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

Primary Purpose

Colon Cancer Liver Metastases, Liver Neoplasms, Liver Diseases

Status

Unknown status

Phase

Not Applicable

Locations

Switzerland

Study Type

Interventional

Intervention

ALPPS

TWO STAGE HEPATECTOMY

About this trial

This is an interventional treatment trial for Colon Cancer Liver Metastases focused on measuring Colorectal liver metastases, Liver Surgery, ALPPS, Two Stage Hepatectomy, Surgical Oncology, Hepatectomy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients fulfilling all of the following inclusion criteria may be enrolled in the study:

Male or female patients above 18 years of age.
Patients with multifocal CRLM with a FLR/TLV (Total Liver Volume)< 30% OR a FLR/BW (Bodyweight) ratio of < 0.5.
Patients with colorectal primary tumor not yet resected may be included as long as the extrahepatic disease may be cured surgically (liver first strategy).
Patients with lung metastases may be included in the study as long as the lung metastases are potentially curable by resection by judgment of a thoracic surgery consultant.
Chemotherapy response according to RECIST: regression or stable disease.
The indication for surgery should be discussed at a multidisciplinary tumor board attended by hepatobiliary surgeons, oncologists, hepatologists and radiologists.
Written informed consent given by the patient after discussing the trial with the patient in a language he/she understands.
For women of chlidbearing age: Not currently breastfeeding; usage of effective contraception if sexually active; not pregnant and agreement not to become pregnant during the 12 months thereafter. A negative pregnancy test before inclusion into the trial is required for women, who are not yet menopausal, had their last menses within less than 12 months or have not had uterus and or ovaries removed surgically or undergone tubal ligation.

Exclusion Criteria:

The presence of any one of the following exclusion criteria will lead to exclusion of the participant:

Male or female patients under 18 years of age.
Unilobar tumorload qualifying the subject for a standard hepatectomy.
Patients with multifocal CRLM with a FLR/TLV > 30% OR a FLR/BW ratio of > 0.5.
Patients with a baseline FLR of less than 15%.
Patients with extrahepatic metastatic disease (except potentially resectable lung metastases).
Patients not having received chemotherapy before study enrollment.
If the liver biopsy prior to enrollment or the first liver biopsy in stage I shows fibrosis (Metavir stage ≥F3) or >30% macrosteatosis.
Significant concomitant diseases making the patient unsuitable for major liver surgery by the judgment of the physicians involved.
Known or suspected non-compliance (e.g. drug- and/or alcohol abuse).
Enrollment into a clinical trial interfering with the endpoints.
Intention to become pregnant during the course of the study.
Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases.
Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant.
Previous enrollment in the current study.

Sites / Locations

University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ALPPS

TWO STAGE HEPATECTOMY

Arm Description

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: Partial resection + portal vein ligation (RES PVL) 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.

Outcomes

Primary Outcome Measures

1 Year Disease-free Survival

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.

Secondary Outcome Measures

Procedure-associated Mortality

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.

Procedure-associated Complications

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.

Percentage of patients in which complete curative two-staged surgery was possible.

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).

Complete (R0) vs. incomplete (R1/2) resection (oncological outcome)

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.

Overall survival (oncological outcome)

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.

Quality of Life (QoL)

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.

Radiographic liver volumetric changes

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).

Incidence of posthepatectomy liver failure

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.

Incidence of posthepatectomy liver failure

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.

Incidence of posthepatectomy renal failure

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.

Full Information

NCT ID

NCT02758977

First Posted

April 5, 2016

Last Updated

April 28, 2016

Sponsor

University of Zurich

1. Study Identification

Unique Protocol Identification Number

NCT02758977

Brief Title

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

Acronym

ALPPSforCRLM

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2016

Overall Recruitment Status

Unknown status

Study Start Date

May 2016 (undefined)

Primary Completion Date

April 2019 (Anticipated)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Zurich

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colon Cancer Liver Metastases, Liver Neoplasms, Liver Diseases, Secondary Malignant Neoplasm of Liver, Malignant Neoplasm of Large Intestine Metastatic to Liver, Hepatectomy, Surgery

Keywords

Colorectal liver metastases, Liver Surgery, ALPPS, Two Stage Hepatectomy, Surgical Oncology, Hepatectomy

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

214 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ALPPS

Arm Type

Experimental

Arm Description

Arm Title

TWO STAGE HEPATECTOMY

Arm Type

Active Comparator

Arm Description

Intervention Type

Procedure

Intervention Name(s)

ALPPS

Other Intervention Name(s)

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

Intervention Description

For detailed information please refer to description of experimental arm

Intervention Type

Procedure

Intervention Name(s)

TWO STAGE HEPATECTOMY

Other Intervention Name(s)

TSH

Intervention Description

For detailed information please refer to description of active comparator arm

Primary Outcome Measure Information:

Title

1 Year Disease-free Survival

Description

Time Frame

1 year after Randomization

Secondary Outcome Measure Information:

Title

Procedure-associated Mortality

Description

Time Frame

Up to 1 year after Randomization

Title

Procedure-associated Complications

Description

Time Frame

Up to 1 year after Randomization

Title

Percentage of patients in which complete curative two-staged surgery was possible.

