ALPPS Versus PVE/PL (LIGRO)

Comparison of Two Different Models of Liver Growth Stimulation in Advanced Colorectal Liver Metastatic Disease, (LIGRO Trial) Enabling Liver Resection

Study Title Comparison of two different models of liver growth stimulation in advanced colorectal liver metastatic disease, (LIGRO Trial) enabling liver resection

Methodology Scandinavian Multiple Center Randomized Registry Based Clinical Trial

Study duration The planned duration of study participation for an individual subject from inclusion to follow-up are 3 years

Primary investigator:

Per Sandstrom (Linköping)

Number of subjects 100 patients randomized in a 1:1 randomization

Diagnosis and main inclusion criteria Patients with colorectal liver metastasis requiring liver resection, but are not resectable in one step because of a future liver remnant/standardized total liver volume of < 30 % extrahepatic metastatic disease is not an exclusion criteria if they can be addressed surgically in the future

Overall goal To evaluate if the ALPPS approach is superior to PVE in enabling patients, primarily unresectable due to inadequate FLR, to be resected and reach an R0 situation with an acceptable level of complications and perioperative mortality.

To evaluate if the ALPPS approach increases the growth rate of the liver compared to portal embolization or portal ligation leading to a shorter treatment period.

In addition the investigators aim to study if ALPPS may reach these goals without detectable or improved differences in tumor activity (PFS and OS), but with a shorter recovery and a higher proportion of patients reaching R0.

Hypothesis A higher proportion of patients can be resected with ALPPS counted as rate resected compared to the previously established methods with portal ligation or embolization.

This increased resection rate will not reduce the R0 rate, or increase the rate of Clavien grade 4 complication or higher (H0).

The ALPPS approach will increase the growth rate compared to portal embolization/ligation measured one week after the primary intervention.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer; Liver Metastases
• Intervention / Treatment: Procedure: In-situ split; Procedure: Portal embolization or ligation

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Per Sandstrom, MD, PhD; Phone Number: +46 73 4058581; Email: per.sandstrom@liu.se
• Study Contact Backup: Name: Magnus Rizell, MD, Phd; Phone Number: +46705259301; Email: magnus.rizell@surgery.gu.se

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • Departments of Surgical Gastroenterology and Transplantation
    • Principal Investigator: Peter Noergard Larsen, PhD
• Norway
  • Oslo, Norway
    • Recruiting
    • Rikshospitalet Oslo University Hospital
    • Contact: Bard Rosak, MD, PhD; Email: brosok@ous-hf.no
    • Principal Investigator: Bard Rosok, MD, PhD
• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska University hospital
    • Contact: Magnus Rizell
    • Principal Investigator: Magnus Rizell, MD, PhD
  • Linkoping, Sweden
    • Recruiting
    • Department of Surgery, Linköping University Hospital
    • Contact: Per Sandstrom, PhD, MD
    • Principal Investigator: Per Sandstrom, MD, PhD
  • Lund, Sweden
    • Recruiting
    • Department of Surgery, University Hospital
    • Contact: Gert Lindell, MD, PhD; Phone Number: +46707190077; Email: Gert.Lindell@skane.se
    • Principal Investigator: Gert Lindell, MD, PhD
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Contact: Bengt Isaksson, MD, PhD
    • Principal Investigator: Bengt Isaksson, MD, PhD
  • Umea, Sweden
    • Recruiting
    • Norrland University Hospital
    • Contact: Bjarne Andnor, MD
    • Principal Investigator: Bjarne Andnor, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. By liver tumor board found accepted for inclusion
2. Patients with a tumor burden of colorectal liver metastasis
3. Signed informed content
4. Colorectal liver metastatic disease with an estimated FLR/sTLV of <30%
5. Primary tumor and any extrahepatic disease possible to resect in patients with liver first approach or after resection of primary tumor.

Exclusion Criteria:

1. Cirrhosis
2. Significant comorbidity rendering subjects unsuitable for major surgery
3. Progressive disease after preoperative oncological treatment
4. Age<18 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: In-situ split with portal vein ligature; In-situ liver split at time when portal vein ligature is performed	Procedure: In-situ split; The portal branches to the diseased side should be completely divided. The bile duct to the diseased side should not be divided. The parenchyma should be transected all the way through the transection plane and place a plastic sheet on the diseased transection surface.; Other Names: ALPPS
Active Comparator: Portal embolization or ligation; Intervention: Preoperative portal embolization (+/-ablation) followed by liver resection, or local resections and/or ablations followed by lobectomy, two-stage hepatectomy	Procedure: Portal embolization or ligation; Portal vein embolization is performed according to the intervention used at the different sites.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical success rate, the rate of liver resection in each study arm	For both the ALPPS and the portal vein embolization/ligation arm, resection is not allowed within the study if the patient is not reaching a future liver remnant of 30%. For both groups carcinomatosis or more metastases making aiming radical resections impossible will be seen as failures.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver growth rate	Liver growth is measured with regard to the future liver remnant by measuring the kinetic growth rate by performing repeated CT or MRI at one week after portal vein embolization/ligation or after the first step of the ALPPS procedure.	At one week after primary intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radical resection rate	Radical resection at resection line according to histopathology	8 weeks
Composite complication rate	Overall complications will be analysed as a composite endpoint (CEP) including: ascites, postresectional liver failure, bile leak, intra abdominal bleeding, intraabdominal abscess and mortality, all with a Clavien score of at least 3	1 month after final surgery
Treatment time	Treatment time in days from PVE/PL or date of ALPPS op 1 until date of leaving hospital after final surgery.	8 weeks
Progression free survival	Progression free survival according to randomization group.	24 months
Overall survival	Overall survival after inclusion	Up to 24 months after last inclusion
Quality of life	Quality of life is measured by EORTC QLQ C-30 EQ5D ar 1,6,12,24 months.	24 months post final resection
Health economy	An analysis with regard to hospitalisation rate and number of days in-ward between randomization arm.	At 8 weeks

Collaborators and Investigators

• Sponsor: Regionalt Cancercentrum Väst

Publications and helpful links

General Publications

• Hasselgren K, Rosok BI, Larsen PN, Sparrelid E, Lindell G, Schultz NA, Bjornbeth BA, Isaksson B, Larsson AL, Rizell M, Bjornsson B, Sandstrom P. Response to Comment on: Hasselgren K, et al ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO. Ann Surg. 2021;273(3):442-448. Ann Surg. 2022 Nov 1;276(5):e632-e633. doi: 10.1097/SLA.0000000000005268. Epub 2021 Oct 20. No abstract available.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: August 11, 2014
• First Submitted That Met QC Criteria: August 12, 2014
• First Posted (Estimate): August 13, 2014

Study Record Updates

• Last Update Posted (Estimate): August 13, 2014
• Last Update Submitted That Met QC Criteria: August 12, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: embolization; two-stage; hepatectomy; portal vein; cancer, colorectal
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: SweLiv 1-2014