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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Background:

Portal vein embolization (PVE) has become a standard procedure to increase the future liver remnant (FLR) and enable curative resection of initially unresectable liver tumours. This study investigated the safety and feasibility of a new two-stage liver resection technique that uses in situ liver transection (ISLT) and portal vein ligation before completion hepatectomy.

Methods:

A consecutive series of patients undergoing ISLT and extended right hepatectomy between 2009 and 2011 were compared with consecutive patients undergoing extended right hepatectomy after PVE. All patients had initially unresectable primary or secondary liver tumours, owing to an insufficient FLR (liver segments II/III).

Results:

Fifteen patients who had PVE and seven who underwent ISLT before extended right hepatectomy were evaluated. ISLT induced rapid growth of the FLR within 3 days, particularly after insufficient PVE, from a mean(s.d.) of 293(58) ml to 477(85) ml, corresponding to a volume increase of 63(29) per cent. All patients who had ISLT underwent completion extended right hepatectomy within 8 days (range 4–8 days).

Conclusion:

ISLT is an effective and reliable technique to induce rapid growth of the FLR, even in patients with insufficient volume increase after PVE. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Hepatic resection has become the standard treatment for patients with liver tumours and remains the only potentially curative therapy in most instances. Extended liver resections are frequently necessary to achieve tumour-free resection margins1, 2. Complications after extended hepatic resections are related to the residual liver volume after resection, rather than the amount of liver resected3.

Computed tomography (CT) liver volumetry is used to measure the future liver remnant (FLR) as a predictor of postoperative hepatic dysfunction4, 5. A 25–30 per cent remnant liver is considered the minimum volume, as major postoperative complications increase when the remnant volume is smaller than this6, 7. Portal vein embolization (PVE) is effective in inducing hypertrophy of non-embolized hepatic segments and is useful before major hepatic resections8, 9. An increase in FLR volume of 20–46 per cent may be achieved 2–8 weeks after PVE8, 10. Today preoperative PVE is considered standard therapy for patients with an insufficient FLR before extended liver resection11. However, insufficient hypertrophy of the FLR or disease progression after PVE may prevent curative liver resection in up to 20 per cent of patients9, 12, 13.

Recently, in situ liver transection (ISLT) combined with portal vein ligation has been described for growth induction of the FLR in two-stage liver resections14–17. The feasibility and usefulness of this new strategy, particularly after PVE, has still to be determined. The use of ISLT instead of PVE for growth induction of the FLR arose initially from the situation in which intraoperative frozen-section analysis in a patient scheduled for right hepatectomy revealed infiltration of liver segment IV so that extended right hepatectomy was indicated. Because of an insufficient FLR volume (segments II and III) on CT volumetry, the decision was made to transect the liver to the right side of the falciform ligament, leaving the liver arterialized, while dissecting and ligating all portal vein branches to the right liver and segments I and IV, similar to interventional PVE. The rationale for ISLT instead of PVE was to decrease the surgical risk of subsequent completion surgery as the dissection was already advanced. Completion surgery a few days later entailed merely dividing the right bile duct, the right artery, and the middle and right hepatic vein.

The present study evaluated the usefulness of ISLT in inducing effective and rapid growth of the FLR in comparison with PVE in patients with initially unresectable liver tumours owing to an insufficient FLR.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Patients scheduled for extended right hepatectomy with initially unresectable primary and secondary liver tumours owing to an insufficient FLR (liver segments II/III), and who underwent PVE before surgery between 2004 and 2011, were identified retrospectively. Data from patients with similar tumours who had ISLT between 2009 and 2011 were analysed prospectively with regard to the feasibility and safety of the surgical technique (ISLT with portal vein ligation and two-stage liver resection versus primary extended right hepatectomy following PVE). Data on 30-day mortality and morbidity, postoperative liver function, volume gain of the FLR, development of intrahepatic oedema, and time to surgery were collected. Patients who did not undergo at least exploratory laparotomy after PVE and those with signs of cirrhosis were excluded. Initial unresectability was defined as a FLR of less than 20 per cent.

