The DRAGON 2 Trial

Study Overview
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Brief Summary
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In the randomized controlled DRAGON 2 trial study subjects will be randomized between two arms, PVE alone (control group) and PVE/HVE (interventional group).

Detailed Description
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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. Extended liver resections are sometimes necessary to resect primarily unresectable/ potentially resectable (PU/PR) colorectal liver metastases. These resections are generally performed if the volume of the future liver remnant (FLR) comprises at least 30% of the total volume of the liver (without the volume of the metastases) or when liver function of the FLR on technetium-99m (99mTc) scintigraphy exceeds 2.67%/min/m2. When this liver volume or function criterion is not met, a high chance of post-hepatectomy liver failure exists. To prevent this, the induction of liver regeneration between a two-stage hepatectomy is commonly performed. The current standard procedure to induce regeneration is the embolization of the portal vein branches to the tumor carrying liver (PVE) to induce hypertrophy of the remaining part of the liver which will serve as the FLR. Recently, combined embolization of both portal and hepatic veins (PVE/HVE) has been described as a possible superior alternative to PVE, as it increases and accelerates hypertrophy of the FLR. PVE/HVE combines simultaneous embolization of the main portal vein branches into the tumor carrying liver and the hepatic vein draining this part of the liver. Preclinical studies in pigs, several retrospective studies, and the prospective DRAGON 1 interim analysis (n=60) have demonstrated the safety and feasibility of this novel technique. However, no international randomized controlled trial has been performed, in which combined PVE/HVE is compared with PVE

Official Title
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An International Multicenter Randomized Controlled Trial to Compare Combined Portal and Hepatic Vein Embolization (PVE/HVE) With PVE Alone in Patients With Colorectal Liver Cancer Metastases (CRLM) and a Small Future Liver Remnant (FLR)

Conditions
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Colorectal Cancer Liver Metastases (CRLM), Small Future Liver Remnant (FLR)

Intervention / Treatment
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* Procedure: Embolization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with primarily unresectable/ potentially resectable CRLM with a FLR <30% (<40% in chemotherapy damaged livers) Patients with non-resected primary CRC may be included if there is an intention to resect the CRC after the liver treatment (liver first approach) or simultaneously during one of the liver procedures. Patients with resectable or ablatable lung or brain metastases can be included (statement about the resectability of these extrahepatic metastases by a tumor board needs to be available) 18 Years and older Men and women Able to understand the trial and provide informed consent. Exclusion Criteria: Pregnant or lactating female. Premenopausal females not able or willing to commit to oral contraception Patients with prohibitive comorbidities, decision made by local team Any patient with non-resectable or non-ablatable extrahepatic disease Patients with hepatic malignancies other than CRLM Progression of disease by RECIST criteria after cytoreduction chemotherapy Complete response after conversion chemotherapy Staging CT and (if indicated) CT/MRI brain that demonstrates non-resectable extrahepatic disease The anatomy of the liver or manifestation of tumors in relation to the liver veins prohibits the use of combined PVE/HVE.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 Randomization between control and interventional group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Portal Vein Embolization (PVE) alone - (control arm)<br>Portal Vein Embolization (PVE) alone | Procedure: Embolization<br>* Portal Vein embolization with Glue by a transhepatic approach vs. PVE and Hepatic Vein Occlusion with Vascular plugs via a transjugular or transfemoral approach in the same session as the PVE procedure<br>|
| Experimental: Combined Portal and Hepatic Vein Embolization (PVE/HVE) - (interventional arm)<br>Combined Portal and Hepatic Vein Embolization (PVE/HVE) - (interventional arm) | Procedure: Embolization<br>* Portal Vein embolization with Glue by a transhepatic approach vs. PVE and Hepatic Vein Occlusion with Vascular plugs via a transjugular or transfemoral approach in the same session as the PVE procedure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volume sufficient for resection at week 3 after the embolization | Volume sufficient for resection will be based on the first week or third week CT/MR Volumetry. Vauthey calculation for TLV will be used and the FLR volume will be measured centrally (objective panel) | 3 weeks | 
| 5-year Overall Survival | survival data will be recorded up to 5-years. | 5 years |