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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.

University of Zurich

SALT operation plan for patients who meet the enrollment conditions and successfully match the donor liver: Hemihepatectomy combined with left lateral lobe liver transplantation was performed first, and residual liver resection was performed after the graft grew to a sufficient functional liver volume.

Hemihepatectomy combined with left lateral lobe liver transplantation was performed first, and residual liver resection was performed after the graft grew to a sufficient functional liver volume.

sequential adult left lateral lobe liver transplantation (SALT)

Colon cancer is a common malignancy with a low survival rate worldwide, and unresectable colon cancer liver metastases (ICRLM) have a worse prognosis. The liver is the most common metastatic organ of colorectal cancer, and palliative chemotherapy is the only option for most ICRLM patients. Regrettably, the median survival time of all patients receiving chemotherapy is only 2 years, and the 5-year survival rate is only 10%. Liver transplantation is an ideal choice for patients with ICRLM, which can significantly improve the postoperative survival rate. But the most serious problem facing such patients is the shortage of donor livers. In 2015, Norwegian scholars proposed a new surgical method, that is, resection and partial liver segment (2-3 segment) transplantation combined with delayed total hepatectomy can greatly alleviate the shortage of liver donors in the above-mentioned patients. Based on the experience of clinical operation, our center proposes and designs a clinical study of sequential adult left lateral lobe liver transplantation (SALT) for the treatment of iCRLM. On the basis of RAPID, the safety and efficacy of sequential adult left lateral lobe liver transplantation were evaluated for the above patients.

Colorectal cancer is currently the third most common malignant tumor in the world, and about 20%-50% of patients have liver metastases at the time of diagnosis or progress to liver metastases thereafter. The liver is the most frequently invaded organ by colorectal cancer, and liver resection is considered to be the best and only treatment option for patients with colorectal liver metastases (CLMs). However, only about 20% of patients are candidates for radical hepatectomy. For most patients who are not candidates for hepatectomy, palliative chemotherapy is the only option. Regrettably, the median survival time of all patients receiving chemotherapy is only 2 years, and the 5-year survival rate is only 10%.

Theoretically, liver transplantation is an ideal choice for patients with unresectable colorectal liver metastases (Irresectable Colorectal Liver Metastases, iCRLM). In a clinical study in Norway, 21 patients with iCRLM were enrolled and treated with liver transplantation, although 19 patients had recurrence and metastasis after transplantation (median time 6 months, range 2-24 months). However, the 1-year, 3-year and 5-year survival rates rose to 95%, 68% and 60% after surgery. In this study, the risk factors for poor prognosis after liver transplantation in iCRLM patients were summarized: the largest tumor diameter was more than 5.5 cm, CEA before transplantation was \>80ug/ml, the interval between primary disease surgery and transplantation was less than 2 years, and poor response to chemotherapy. Subsequently, the center conducted a second study and performed liver transplantation on 15 patients with iCRLM after optimizing the inclusion criteria. The 1-year, 3-year, and 5-year survival rates were 100%, 83%, and 83%, and the recurrence-free survival rates were 53%, 44%, and 35%. The above studies have proved that liver transplantation can significantly improve the prognosis of patients with iCRLM. However, the shortage of donor livers is the most serious problem faced by iCRLM patients. Moreover, iCRLM is generally considered a contraindication for liver transplantation, so it is more difficult for patients with iCRLM to obtain a donor liver.

Therefore, expanding the donor liver pool is urgently needed for the treatment of patients with iCRLM. In 2015, Norwegian scholars proposed a new surgical method, that is, resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (RAPID) . This approach allows transplantation of the left liver (segments 2+3) to an adult recipient, while the remaining enlarged right hemi-liver is transplanted to another adult recipient, effectively avoiding some unsuitable left lateral lobe livers for pediatric recipients to be wasted. Recipients who received right-hemi-liver transplantation had a similar prognosis compared with those who received whole-liver transplantation. Therefore, if the RAPID technique is confirmed to be feasible, it can greatly alleviate the shortage of liver donors. In addition to cadaver sources, living adult donors can also be considered as the source of liver donors. A smaller left lateral lobe donor liver also places less burden on the donor than a left or right hemiliver.

To sum up, our center proposed and designed a clinical study of sequential adult left lateral lobe liver transplantation (SALT) in the treatment of patients with iCRLM based on clinical surgical experience. On the basis of RAPID surgery, the overall survival rate of patients with iCRLM was evaluated by SALT.

SALT for Unresectable Colorectal Liver Metastases

Sequential Adult Left Lateral Lobe Liver Transplantation (SALT) in Patients With Unresectable Colorectal Liver Metastases: a Single-center, Prospective, Single-arm Study

To describe overall survival in patients with unresectable colorectal cancer liver metastases treated with sequential adult left lateral lobe liver transplantation.

Describe the tumor-free survival period of SALT in the treatment of iCRLM

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Two-Stage Hepatectomy (TSH) for Marginally Resectable Colorectal Liver Metastases (CRLM)	NCT02758977	Colon Cancer Li... Liver Neoplasms Liver Diseases Secondary Malig... Malignant Neopl... Hepatectomy Surgery	ALPPS TWO STAGE HEPAT...	18 Years -	University of Zurich
SALT for Unresectable Colorectal Liver Metastases	NCT06069960	Colon Cancer Li...	sequential adul...	18 Years - 75 Years	RenJi Hospital

Spots Global Cancer Trial Database for colon cancer liver metastases