Computed tomography

Data sets were obtained from helical CT using intravenous contrast and imaging of the upper abdomen in the portal venous phase. A baseline examination was followed by weekly examinations. At baseline, total liver volume (TLV) and volume of liver segments II and III (FLR) was calculated. During follow-up only FLR was measured. All patients who had ISLT underwent CT 3 days after the first operation to evaluate growth of the FLR. The very early scan on day 3 after ISLT was felt necessary for close monitoring of liver growth and also because a plastic bag had been left around the right liver lobe to avoid adhesions (see surgical details below). Densitometric analysis of scans was performed to differentiate between a true increase in liver tissue of segments II/III and postoperative oedema.

Portal vein embolization

Using a transileocolic portal venous approach, a 5-Fr vascular sheath (Terumo, Leuven, Belgium) was placed via direct cannulation in the portal vein under general anaesthesia. The portal venous tree was imaged using a 5-Fr angiographic cobra catheter (Terumo) in the main portal vein. Polyvinyl alcohol particles (Contour; Boston Scientific, Cork, Ireland) and a histoacryl/lipiodol mixture (Braun, Tuttlingen, Germany and Guerbet, Roissy, France) were used to occlude portovenous branches to liver segments I and IV–VIII. Successful embolization was documented by repeat imaging.

In situ liver transection

Initial preparation of the liver was performed as for extended right hepatectomy. After cholecystectomy, the hepatoduodenal ligament was dissected and a radical lymphadenectomy performed for oncological reasons and vascular identification. The right branches of the portal vein were identified, suture ligated and divided. Portal branches to segment I were routinely ligated and transected for anatomical reasons, and branches to segment IV were also ligated and divided, similar to interventional PVE. The right hepatic duct, the bile ducts to segments I and IV, and the corresponding arteries were preserved and marked with a vessel loop for easy transection during the subsequent procedure. Care was taken to preserve the branches of the left artery and bile duct. Complete mobilization of the right liver lobe, including ligation and transection of all right and left retrohepatic veins, was performed after hilar dissection. The isolated right and middle hepatic veins were marked with vessel loops, and transection of the liver parenchyma between segments II and III on one side, and I and IV–VIII on the other side, was performed with a cavitron ultrasonic surgical aspirator (CUSA®; Valleylab, Boulder, Colorado, USA). If the left bile duct had to be resected, a hepaticojejunostomy was performed to liver segments II and III during the initial operation. After completion of the ISLT procedure, liver segments I and IV–VIII (the extended right hepatectomy specimen), still arterialized, were wrapped in a soft plastic bag to avoid adhesions to the surrounding tissue before completion surgery.

Definitive resection

After sufficient liver volume increase had been confirmed by CT, removal of the isolated segments I and IV–VIII was scheduled. In this second operation the bag was removed and the remaining structures to the specimen were divided, that is the arteries, bile ducts and hepatic veins already isolated and tagged by vessel loops.

Statistical analysis

Continuous data are presented as mean (s.d.). Statistical differences between groups were determined by one-way ANOVA for unbalanced design, followed by Student's t test. P < 0·050 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Twenty-two consecutive patients (14 men, 8 women) with malignant primary (11) or secondary (11) liver tumours were enrolled. Median age was 67 (range 55–81) years. The indications for treatment were intrahepatic cholangiocellular carcinoma (5), Klatskin tumour (3), gallbladder cancer (2), hepatocellular carcinoma (1), liver metastases from colorectal cancer (10) and neuroendocrine tumours (1). In all patients but one, in whom the extent of resection became obvious only during surgery, extended right hepatectomy was planned before surgery. All 22 patients had a FLR of less than 20 per cent. They all had normal liver function before operation.

