Background
Methods/design
Aim of the study
Tolerance | |
Post-operative mortality | |
Post-operative morbidity | |
Post-hepatectomy liver failure | |
Rate of non-resectability due to insufficient FRL | |
Rate of non-resectability due to tumor progression | |
Per-operative difficulties (adhesions, pedicular dissection …) | |
Blood loss, operating time, transfusions | |
R0 resection rate | |
Post-operative liver volume | |
Overall survival |
Sample size and follow-up period
Selection of study population
Study population
Inclusion criteria
- Liver metastases considered as resectable from colo-rectal origin (as validated by a multidisciplinary committee with at least one senior hepatic surgeon)
- Percentage of FLR volume < 30%
- Age ≥ 18 years
- General health status WHO 0 or 1
- Estimated life expectancy > 3 months
- Patients whose biological parameters are:
- Platelets ≥100,000/mm3,
- Polynuclear neutrophils ≥1000/mm3,
- Hemoglobin ≥9 g/dL (even transfused patients can be included)
- Creatininemia < 1.5 N
- Bilirubinemia ≤2 N
- AST and ALT ≤5 N
- PT > 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
- 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 (βHCG positive), breast-feeding or the absence of effective contraception for women of child-bearing age
- Contraindication to MRI (in the following cases, a CT-scan must be used instead): Pacemaker or neurosensorial stimulator or implantable defibrillator, cochlear implant, ferromagnetic foreign body
- Allergy or contra-indication to iodine contrast agents
- Treatment with anticoagulants (heparin or AVK) that cannot be interrupted for 48 h
- Treatment with anti-platelets that cannot be interrupted for 5 days for aspirin or clopidogrel
- 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
Randomization
Study endpoints
- Evaluation of pre- and post-operative liver function. This will be evaluated using 99mTc-mebrofenin scintigraphy through SPECT/CT acquisitions by calculating mebrofenin clearance in %/min/m2 of whole liver and FLR (described in [8]) at the same time points as CT/MRI (central review).
- To search for biomarkers predictive of liver hypertrophy (EGF, HGF, VEGF, H-EGF, TGF-beta, TNF-alpha, IL-10, IL-6, surviving, FGL-1). Blood samples will be stored by sponsor’s biological resource center (CRB MONTPELLIER). The biological studies on the samples will be managed by a biological committee and funded separately.
Tolerance (toxicities are evaluated according to NCI-CTCAE version 4.03 published 14 June 2010). | |
Post-operative mortality defined as any death within 90 days after surgery or within the hospital stay. | |
Post-operative morbidity defined as the percentages of grade I/II/II/IV/V complications according to the Clavien-Dindo classification within the 90 days after surgery or within the hospital stay. | |
Post-hepatectomy liver failure defined according to the “50–50” criteria (Balzan, Ann Surg 2005) or peak bilirubin > 7 mg/dL (Mullen, J Am Coll Surg 2007). | |
Rate of non-resectability due to insufficient FLR defined as the percentage of patients for whom resection will be not attempted due to insufficient FLR. | |
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. | |
Rate of per-operative difficulties defined as the percentage of patients for whom per-operative difficulties are encountered by the surgeon (especially adhesions and challenging pedicular dissection or any other unscheduled surgical difficulties). | |
Blood loss, operating time, transfusions. Blood loss (in mL), operating time (in minutes), transfusions (number of packed red blood cells) will be recorded. | |
R0 resection rate defined as no microscopic tumor residual. | |
Pre- and post-operative liver volumes: This will be evaluated through CT or MRI acquisitions by calculating whole liver, tumor and FRL volumes at week 2, 3 then every 2 weeks until surgery or week #7, and 4 weeks after surgery (central review). | |
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. |
Intervention description
Baseline | Liver preparation | After liver preparation | Surgeryb | Post-op follow-up | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Treatment | During hospitalization | Week 1 | Week 3 | Every 2 weeks or week 7 | During hospitalization | Week 4 | Day 90 | |||
D-30 – D0 | D-8 – D0 | D0 | Each daya | D0 + 7 days (+/− 1 day) | D0 + 21 days (+/− 1 day) | Each dayc | Surgery + 28 days (+/− 1 day) | Surgery + 90 days (+/− 1 day) | ||
Inclusion/exclusion criteria | X | X | ||||||||
Written consent | X | |||||||||
Demographics | X | |||||||||
Medical history | X | |||||||||
Clinical evaluation | X | X | X | X | X | X | X | X | ||
ECOG performance status | X | X | X | X | X | X | X | X | ||
Prior/concomitant medications | X | X | X | X | X | X | X | X | ||
Biological evaluation | X | Xf | X | X | X | Xg | X | X | ||
Serum pregnancy | X | |||||||||
Biological collection (translational research) | Xd | Xd | X | Xe | ||||||
Liver biopsy (translational research) | X | Xh | ||||||||
99 m-Tc mebrofenin scintigraphy (translational research) | X | X | X | X | X | |||||
Spiral CT/MRI of abdomen | X | X | X | X | X | X | ||||
Randomization | X | |||||||||
Liver venous deprivation/portal vein embolization | X | |||||||||
Adverse events/Serious adverse events | X | X | X | X | X | X | X |