Simultaneous Portal and Hepatic Vein Versus Portal Vein Embolizations for Hypertrophy of the Future Liver Remnant (HYPER-LIV01)

Simultaneous Portal and Hepatic Vein Embolization Versus Portal Vein Embolization for Hypertrophy of the Future Liver Remnant Before Major Hepatectomy of Non-cirrhotic Liver : a Multicentric Comparative Randomized Phase II Trial

The hypothesis is that liver venous deprivation (LVD) could strongly improve hypertrophy of the future remnant liver (FRL) at 3 weeks, as compared to portal vein embolization (PVE) in patient with liver metastases from colo-rectal origin considered as resectable.

Study Overview

• Status: Recruiting
• Conditions: Liver Metastasis Colon Cancer
• Intervention / Treatment: Procedure: Liver preparation before major hepatectomy

Detailed Description

Portal vein embolization (PVE) has been widely used to generate hypertrophy of the nonembolized lobe in patients undergoing major hepatectomy in order to prevent small-for-size remnant liver resulting in post-operative liver insufficiency.

Although PVE is a safe and effective procedure, it does not always induce sufficient hypertrophy of the future remnant liver (FRL) even after a long time. In case of insufficient liver regeneration following PVE, some authors suggested to embolize hepatic vein(s) (Hwang, Ann Surg 2009).

Interestingly, the sequential right hepatic vein embolization (HVE) after right PVE demonstrated an incremental effect on the FRL. Although attractive, this approach requires two different procedures and does not spare time as compared to PVE alone.

To shorten and optimize the phase of liver preparation before surgery,the so-called liver venous deprivation (LVD) technique that combines both PVE and HVE during the same procedure was developed.

The aim of this randomized phase II trial is to compare the percentage of change in FRL volume at 3 weeks after LVD or PVE using MRI or CT-scan.

• Study Type: Interventional
• Enrollment (Anticipated): 64
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Boris GUIU, MD; Phone Number: 0467337546; Email: b-guiu@chu-montpellier.fr

Study Locations

• France
  • Angers, France, 49933
    • Recruiting
    • CHU d'Angers
    • Contact: Antoine Bouvier, MD
  • Bordeaux, France
    • Recruiting
    • Bordeaux University Hospital
    • Contact: Bruno LAPUYADE
  • Dijon, France, 21079
    • Not yet recruiting
    • CHU de Dijon
    • Contact: Romaric LOFFROY, MD
  • Grenoble, France, 38043
    • Not yet recruiting
    • CHU de Grenoble
    • Contact: Christian Sengel, MD
  • Lyon, France, 69373
    • Not yet recruiting
    • Centre Leon Berard
    • Contact: Charles MASTIER, MD
  • Lyon, France, 69317
    • Recruiting
    • Hospices Civils de Lyon
    • Contact: Agnès Rode, MD
  • Nice, France, 06202
    • Recruiting
    • CHU de Nice
    • Contact: Patrick CHEVALLIER, MD
  • Paris, France
    • Recruiting
    • APHP - Cochin hospital
    • Contact: Anthony DOHAN
  • Poitiers, France, 80000
    • Not yet recruiting
    • CHU de Poitiers
    • Contact: Guillaume Vesselle, MD
  • Villejuif, France, 94805
    • Not yet recruiting
    • Institut Gustave Roussy
    • Contact: Thierry BAERE
  • Villejuif, France, 94800
    • Not yet recruiting
    • Hopital Paul Brousse
    • Contact: Oriana Ciacio, MD
  • Hérault
    • Montpellier, Hérault, France, 34295
      • Recruiting
      • CHU de Montpellier
      • Contact: Boris GUIU, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Liver metastases from colo-rectal origin considered as resectable (as validated by a multidisciplinary committee with at least one senior hepatic surgeon) provided sufficient FRL volume
• Percentage of FRL volume < 30%
• Age ≥ 18 years
• General health status World Health Organisation 0,1
• Estimated life expectancy > 3 months

• Patients whose biological parameters are :

  • Platelets ≥100,000/mm3,
  • Polynuclear neutrophils ≥ 1000/mm3,
  • Hemoglobin≥ 9g/dL (even transfused patients can be included)
  • Creatininemia < 1.5 times the normal value
  • Creatinine clearance > 30 milliliters (mL)/min
  • Bilirubinemia ≤ 1,5 times the normal value
  • liver transaminases ≤ 5 times the normal value
  • prothrombin rate > 70%
• Reference liver CT-Scan or MRI done during the 30 days preceding PVE or LVD.
• Written informed consent
• National health insurance cover