None of the 11 patients with primary liver tumours had neoadjuvant chemotherapy before PVE or ISLT and consecutive liver resection. Five patients with colorectal metastases received four to six adjuvant cycles of FOLFOX4 (oxaliplatin, folinic acid, fluorouracil) before liver metastases became apparent. One patient received neoadjuvant irinotecan and bevacizumab in combination with 5-fluorouracil and leucovorin before ISLT. Four patients with synchronous colorectal metastases and indication for liver resection, and one with neuroendocrine liver metastases received no chemotherapy before PVE and ISLT.

Between 2004 and 2011, 15 patients underwent PVE only to induce hypertrophy of the non-embolized FLR before exploratory laparotomy. Between 2009 and 2011, ISLT was performed in seven patients (Fig. 1). Following the finding of dramatic FLR growth in a patient in whom an intraoperative decision was made to perform ISLT, three consecutive patients underwent ISLT instead of PVE to prove its effectiveness for FLR growth induction. In three other patients insufficient growth of the FLR after PVE triggered ISLT as an additional procedure to explore whether this would induce sufficient growth of the FLR. In all seven patients extended right hepatectomy was completed after ISLT in the second operation.

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Figure 1. Intraoperative view on day 4 after in situ liver transection (ISLT) in a patient with intrahepatic cholangiocellular carcinoma. a At relaparotomy, liver segments I and IV–VIII of the split liver are still in a plastic bag to avoid adhesions. b After removal of the plastic bag, the red rubber band marks the right hepatic artery. c After completion extended right hepatectomy. The hepaticojejunostomy had already been performed after ISLT; the resection margin is covered by a haemostatic sponge. FLR, future liver remnant

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Growth of future liver remnant following portal vein embolization or in situ liver transection

In both groups, the initially insufficient FLR volume was increased in all patients to a FLR/TLV ratio of more than 20 per cent or a critical FLR/bodyweight ratio of 0·5 (Fig. 2, Fig. 3a).

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Figure 2. Computed tomography a before, and b 3 days and c 10 days after two-stage extended right hepatectomy for intrahepatic cholangiocellular carcinoma (CCC). Future liver remnant (FLR) volume was 281 ml before surgery, 500 ml after in situ liver transection (day 3) and 937 ml 7 days after completion surgery

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Figure 3. Future liver remnant (FLR) volume gain after in situ liver transection (ISLT) or portal vein embolization (PVE). a Increase in FLR to bodyweight ratio 3 days after ISLT in seven patients. The dotted line indicates the critical FLR to bodyweight ratio of 0·5. b Mean(s.d.) FLR volume before and after ISLT (7 patients) or PVE (15). c FLR volume increase in three patients who had ISLT after failed PVE; note the rapid growth of the FLR induced by ISLT after insufficient FLR hypertrophy induced by PVE

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After PVE (15 patients) the mean FLR volume increased from 295(94) ml to 404(95) ml (Fig. 3b). This corresponded to an increase in volume of 37(29) per cent, reached after a mean of 27(20) (range 7–81) days. The FLR/TLV ratio increased from 18(4) per cent to 25(6) per cent following PVE.

After ISLT, rapid growth of the FLR was observed within 3 days, from a mean of 293(58) ml to 477(85) ml, corresponding to a FLR increase of 63(29) per cent (Fig. 3b). Within 3 days, the FLR/TLV ratio increased from 18(3) per cent to 26(7) per cent before second-stage surgery.

The difference in FLR hypertrophy after PVE versus ISLT (43 versus 65 per cent) before surgery was not statistically significant. However, FLR increased much faster after ISLT than PVE: 22(10) versus 3(3) per cent per day (P = 0·001).

Growth of future liver remnant following in situ liver transection after portal venous embolization

In three patients PVE was followed by ISLT, because the FLR volume was insufficient following PVE. FLR hypertrophy after PVE reached 92 per cent in one patient and in the other two it was 20 and 27 per cent, but despite this the FLR volume was still below critical FLR volume ratios. This left these patients unresectable after more than 5 weeks (mean 38 days) and the decision was made to use ISLT. After ISLT and portal vein ligation, the FLR started growing again in all three patients and exceeded the critical FLR ratios for safe liver surgery within 3 days (Fig. 3c). The mean FLR volume increased by 65 per cent, from 316(16) ml to 521(90) ml.

