DRAGON 1- Training, Accreditation, Implementation and Safety Evaluation of Combined PVE/HVE

Study Overview
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Brief Summary
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Brief Summary: Some colorectal liver metastases can only be resected after inducing liver regeneration by portal vein embolization (PVE) to increase size function of the future liver remnant (FLR). While PVE is standard, embolization of portal vein and hepatic veins (PVE/HVE) on one side of the liver may faster and more extensive liver size and function growth. PVE/HVE is a novel procedure and requires a safety and feasibility evaluation in a pretrial (DRAGON1) to then be compared in a randomized controlled trial (RCT) to PVE (DRAGON 2).

Detailed Description
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Detailed Description: Resection of liver metastases from colorectal cancer (CRLM) improves survival compared to chemotherapy alone and may lead to cure in up to 40% of patients. Surgical resectability is limited by location of metastases and by FLR size and function. Commonly, the volume of the future liver remnant (FLR) should be at least 30% of the functional FLR volume. If this volume criterion is not met, the induction of liver regeneration between a two-stage hepatectomy is performed at many centers, with the aim to render patients resectable and reduce the risk of post hepatectomy liver failure. Gold standard to induce regeneration is the embolization of the portal vein branches to the tumor carrying liver (PVE) to induce regeneration of the FLR. Recently, combined embolization of both portal and hepatic veins (PVE/HVE) has been described as an alternative to portal vein embolization because it accelerates and increases growth of the FLR. PVE/HVE combines simultaneous embolization of the portal main branches into the tumor bearing liver and the hepatic vein draining them. The tissue in the part of the liver treated with PVE/HVE stays viable because the hepatic artery continues to supplies the liver deprived of portal and hepatic veins. Preclinical studies in pigs have demonstrated feasibility of this method and human case series show accelerated and increased liver growth. No multi-center evaluation has been performed so far. DRAGON 1 is an international, prospective, multi-center trial to test enrolment capacity of participants and safety of portal and hepatic vein embolization (PVE/HVE). DRAGON 1 will form the basis of the RCT DRAGON 2 to compare PVE with PVE/HV. DRAGON 2 is expected to start in 2021.

Official Title
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DRAGON 1- Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization to Accelerate Future Liver Remnant (FLR) Hypertrophy

Conditions
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Colorectal Cancer Liver Metastases

Intervention / Treatment
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* Procedure: Portal and Hepatic Vein Embolization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with primarily unresectable/potentially resectable CRLM after conversion chemotherapy with a FLR <30% in normal livers, or 40% in livers chemotherapy damaged livers. 18 years and older Patients up to ECOG 3 (not more than 50% bedbound) Patients with non-resected primary colorectal cancer (CRC) may be included if and only if there is an intent to remove the CRC after the liver treatment (liver first approach) Staging CT chest and (if symptomatic) CT/MRI excludes unresectable extrahepatic disease, while metastatic disease that may be cured in the future, is included. Patients with resectable lung metastases or lung metastases that and be ablated can be included only after statement about resectability/ablatability by tumor board Patients have to be to understand the trial and provide informed consent. Exclusion Criteria: Patients with extrahepatic disease other than lung metastases Patients with metastatic disease to the lung that cannot be ablated or resected will be excluded Patients with intrahepatic Cholangiocarcinoma (IHCC) Patients with Perihilar Cholangiocarcinoma (PHCC) Patients with Hepatocellular Carcinoma (HCC) Pregnant or lactating women will not be eligible Potential to get pregnant has to be excluded (obligatory contraception etc.) Progression by modified RECIST criteria on cross-sectional imaging after conversion chemotherapy is an exclusion criterion. Complete response in cross-sectional imaging after conversion chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Multicenter, international, prospective, multi-center trial to test enrolment capacity of participants and safety of Portal and Hepatic Vein Embolization (PVE/HVE): DRAGON 1 will form the basis of a planned subsequent trial (DRAGON 2) that will compare PVE with PVE/HVE. In DRAGON 1 every center has to demonstrate the ability to enroll 3 patients in 12 months safely
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Portal and Hepatic Vein Embolization<br>3 patients per center over one year approximately 90 patients in total. Patients will undergo portal vein and hepatic vein embolization instead of only portal vein embolization. | Procedure: Portal and Hepatic Vein Embolization<br>* Procedure/Surgery: Combined portal vein embolization and hepatic vein embolization (PVE/HVE) • All techniques of PVE allowed (ipsi-lateral, contra-lateral, trans-splenic, all embolization agents except for ethanol alone) • All modifications of HVE allowed (venous occlusion umbrellas; trans-jugular, trans-hepatic, no use of vein glue to avoid lung embolization; staged approach allowed, but first PVE, then HVE and within 48 hours)<br>* Other names: Double embolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability of each center to enroll 3 patients in 12 months without mortality due to the intervention. | Ability of each center to enroll 3 patients for PVE/HVE in 12 months safely and perform the procedure including the liver resection without 90-day mortality after resection due to complications. If this goal is achieved center will be enrolled in DRAGON 2. | 1 year/ 90 day mortality | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy assessment: standardized future liver remnant volume | Increased of standardized future liver remnant volume between initial imaging and imaging at 1 week, 3 weeks, 6 weeks, degree of hypertrophy based on standard future liver remnant volume, kinetic growth | 6 weeks | 
| Feasibility assessment: resection rate | ion of patients proceeding to complete resection (=resection rate) | 1 year follow up | 
| Mortality assessment | 90-mortality after resection | 90 days | 
| Overall survival after PVE/HVE | Overall survival | 1 year follow up | 
| Oncological effectiveness of PVE/HVE | Disease-free survival after 1 year | 1 year | 
| General complication assessment | 90-day complications, general (Clavien-Dindo) | 90 days | 
| Liver specific complication assessment | 90-day complications, liver specific (FABIB-classification) | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Future Liver Remnant, Portal and Hepatic Vein Embolization, Colorectal Liver Metastases