Description

Time Frame

Up to 1 year after Randomization

Title

Complete (R0) vs. incomplete (R1/2) resection (oncological outcome)

Description

Time Frame

1 year after Randomization

Title

Overall survival (oncological outcome)

Description

Time Frame

Up to 10 years after Randomization

Title

Quality of Life (QoL)

Description

Time Frame

Up to 1 year after Randomization

Title

Radiographic liver volumetric changes

Description

Time Frame

Up to 1 year after Randomization

Title

Incidence of posthepatectomy liver failure

Description

Time Frame

Up to 1 year after Randomization

Title

Incidence of posthepatectomy liver failure

Description

Time Frame

Up to 1 year after Randomization

Title

Incidence of posthepatectomy renal failure

Description

Time Frame

Up to 1 year after Randomization

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients fulfilling all of the following inclusion criteria may be enrolled in the study: Male or female patients above 18 years of age. Patients with multifocal CRLM with a FLR/TLV (Total Liver Volume)< 30% OR a FLR/BW (Bodyweight) ratio of < 0.5. Patients with colorectal primary tumor not yet resected may be included as long as the extrahepatic disease may be cured surgically (liver first strategy). Patients with lung metastases may be included in the study as long as the lung metastases are potentially curable by resection by judgment of a thoracic surgery consultant. Chemotherapy response according to RECIST: regression or stable disease. The indication for surgery should be discussed at a multidisciplinary tumor board attended by hepatobiliary surgeons, oncologists, hepatologists and radiologists. Written informed consent given by the patient after discussing the trial with the patient in a language he/she understands. For women of chlidbearing age: Not currently breastfeeding; usage of effective contraception if sexually active; not pregnant and agreement not to become pregnant during the 12 months thereafter. A negative pregnancy test before inclusion into the trial is required for women, who are not yet menopausal, had their last menses within less than 12 months or have not had uterus and or ovaries removed surgically or undergone tubal ligation. Exclusion Criteria: The presence of any one of the following exclusion criteria will lead to exclusion of the participant: Male or female patients under 18 years of age. Unilobar tumorload qualifying the subject for a standard hepatectomy. Patients with multifocal CRLM with a FLR/TLV > 30% OR a FLR/BW ratio of > 0.5. Patients with a baseline FLR of less than 15%. Patients with extrahepatic metastatic disease (except potentially resectable lung metastases). Patients not having received chemotherapy before study enrollment. If the liver biopsy prior to enrollment or the first liver biopsy in stage I shows fibrosis (Metavir stage ≥F3) or >30% macrosteatosis. Significant concomitant diseases making the patient unsuitable for major liver surgery by the judgment of the physicians involved. Known or suspected non-compliance (e.g. drug- and/or alcohol abuse). Enrollment into a clinical trial interfering with the endpoints. Intention to become pregnant during the course of the study. Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant. Previous enrollment in the current study.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Marcel A Schneider, MD

Phone

0041 442553300

MarcelAndre.Schneider@usz.ch

First Name & Middle Initial & Last Name or Official Title & Degree

Pierre-Alain Clavien, MD, PhD

Phone

0041 442553300

clavien@access.uzh.ch

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pierre-Alain Clavien, MD, PhD

Organizational Affiliation

University of Zurich

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospital

City

Zurich

State/Province

ZIP/Postal Code

8091

Country

Switzerland

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marcel A Schneider, MD

Phone

0041 442553300

MarcelAndre.Schneider@usz.ch

First Name & Middle Initial & Last Name & Degree

Pierre-Alain Clavien, MD PhD

Phone

0041 442553300

clavien@access.uzh.ch

First Name & Middle Initial & Last Name & Degree

Pierre-Alain Clavien, MD PhD

First Name & Middle Initial & Last Name & Degree

Marcel A Schneider, MD

First Name & Middle Initial & Last Name & Degree

Mickaël Lesurtel, MD PhD

First Name & Middle Initial & Last Name & Degree

Michael Linecker, MD

First Name & Middle Initial & Last Name & Degree

Henrik Petrowsky, MD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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