Densitometric analysis

The presence of true parenchymal hypertrophy of the FLR, rather than postoperative liver oedema, was confirmed by densitometric analysis of the CT images from the seven patients who had ISLT. Before and after ISLT there were only minor differences in Hounsfield units (HU). The density of segments II and III ranged from 81 to 119 HU in all patients, without major differences before and after ISLT. A maximum of 114 HU was measured after PVE.

Time to tumour resection

The two-stage extended liver resection with ISLT was completed successfully in all seven patients within 8 days. The mean time between ISLT and completion surgery was 6 (range 4–8) days. The difference in time between post-ISLT CT (day 3), revealing sufficient FLR volume, and completion surgery was explained by logistic factors (limited intensive care unit or operating theatre capacity). In the three patients in whom ISLT was carried out after failed PVE, completion surgery was performed successfully 5, 7 and 6 days after the first stage of the operation (43, 45 and 43 days after PVE).

After PVE alone, the mean time to surgery was 35 (range 13–98) days and extended right hepatectomy could be performed successfully in 12 of the 15 patients The wide range of times to surgery after PVE was explained by slow liver volume gain in some patients. As ISLT was introduced only in 2009 and PVE had been performed since 2004, some patients in the earlier years had to wait for prolonged periods for curative surgery as no alternative existed. In three patients in the PVE group tumour progression or peritoneal carcinomatosis precluded liver resection at exploratory laparotomy.

Thirty-day morbidity and mortality

There were no significant differences in major or minor postoperative complications between the ISLT and PVE groups. No patient developed postoperative liver failure after extended right hepatectomy following either PVE or ISLT. Laboratory results after ISLT and completion extended right hepatectomy showed only slightly increased bilirubin levels (Fig. 4a) and moderately increased aspartate and alanine aminotransferase levels, which returned almost to normal within 1 week (Fig. 4b).

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Figure 4. Mean (s.d.) a bilirubin and b aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels after in situ liver transection (ISLT) and completion extended right hepatectomy

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In the ISLT group (7 patients) major complications were intestinal bleeding (1), bile leak (2), anastomotic leak (1) and fatal acute respiratory distress syndrome following aspiration 7 days after completion surgery (1). Minor complications (ascites and wound infection) occurred in one patient. In two patients the postoperative course was uneventful.

In the PVE group (15 patients) complications were bile leak (2), pleural effusion (2), wound infection (2), persistent postoperative ascites (2) and cholangitis (1). The postoperative course after PVE and extended right hepatectomy was uneventful in nine patients.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

This study investigated a new surgical strategy, consisting of an in situ split liver procedure, with portal vein ligation and transection as the first step of a two-stage operation, followed by definitive resection 4–8 days later. The first stage leaves the left branch of the portal vein and branches to segments II/III, and involves ligation and division of all right portal branches as well as segment I and IV branches. This induces rapid growth of the FLR (liver segments II/III). Comparison of patients undergoing this procedure with those undergoing standard extended right hepatectomy after PVE demonstrated the feasibility and safety of the ISLT procedure, which induced more rapid FLR growth than PVE. In addition, the study demonstrated that ISLT offers an opportunity for curative liver resection even after failed PVE with insufficient growth of the FLR.

ISLT has recently been described by several other groups14–17. It was established at the University Hospital Düsseldorf in 2009 as an alternative to PVE for patients with insufficient FLR at diagnosis, for patients with tumour margins close to the FLR and for those with insufficient FLR growth after PVE.

In general it takes 2–6 weeks to achieve sufficient growth of the FLR for curative liver resection after PVE. A meta-analysis of 1088 patients demonstrated that a mean interval of 29 days was needed from PVE to surgery, with a percentage increase of the FLR of 8–27 per cent12. However, in 17 per cent of patients resection was not possible after PVE, owing to disease progression or insufficient hypertrophy of the FLR12.

