented with a CT scan. This patient also had isolated right biliary obstruction without jaundice that was not treated with percutaneous or endoscopic drainage before PVE. At the time of the procedure, drainage was not performed in this patient because biliary dilatation was not considered a contraindication. The patient was alive 18 months after resection without sequelae.

The other patient developed a subcapsular hematoma after PVE, and the hematoma was evacuated at the time of successful resection. No blood transfusion was required. The hemorrhage was believed to be the result of transhepatic access through a large tumor. Postoperative complications are shown in Table 3, and they include subphrenic abscess (n = 1), bile leak (n = 2), small-bowel perforation 7 days after resection (n = 1), wound infection (n = 1), and transient hepatic failure (n = 1) in a patient with minimal regeneration (FLR volumes before and after PVE were 12% and 14%, respectively). All other patients had an uneventful postoperative course.


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TABLE 3. Patients Who Underwent Surgery

 
The median values for liver function tests obtained before PVE, after PVE, and after resection are presented in Table 4. Because of the retrospective nature of this study, data obtained before and after PVE were available for 24 patients and data obtained after resection were available for 10 patients.


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TABLE 4. Median Laboratory Values before and after PVE and after Resection

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many authors have observed that occlusion of the portal vein secondary to tumor invasion or ligation leads to atrophy of the ipsilateral lobe and hypertrophy of the contralateral lobe (12,2528). These findings provide the groundwork for liver regeneration research and the foundation for the technique of PVE.

The underlying mechanisms for liver regeneration are complex. First, the hepatocyte has the ability to dedifferentiate and clonally expand, and this ability leads to increases in hepatocyte cell mass and number (29). Second, intrahepatic and extrahepatic factors contribute to induction and control of hepatocyte growth. Hepatocyte growth factor is the most important and potent stimulus for regeneration, since it is released from hepatocytes in response to hepatocellular injury. In addition to hepatocyte growth factor, other mitogenic factors and cytokines lead to rapid gene induction and regeneration (30,31). Extrahepatic factors are carried primarily by the portal vein and not the hepatic artery (32).

The rationale for performing PVE before hepatic resection that is anticipated to leave a small remnant liver was first described by Makuuchi et al (1,2). They observed that at resection PVE minimizes the sudden elevation in portal pressure that can result in hepatocellular damage in the residual liver. This change in portal pressure, in addition to operative manipulation, may combine to result in hepatic congestion and postresection dysfunction. Changes in liver function test values are usually minor and transient after PVE in patients whose values before PVE were normal, as we again determined in this study (21). In almost 50% of patients, there is no appreciable change in liver function test values after PVE.

When serum alanine aminotransferase and aspartate aminotransferase values increase, they usually peak at a level less than three times the baseline value 1–3 days after embolization and return to the baseline value at 7–10 days, regardless of the embolic material used (2,4,9,13,14,17,24). A slight change in total serum bilirubin value and white blood cell count may be seen. PVE is associated with minimal side effects and is considerably less toxic than arterial embolization. Symptoms of postembolization syndrome, such as nausea and vomiting, are rare. Fever and pain are minimal. This is because PVE produces no distortion of anatomy, minimal inflammation except immediately around the embolized vein, and little if any parenchymal or tumor necrosis (2,21,33). Findings in studies with animals indicated that hepatocytes undergo apoptosis and not necrosis after portal venous occlusion (20,34).

The absolute minimum volume of liver necessary to support postresection hepatic function has not been clearly defined. For patients with normal underlying liver, 25% of the standardized liver volume is probably sufficient (15,21,35), whereas 40% is probably the minimum in patients with compromised underlying liver (10,11). In this series of patients with normal underlying liver, the volume cutoff used was thus 25% of the TELV. However, despite a number of patients who do not meet the criterion of a 25% FLR volume, we have gone ahead with resection in all patients in whom there has been hypertrophy. As suggested by Nagino and colleagues (7), a right trisegmentectomy with caudate lobectomy is equivalent to 81% hepatic resection (ie, FLR of 19%).

The relatively short hospital stay after extended resection after PVE (median, 7 days) is better than historically reported for extended hepatic resection without PVE (historical control, approximately 14 days [21,36]). Thus, decreased length of overall hospital stay is indirect evidence of the physiologic effect of a larger liver remnant in each patient. Postoperative infections may result in death caused by liver failure in patients with insufficient hepatic reserve. This cascade of events is less likely to occur in patients with an adequate liver remnant. Shirabe et al (37) indicated that no patient with underlying liver disease who had a standardized liver volume greater than 285 mL/m2 body surface area died after liver resection.

