Comparison of Three Methods of Inducing Liver Hypertrophy Before Resection - a Randomized Controlled Trial

Liver resection is the treatment of choice in patients with malignant liver lesions. Unfortunately, the surgery is not always an option, as in same patients the future remnant liver (FRL) is too small to supply all the functions. Therefore, some additional methods have been proposed to increase the size of the FRL.

The aim of this study is to compare the efficacy and safety of three methods of increasing the future remnant liver - Portal Vein Embolization (PVE) - embolization of one of the portal branches; Liver Vein Deprivation (LVD) - embolization both of the portal branch as well as the hepatic vein; and partial ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) - ligation of portal vein branch with partial liver transection.

The efficacy of those three methods will be assessed both by analyzing the volumetric increase (by computer tomography scans) and by functional increase (by 99mTc-mebrofenin scintigraphy). Functional assessment of the liver hypertrophy seems to be of crucial importance, as some of the previous studies suggest that there might be a significant discrepancy in the increase of size comparing to the increase of function.

This is a prospective, interventional randomized study. The study group (154 patients) will consist of patients being considered as candidates for major hepatic resection, after inducing hypertrophy of the future remnant liver.

The primary study hypothesis is greater efficacy of ALPPS in preparing patients for large hepatic resection by inducing hypertrophy of the future remnant liver, as compared both to PVE and LVD.

In case of unsuccessful induction of hypertrophy by the embolization techniques, patients may be qualified to rescue ALPPS procedure.

Primary end-point:

Percentage of patients with successful resection (patients, who gained sufficient increase of the FRL to proceed to the liver resection) with no post-surgical 90-day mortality.

Secondary end-points:

1. the rate and degree of volume increase in different groups
2. the rate and degree of functional increase in different groups
3. CCI index and complication rate >=3 degree according to the Clavien-Dindo classification after the first stage of treatment
4. CCI index and complication rate >=3 degree according to the Clavien-Dindo classification after the second stage of treatment
5. overall duration of hospital stay

Patient will be randomly assigned to the three study groups. All patients will undergo an abdominal contrast enhanced computed tomography and 99mTc-mebrofenin scintigraphy prior to the first stage of treatment. During the first stage of treatment, patients will undergo, according to their group:

1. Embolization of portal vein branch (PVE, portal vein embolization)
2. Embolization of both portal vein branch and hepatic vein (LVD, liver venous deprivation)
3. Partial ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) - ligation of portal vein branch with partial liver transection, preferentially by laparoscopic technique Computed tomography scans and scintigraphy will be repeated at day 7, 14 and 21 after the first stage of treatment. The second stage of treatment, the liver resection, will be performed after achievement of sufficient mebrofenin clearance rate (>=2,69%/min/m2). In case of failure to reach the desired clearance rate, the measurements will be continued every 7 days up to day 42. In case of uncertainty and discrepancy between the volumetric assessment in the computed tomography scan and the mebrofenin scintigraphy, it will be allowed to proceed to stage two (partial hepatectomy) after joint consultation of at least 3 hepatobiliary surgeons, 1 radiologist and 1 nuclear medicine specialist. Routine blood tests will be performed according to the standard procedure in the Department, depending on the patient clinical status. An additional blood sample will be collected from patients (after receiving and additional informed consent from the patient) and will be stored in the biobank.

All patients will be monitored for surgical and 90-day complications. The volume increase after first stage of treatment, the functional increase after first stage of treatment, percentage of patients successfully proceeding to the second stage of treatment and complication rate will be calculated.

The percentage of patients with complications >= 3 degree in Clavien-Dindo classification and CCI index for each patient will be calculated.

Furthermore, the blood test results will be assessed to search for associations with patients' outcomes. Any possible differences in terms of baseline patients characteristics between groups will be addressed.

Statistical analysis will be performed using U Mann-Whitney test, exact Fisher's test, logistic regression, general linear models, Kaplan-Meier method and log-rank test. All three groups will be assessed in terms of occurrence of primary and secondary end-points.