The present finding of a FLR volume increase of 43 per cent, in a mean of 27 days following PVE, is in accordance with previous studies8, 18. A more rapid increase in FLR volume occurred after ISLT; the liver volume had already increased by a mean of 63 per cent after 3 days. This decreased the time to surgery to a mean of 6 days, compared with 35 days after PVE. All patients underwent successful completion surgery within 8 days after ISLT.

The present results confirm data published by other groups showing hypertrophy of the FLR by 40–80 per cent within 6–9 days after ISLT15, 17. This corresponds to an enormous daily FLR volume gain of 22 per cent per day after ISLT, in contrast to approximately 3 per cent per day after PVE. Even though the growth rate after PVE could be increased by portal CD133-positive stem cell application, this still did not come close to the FLR hypertrophy after ISLT19.

Liver density was measured in an attempt to prove that the rapid growth of the FLR after ISLT is a result of real parenchymal hypertrophy. In the analysis of Hounsfield units in liver segments II and III, there were only small differences in CT images from before and 3 days after ISLT. Significantly lower density values would be expected in the event of liver oedema. Therefore, it can be assumed that hypertrophy really occurred, in accordance with the clinical results. In keeping with this, there was no liver failure after completion surgery as early as 4 days (range 4–8 days) after ISLT.

Insufficient growth of the FLR after technically successful PVE remains an unsolved challenge in liver surgery. In the present series, ISLT induced an increase in the FLR after failed PVE, rendering these patients resectable. PVE redirects portal blood flow to the intended FLR in an attempt to initiate hypertrophy. Besides a cascade of cytokines and growth factors, the increase in portal blood flow through the FLR after PVE is probably the most important trigger for liver regeneration20. In experimental studies the resulting hypertrophy rate of the non-embolized liver lobes after PVE correlated with the portal blood flow rate20. Therefore, it has been assumed that vascular recanalization of the embolized portal vein branches and the presence of intrahepatic or portosystemic shunts may explain the failure of hypertrophy after technically successful PVE20.

In this study ISLT involved complete separation of the FLR (liver segment II/III) from the liver lobes to be resected. The disconnection of all possibly persisting intrahepatic shunts or recanalized portal vein branches after PVE might explain the effectiveness of ISLT by increasing portal blood flow through the FLR. Moreover, it has been shown that posthepatectomy regeneration is not restricted after PVE21, 22. The present results indicated that growth induction by ISLT is not impaired by previous PVE. Indeed, it was demonstrated that, in the event of insufficient FLR volume gain after PVE, the potential for liver regeneration might not be fully exhausted. This means that ISLT may be offered to patients after failed PVE.

Another issue that has been explored and stressed by several authors is the acceleration of tumour growth after PVE23, 24. Kokudo and colleagues25 assessed the proliferative activity of intrahepatic metastases in the embolized liver after PVE in 18 patients with colorectal metastases. They found a significantly increased tumour Ki-67 labelling index in the group that had undergone PVE compared with the group without PVE. In this study ISLT significantly reduced the time until curative liver resection compared with PVE and potentially reduced the risk of disease progression during the waiting time before hepatectomy. ISLT could be a good alternative to avoid tumour infiltration into the FLR by liver splitting and separation of the diseased liver lobes from the healthy FLR, especially in patients with tumour margins close to the FLR.

Although this study is limited by the small number of patients, the results are in line with previous studies and add valuable data to previously published series on ISLT15, 17.

In the present series, segment I was routinely resected for extended right hepatectomy even in the absence of tumour infiltration, as it facilitates the splitting procedure especially with regard to bile duct preparation and reduces risks of postoperative complications such as necrosis or bile leakage. The ISLT procedure adds to the armamentarium for liver growth induction and certainly does not replace PVE. It should be considered in patients with a very small FLR or tumour margin close to the FLR.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

The authors declare no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
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