Liver regeneration usually peaks within 2 weeks after PVE. Findings in studies in animals indicated that regeneration peaks within 7 days of PVE, with 14% of hepatocytes undergoing replication (20). Regeneration rates reported in patients are similar to those reported in animals. Noncirrhotic livers have the fastest regeneration rate, which is 12–21 cm3/d at 2 weeks after PVE, approximately 11 cm3/d at 4 weeks after PVE, and 6 cm3/d at 32 days after PVE (4,1215). Patients with cirrhotic livers or diabetes have a slower regeneration rate, which is approximately 9 cm3/d at 2 weeks after PVE (1315).

Many embolic materials have been used for PVE, without significant differences in the hypertrophy rate (15). These materials include cyanoacrylate and ethiodized oil, absorbable gelatin and thrombin, coils, PVA particles, microspheres, and absolute alcohol. Some authors prefer cyanoacrylate because it leads to fast reliable hypertrophy and minimizes the delay in acbievement of definitive resection (9). This material ensures portal vein occlusion, which persists after 4 weeks, whereas the combination of absorbable gelatin and thrombin tends to lead to recanalization (16). In animals, Matsuoka (16) compared thrombin, fibrin glue, and cyanoacrylate and found that they provide short-, moderate-, and long-term embolization, respectively.

de Baere et al (9) reported that cyanoacrylate embolization led to a 90% increase in liver volume after 30 days, whereas the absorbable gelatin–thrombin combination resulted in only a 53% volume increase after 43 days. One drawback of cyanoacrylate embolization is the induction of an inflammatory process (ie, peribiliary fibrosis, casting of the portal vein), which may increase the difficulty of the subsequent surgical procedure (9,17). PVE performed with absolute alcohol has been found to be particularly useful in the treatment of hepatocellular carcinoma, although greater changes in liver function test values are found with this agent than with any other agent (18). Although absolute alcohol causes substantial periportal fibrosis and necrosis, recanalization is rare. In two reports, researchers claimed increased hypertrophy rates, but the numbers of patients in these series were too small for the findings to be conclusive (13,19).

The ideal agent is one that causes permanent embolization without recanalization, is tolerated well by the patient, and is easy to administer. PVA particles are safe, cause minimal periportal reaction, and generate durable portal vein occlusion when they are used in combination with coils (20). PVA particles, as well as absorbable gelatin and thrombin, are easy to administer, but these agents appear most useful when they are used in combination with coils. We believe that, theoretically, our technique may meet this need. PVA particles are used to occlude the distal small outflow branches, and coils are used to embolize large inflow portal branches. In addition, the coils are used to prevent reflux of particles, which can lead to nontarget embolization. Combination therapy with PVA particles and coils may ensure the desired permanent occlusion necessary for PVE and lead to an adequate rate of hypertrophy (ie, mean absolute FLR increase of 41.1% and mean FLR/TELV ratio increase after PVE of 7.7%), but further study is necessary to evaluate this finding.

Until this time, treatment with the combination of PVA particles and coils has been reported in only one study in swine and was used for inducing selective hepatic lobe hypertrophy for gene therapy induction (20). Further studies of PVA particles with coils, other previously used agents, and newer agents may help better elucidate those agents that may lead to improved liver hypertrophy. Although each of the embolic agents presented has advantages and disadvantages, no agent has been proved to be consistently superior to any other, as seen in Table 3.

Although findings in this study show the potential benefits of PVE, there remain several limitations and unresolved issues. First, although CT results are the cornerstone of surgical planning, there is no universal agreement regarding the method for measuring liver volumes. Some authors measure the resected and total liver volumes and estimate the size of the normal liver by subtracting the tumor volume, as with the following calculation: (resected volume - tumor volume)/(total liver volume - tumor volume) (11,38). With multiple tumors, this method can be demanding, and it does not account for the actual functional liver volume when there is biliary dilatation or vascular obstruction (11,15,21,38). With our method, the FLR can be measured, and the total liver volume can be estimated with a formula so that the FLR/TELV ratio can be calculated (21). This method allows for uniform comparison of FLR volume prior to extended resection, with or without preoperative PVE. From this method of calculation, a correlation between FLR and operative outcome was established (21).

Second, the currently available imaging modality (ie, CT) used in this study cannot depict micrometastatic disease. The presence of micrometastatic disease in the FLR or at distant sites would be a contraindication to PVE and subsequent resection. At present, no imaging study can accurately depict micrometastatic disease. Although positron emission tomography may have potential use in the future, its current resolution may not be helpful in reducing the number of patients who do not ultimately benefit from resection.

