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ASSOCIATING LIVER PARTITION WITH PORTAL VEIN LIGATION FOR STAGED HEPATECTOMY (ALPPS)

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) is performed according to local practice in the respective centers. Preconditions to participation are experience with major liver resections and documentation of having performed at least 5 ALPPS cases prior to participation due to the learning curve with this quite complex procedure.

The amount of transsection (in-situ split/liver partition) in Step 1 is left to the participating center, no minimal % of transsection is specified.

TWO STAGE HEPATECTOMY (TSH)

Two-Stage Hepatectomy is defined as:

1. Partial resection + portal vein ligation (RES PVL)
2. Partial resection + secondary portal vein embolization (RES PVE). Followed by (extended) hemihepatectomy after an interval to induce hypertrophy of the liver.

Conventional Two- Stage Hepatectomies will be standard procedures of the centers participating in the study.

For detailed information please refer to description of experimental arm

ALPPS

For detailed information please refer to description of active comparator arm

TWO STAGE HEPATECTOMY

Marcel A Schneider, MD

Pierre-Alain Clavien, MD, PhD

Pierre-Alain Clavien, MD PhD

Mickaël Lesurtel, MD PhD

Michael Linecker, MD

Henrik Petrowsky, MD

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 future liver remnant (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 and portal vein ligation in two-stage hepatectomies have been implemented, but they need an interval of 4-8 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.

The investigators conclude that it is time to perform a randomized study comparing the two surgical approaches in regard to oncological outcome.

Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Two-Stage Hepatectomy (TSH) for Marginally Resectable Colorectal Liver Metastases (CRLM)

Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Conventional Two-Stage Hepatectomy (TSH) for Surgical Treatment of Marginally Resectable Colorectal Liver Metastases (CRLM) - A Multicentric, Randomized Controlled Trial

The primary objective will be disease-free survival at one year after randomization as determined by PET-CT (Positron emission tomography - Computer tomography), when not available by CT (Computer tomography) Thorax/Abdomen. This will be assessed by two independent radiologists who will be blinded to which arm the patient was enrolled in.

Patients who died, are lost to follow up or are too sick to undergo imaging will be censored and counted as failures to reach the primary endpoint.

Patients may need resection of their primary tumor after the study intervention (liver first strategy). They may develop recurrence within the study period, systemic or in the liver. In these patients ablation, reoperation and chemotherapy are used as customary clinical routine. Whether they achieved tumor free survival however depends only on the PET-CT or CT Thorax Abdomen at one year.

All deaths will be recorded in the 12 month-period after randomization. Specifically, the number of patients, which suffer a fatal event due to the procedure during the postoperative period, will be calculated to assess the safety of the two interventions.

Complications during the postoperative period will be recorded using the Clavien-Dindo Classification, also known as the Zurich Classification, which grades surgical Complications on a scale from 1 to 5 (death of patient).

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 Aug;240(2):205-13.

The percentage of patients, in which a complete curative two-staged surgical procedure was possible, will be assessed.

"Complete" is defined as successful completion of both surgical steps of the procedure, i.e.:

* step 1: cleaning of tumorlesions in the future liver remnant (FLR) and portal vein ligation of the contralateral segments to induce hypertrophy of the FLR (with or without in situ split/transsection).
* step 2: resection of the tumorbearing part of the liver, leaving a tumor-free FLR in situ.

"Curative" is defined as achieving a tumorfree FLR after step 2 with no signs of extrahepatic tumor existance.

(If patients have the primary tumor or potentially resectable lung metastases, which will be approached surgically in the future treatment of the patient in a curative intent, then the procedure does count as curative).

A consensus between pathologists and surgeons on the R-status of the resection, judging both stages separately and together. Through re-resection R0 may be achieved overall even if there was a R1 resection after stage 1.

From date of randomization until the date of death from any cause, assessed up to 10 years.

Regular further follow up-visits after assessment of the primary endpoint at 1 year are planned 1.5, 2, 3, 5 and 10 years after Randomization.

Will be evaluated by the Visual Analogue Scale (VAS) for Quality of Life in Cancer.

Visual Analogue Scale determines QoL on a scale of 1 (worst) to 10 (best).

First Baseline Assessment before stage 1 procedure. Assessment after procedure step 1. Assessment before stage 2 procedure. Assessment after procedure step 2. Regular assessments during scheduled and unscheduled follow-up visits.

Volumetry 1 performed before stage 1 of procedure Volumetry 2 performed before stage 2 of procedure

All volumetries are performed locally via magnet resonance Imaging or computertomography and reported into a respective volumetry Case Report Form (CRF).

The incidence of posthepatectomy liver failure is assessed according to the definition and grading by the International Study Group of Liver Surgery (ISGLS), which separates 3 different grades of posthepatectomy liver failure (Grade A to C).

Rahbari, N. N., et al. (2011). "Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS)." Surgery 149(5): 713-724.

The incidence of posthepatectomy liver failure is assessed according too the "50:50 Criteria".

Balzan, S., et al. (2005). "The "50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy." Ann Surg 242(6): 824-828, discussion 828-829.

Measurement of the following parameter at screening visit, during the postoperative course of stage 1 \& 2 (postoperative days 1,2,3,5,7) and at follow-up visits:

* Creatinin \[Unit: µmol/l\]

This parameter is used to calculate and assess the incidence of posthepatecomy renal failure according to the AKIN-criteria.

Ricci, Z., et al. (2011). "Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria." Nat Rev Nephrol 7(4): 201-208.

Spots Global Cancer Trial Database for malignant neoplasm of large intestine metastatic to liver