Exclusion criteria

• Patient with cirrhosis
• Presence of clinical ascites
• Ongoing participation or participation within the 21 days prior to inclusion in the study in another therapeutic trial with an experimental drug
• Serious non-stabilized disease, active uncontrolled infection or other serious underlying disorder likely to prevent the patient from receiving the treatment
• Pregnancy (betaHCG positive), breast-feeding or the absence of effective contraception for women of child-bearing age
• Contraindication for the MRI : Pacemaker or neurosensorial stimulator or implantable defibrillator, cochlear implant, ferromagnetic foreign body similar to the nervous structure.
• Allergy or contra-indication to iodine contrast agents (thyrotoxicosis, allergy to the active substance or excipients)
• Treatment with anticoagulants (heparin or AVK) that cannot be interrupted for 48 hours
• Treatment with anti-platelets that cannot be interrupted for 5 days for aspirin or Plavix
• Legal incapacity (persons in custody or under guardianship)
• Deprived of liberty Subject (by judicial or administrative decision)
• Impossibility to sign the informed consent document or to adhere to the medical follow-up of the trial for geographical, social or psychological reasons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: portal vein embolization; Liver preparation before major hepatectomy : portal vein embolization (PVE) in patient with liver metastases from colo-rectal origin considered as resectable.	Procedure: Liver preparation before major hepatectomy; Simultaneous portal and hepatic vein embolization versus Portal vein embolization, also called venous deprivation OR portal vein embolization.
Experimental: liver venous deprivation; Liver preparation before major hepatectomy : Patients with the liver venous deprivation (LVD) technique that combines both PVE and hepatic vein embolization (HVE) during the same procedure.	Procedure: Liver preparation before major hepatectomy; Simultaneous portal and hepatic vein embolization versus Portal vein embolization, also called venous deprivation OR portal vein embolization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
increase in volume of the future remnant liver (FRL)	The primary outcomes is to compare the increase in volume of the future remnant liver (FRL)	at 3 weeks after liver venous deprivation (LVD) or portal vein embolization (PVE) using MRI or CT-scan

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance	Toxicities are evaluated according to NCI-CTCAE version 4.03 published 14 June 2010	between the day of liver preparation and 90 days after surgery
Post-operative mortality	Post-operative mortality defined as any death within 90 days after surgery or within the hospital stay	90 days after surgery
Post-operative morbidity	Post-operative morbidity defined as the percentages of grade I/II/III/IV/V complications according to Clavien-Dindo classification within the 90 days after surgery or within the hospital stay.	90 days after surgery
Post-hepatectomy liver failure	Post-hepatectomy liver failure defined according to the "50-50" criteria or peak bilirubin >7mg/dL.	between the day of the surgery and 90 days after surgery
Rate of non-resectability due to insufficient FRL	Rate of non-resectability due to insufficient FRL defined as the percentage of patients for whom resection will be not attempted due to insufficient FRL	between the day of the treatment and the day of the surgery
Rate of non-resectability due to tumor progression	Rate of non-resectability due to tumor progression defined as the percentage of patients for whom resection will not be attempted due to tumor progression.	between the day of the treatment and the day of the surgery
Rate of per-operative difficulties	Rate of per-operative difficulties defined as the percentage of patients for whom per-operative difficulties are encountered by the surgeon	between the day of the surgery and 90 days after surgery
Blood loos, operating time, transfusion	Blood loss are evaluated in mL. Operating time avec evaluated in minutes and transfusion are evaluated by number of packed red blood cells	the day of the surgery
R0 resection rate	Rate of R0 resection defined as no microscopic tumor residual	the day of the surgery
R1 resection rate	Rate of R1 resection defined as the percentage of patients resected with margin <1mm	the day of the surgery
Pre and post-operative liver volumes	Pre and post-operative liver volumes will be evaluated through CT or MRI acquisitions by calculating whole liver, tumor and FRL volumes	Baseline, week 1, week 3 then every 2 weeks until surgery or week 7 and 4 weeks after surgery
Recurrence-free survival	Recurrence-free survival defined as the time from date of randomization to date of recurrence or death from their tumor. Patients alive will be censored at the date of last news.	90 days after surgery
Overall survival	Overall survival defined as the time from date of randomization to date of death from any cause. Patients alive will be censored at the date of last news.	Between the liver preparation and 90 days after surgery
Evaluation of pre and post-operative liver function	Evaluation of pre and post-operative liver function will be evaluated using 99mTc mebrofenine scintigraphy through SPECT/CT acquisitions by calculating mebrofenin clearance in %/min/m² of whole liver and FRL at the same time points as CT/MRI	Baseline, week 1, week 3 then every 2 weeks until surgery or week 7 and 4 weeks after surgery
To search for biomarkers predictive of liver hypertrophy/regeneration and immune cell response	Biomarkers predictive of liver hypertrophy/regeneration are evaluated by blood samples and liver biopies	The day of liver preparation, on day 1, day 2 and day 3 after liver preparation and the day of surgery

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: Federation Francophone de Cancerologie Digestive

Publications and helpful links

General Publications

• Deshayes E, Piron L, Bouvier A, Lapuyade B, Lermite E, Vervueren L, Laurent C, Pinaquy JB, Chevallier P, Dohan A, Rode A, Sengel C, Guillot C, Quenet F, Guiu B. Study protocol of the HYPER-LIV01 trial: a multicenter phase II, prospective and randomized study comparing simultaneous portal and hepatic vein embolization to portal vein embolization for hypertrophy of the future liver remnant before major hepatectomy for colo-rectal liver metastases. BMC Cancer. 2020 Jun 19;20(1):574. doi: 10.1186/s12885-020-07065-z.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2019
• Primary Completion (Anticipated): October 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: February 13, 2019
• First Submitted That Met QC Criteria: February 13, 2019
• First Posted (Actual): February 15, 2019

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Colorectal cancer; Liver; Liver resection; Liver metastases; Interventional radiology; Future liver remnant; Portal vein embolization; Portal and hepatic vein embolization; Non-cirrhotic liver; Liver Regeneration
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Pathological Conditions, Anatomical; Neoplastic Processes; Neoplasm Metastasis; Hypertrophy; Hematinics; Liver Extracts
• Other Study ID Numbers: RECHMPL18_0025; UF 7595 (Other Identifier: UH Montpellier)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No