Tumor growth in the FLR prevented resection in only one patient in this series. Tumor growth after PVE has been reported (23), though all tumor-bearing liver was not embolized in this series. PVE should be performed after careful review of the metastatic distribution of the disease. In the present series, all tumor-bearing liver was embolized on the basis of findings at helical CT. We and others (8) emphasize the importance of systematic embolization of segment IV in patients who will undergo an extended right hepatectomy (ie, right trisegmentectomy), because this leads to more reliable FLR hypertrophy and minimizes the probability of interval tumor growth.

Accelerated tumor growth rates after PVE for hepatocellular carcinoma and liver metastases prior to resection have also been reported. Elias et al (23) initially reported this phenomenon in five patients with colorectal metastases in whom tumor growth was accelerated in the nonembolized liver parenchyma. In two subsequent series, investigators (39,40) reported similar findings with an inconsistent technique of PVE; further, in these series, the patient cohorts were not comparable with respect to stage of disease, tumor size, and adjuvant therapy. In the current series, we routinely embolized the entire tumor-bearing liver, including segment IV if needed, to minimize the risks of accelerated tumor growth that may result from increased portal flow and hepatatrophic factors.

Third, although the criterion for performing PVE was an FLR of less than 25%, one patient (patient 20, Table 1) had an FLR/TELV ratio of 37% before PVE. In this case, the decision to perform PVE was determined on the basis of the extent of the anticipated surgical resection (ie, right hepatic lobectomy and pancreaticoduodenectomy) to minimize the risk of surgical complications associated with the overall extent of the procedure. Subsequently, the FLR/TELV ratio after PVE in this patient was 48%, which represented an increase of 11%. For these reasons, three factors are important to consider when a decision is made to perform PVE: the estimated size of the FLR, the presence or absence of underlying liver disease (ie, FLR/TELV ratio < 25% in otherwise normal liver and 40% in the compromised liver), and the extent of the anticipated procedure (15).

Embolization was performed in patient 18, despite an FLR/TELV ratio of 26% caused by the need for an extended hepatic resection with bile duct resection and an estimated increased postoperative risk caused by associated comorbid medical conditions. However, atrophy of the FLR was noted, since the patient had a large tumor that invaded the falciform ligament, with substantial compression of the left portal vein.

Fourth, only 16 (62%) of the 26 patients in this study in whom PVE was performed underwent resection. In the literature (35,9,12,14,17,21,24,4143), the range is 58%–100% (weighted mean, 81% [302 of 371] in studies in which the proportion of patients who underwent successful resection was reported). A reason for our lower rate of resection may be that our hospital is a designated specialty cancer center. Patients treated at our hospital may have more advanced hepatobiliary malignancies than the patients treated at other centers. Further, the 62% rate reported herein is within the range of 41%–79% for resectability rates reported elsewhere in patients who underwent resection for hepatobiliary malignancies without preoperative PVE (44,45).

Today, preoperative PVE is a valuable procedure to be considered prior to major liver resection in the appropriate clinical setting. This technique may help diminish postresection morbidity evidenced by minimal changes in postresection liver function and decreased length of hospitalization in patients with increased FLR mass (21).

Reporting of the median hospital stay is important, particularly after hepatic resection, as it directly relates to postoperative morbidity (eg, cholestasis, impaired synthetic function, fluid retention) and mortality (21). In addition, many patients who were initially not considered for resection because of a lack of sufficient remaining normal hepatic parenchyma can be added to the pool of candidates for surgical treatment, and these patients have been shown to have an overall survival equal to that of patients who do not require PVE (10,42,46). Further clinical study will help to find the means to better identify patients who are candidates for preoperative PVE, to improve preoperative imaging, and to clarify the extent and type of embolic material to enable maximal liver hypertrophy.


    FOOTNOTES
 
Abbreviations: FLR = future liver remnant, PVA = polyvinyl alcohol, PVE = portal vein embolization, TELV = total estimated liver volume

Author contributions: Guarantors of integrity of entire study, D.C.M., M.E.H., E.K.A., J.N.V.; study concepts, D.C.M., M.E.H., J.N.V.; study design, D.C.M., M.E.H.; literature research, D.C.M., M.E.H., E.K.A., J.N.V.; clinical studies, D.C.M., M.E.H., E.K.A., J.N.V.; data acquisition, D.C.M., J.N.V.; data analysis/interpretation, D.C.M., M.E.H., E.K.A., J.N.V.; statistical analysis, D.C.M., J.S.M.; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, D.C.M., M.E.H., E.K.A., J.N.V.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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