General Information & Endpoints

Background & Rationale

Surgical resection has offered the best option for prolonged survival in patients with colorectal liver metastases. Limiting factor for major liver resections is the size of the FLR. In case of normal liver function 30% of the total liver volume is considered to be sufficient to maintain adequate liver function after resection. In an attempt to further increase “resectability” criteria for patients with too small FLR surgical and interventional maneuvers such as portal vein embolization, portal vein ligation in two-stage hepatectomies have been implemented, but they need an intervall of 6-8 weeks to achieve sufficient hypertrophy. In order to obtain adequate but rapid parenchymal hypertrophy a new surgical two-step technique, ALPPS, was introduced for oncological patients requiring extended hepatic resection with limited functional reserve. Both procedures can be performed with acceptable morbidity and mortality.

We conclude that it is time to perform a randomized study between the two surgical approaches. Currently, no consensus exists whether ALPPS or Two- Stage Hepatectomy is more effective one year after surgery with regards to oncological outcomes (disease-free survival).

Objective

The overall objective of this trial is to compare two surgical approaches (ALPPS and conventional Two-stage Hepatectomy) to treat marginally resectable CRLM.

The primary objective is assessment of disease-free survival at one year after randomization. 

Study design

Multicentric, randomized, controlled trial comparing two surgical techniques.

Project Population

Consecutive patients subjected to a curative two staged surgical approach for treatment of multifocal CRLM with a FLR/TLV< 30% OR a FLR/BW ratio of < 0.5.

Study intervention

Surgery: ALPPS or Two-Stage Hepatectomy

The percentage of liver transection in ALPPS is not defined and can be performed according to local practice in the respective centers.

Two-Stage Hepatectomy is defined as:

1. Partial resection (“Cleaning of FLR”) + simultaneous portal vein ligation (RES PVL)

2. Partial resection (“Cleaning of FLR”) + secondary portal vein embolization (RES PVE)

Followed by (extended) hemihepatectomy after an interval to induce hypertrophy of the liver.

Not included is portal vein embolization (PVE) before any resection

Primary endpoint

Oncologic outcome: One-year disease free survival assessed by PET-CT or CT Thorax/Abdomen 12 months after randomization.

This will be assessed by two independent radiologists who will be blinded to which arm the patient was enrolled in.

Secondary endpoints

1.       Safety: Mortality

2.       Safety: Complications assessed by Clavien-Dindo Classification and the Comprehensive Complications Index (CCI).

3.       Feasibility of complete resection (accomplishment of both surgical steps of respectitive procedure)

4.       Oncologic outcome: Rate of R0 and R1 resections

5.       Oncologic outcome: Overall survival

6.       Quality of life

7.       Liver volumetric changes (CT or MRI)

8.       Liver synthetic function

9.       Renal function

Hypothesis

Null Hypothesis: There is no difference in the 1 year disease free survival rate between ALPPS and Two- Stage Hepatectomy patient groups.

Alternative Hypothesis: The 1 year disease free survival is superior in the ALPPS patient group when compared to the Two- Stage Hepatectomy group (20% effect difference).

Determination of sample size

The sample size calculation was performed based on the available data in the literature regarding the 1-year disease free survival for Two- Stage Hepatectomy (Brouquet et al., 2011) and ALPPS (Schadde et al., 2014). Table 1 below indicates the test used, the type 1 error, the power, the absolute 1-year disease free survival (DFS) rates for each group and the total sample size required:

Table 1. Sample size calculation

* The final total sample size required was calculated with the addition of a potential 10% drop out rate (i.e. 20 patients) (194 + 20= 214 patients).

Statistical considerations

• The analysis will be performed in an intention-to-treat basis.

• Kaplan-Meier Survival function using the log-rank test

• Uni- & multivariate analysis

Risk-Benefit statement

Complete surgical resection is the only curative option for patients with extended hepatic malignancy and therefore the only chance on prolonged survival.

Patients need to undergo one of the two surgical approaches as part of the multidisciplinary treatment protocol, irrespective of the study.

Both ALPPS and conventional Two- Stage Hepatectomy are safe and effective surgical strategies. Multiple centers have reported on two-stage hepatectomies with portal vein occlusion to make extensive liver resections safe and effective procedures for patients with large and multifocal tumors of the liver.

The largest series on the ALPPS technique demonstrated an overall complication rate of 40% and a mortality of 9% (Schadde et al., 2014). The largest contemporary series on Two- Stage Hepatectomy by Brouquet et al. cited a perioperative mortality of 6% and an overall complication rate of 49%.

GCP-Statement

This study will be conducted in compliance with the most current, IRB-approved study-protocol, the current version of the Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory requirements.