- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04272931
DRAGON 1- Training, Accreditation, Implementation and Safety Evaluation of Combined PVE/HVE (DRAGON)
July 11, 2022 updated by: Maastricht University
DRAGON 1- Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization to Accelerate Future Liver Remnant (FLR) Hypertrophy
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).
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Interventional
Enrollment (Anticipated)
125
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Remon Korenblik, MD
- Phone Number: +31 637297507
- Email: remon.korenblik@mumc.nl
Study Contact Backup
- Name: Ronald M. van Dam, MD, PhD
- Email: r.van.dam@mumc.nl
Study Locations
-
-
New South Wales
-
Camperdown, New South Wales, Australia, NSW 2050
- Recruiting
- Royal Prince Alfred Hospital
-
Contact:
- Oliver Fisher, MD PhD
-
Contact:
- Christopher Rogan, MD PhD
-
Principal Investigator:
- Oliver Fisher, MD PhD
-
Principal Investigator:
- Christopher Rogan, MD PhD
-
Sub-Investigator:
- Michael Crawford, MD PhD
-
Sub-Investigator:
- Daniel Steffens, MD PhD
-
-
Victoria
-
Clayton, Victoria, Australia, VIC 3168
- Recruiting
- Monash Health, Clayton
-
Contact:
- Diederick de Boo, MD PhD
-
Principal Investigator:
- Daniel de Boo, MD PhD
-
Principal Investigator:
- Daniel Croagh, MD PhD
-
-
-
-
-
Vienna, Austria, 1100
- Completed
- Social Medical Center, South
-
-
-
-
-
Liège, Belgium, 4000
- Recruiting
- CHU de Liège
-
Contact:
- Celine Lambrecht
-
Contact:
- Olivier Detry
-
Sub-Investigator:
- Celine Lambrecht
-
Principal Investigator:
- Laurent Gérard, MD PhD
-
-
Bruxelles
-
Brussels, Bruxelles, Belgium, 1070
- Recruiting
- Hôpital Erasme
-
Contact:
- Valerio Lucidi, MD PhD
-
Contact:
- Viviane van Laethem
-
Principal Investigator:
- Valerio Lucidi, MD PhD
-
Principal Investigator:
- Illario Tancredi, MD PhD
-
Sub-Investigator:
- viviane van Laethem
-
-
Namen
-
Yvoir, Namen, Belgium, 5530
- Recruiting
- CHU-UCL Namur site Godinne
-
Contact:
- Aelxandra Dili, MD PhD
-
Contact:
- Claude Bertrand, MD PhD
-
Principal Investigator:
- Alexandra Dili, MD PhD
-
Principal Investigator:
- Jean- François De Wispelaere, MD PhD
-
Sub-Investigator:
- Claude Bertrand, MD PhD
-
-
-
-
-
Montréal, Canada
- Recruiting
- McGill University Health Center
-
Contact:
- Jeniffer Kalil
-
Principal Investigator:
- Peter Metrakos, Prof
-
Principal Investigator:
- David Valenti, Md PhD
-
-
Ontario
-
Ottawa, Ontario, Canada, K1H 8L6
- Recruiting
- The Ottawa Hospital
-
Contact:
- Guillaume Martel, MD
-
Contact:
- Stephen Ryan, MD, PhD
-
Principal Investigator:
- Guillaume Martel, MD
-
Principal Investigator:
- Stephen Ryan, MD, PhD
-
Sub-Investigator:
- Aklile Workneh
-
-
-
-
-
Frankfurt, Germany
- Completed
- Frankfurt University Hospital
-
-
Saarland
-
Saarbrücken, Saarland, Germany, 66119
- Recruiting
- Klinikum Saarbrücken gGmbH
-
Contact:
- habil. Gregor A Stavrou, MD PhD
-
Contact:
- Elmar Spüntrup, Prof.dr.
-
Principal Investigator:
- habil. Gregor A Stavrou, MD PhD
-
Principal Investigator:
- Elmar Spüntrup, Prof. dr.
-
-
Saksen-Anhalt
-
Halle (Saale), Saksen-Anhalt, Germany, 06120
- Recruiting
- University Hospital Halle (Saale)
-
Contact:
- Ulrich Ronellenfitsch, MD, Dr. med
-
Contact:
- Jörg Kleeff, MD, Dr. med
-
Principal Investigator:
- Ulrich Ronellenfitsch, MD Dr. Med
-
Sub-Investigator:
- Jörg Kleeff, MD Dr. Med
-
Principal Investigator:
- Walter A Wohlgemuth, MD Dr. Med
-
Sub-Investigator:
- Zhanna Svatko
-
-
-
-
-
Bologna, Italy, 40138
- Recruiting
- Policlinico Sant'Orsola-Malpighi
-
Contact:
- Matteo Serenari, MD phD
-
Contact:
- Alberta Capelli, MD phD
-
Principal Investigator:
- Matteo Serenari, MD phD
-
Principal Investigator:
- Alberta Capelli, MD phD
-
Brescia, Italy, 25124
- Recruiting
- Fondazione Poliambulanza
-
Contact:
- Mohammad Abu Hilal, MD PhD
-
Contact:
- Claudio Salemmi, MD PhD
-
Principal Investigator:
- Mohammad Abu Hilal, MD PhD
-
Principal Investigator:
- Claudio Salemmi, MD PhD
-
Milan, Italy
- Recruiting
- IRCCS San Raffaele Hospital
-
Contact:
- Luca Aldrighetti, Prof
-
Contact:
- Stephanie Steidler
-
Principal Investigator:
- Luca Aldrighetti, Prof.
-
Principal Investigator:
- Francesco De Cobelli, Prof.
-
Sub-Investigator:
- Francesca Ratti, Dr.
-
Sub-Investigator:
- Simone Gusmini, Dr.
-
Sub-Investigator:
- Salvatore Lamarca, Dr.
-
Sub-Investigator:
- Stephanie Steidler
-
Roma, Italy, 00168 Roma
- Recruiting
- Fondazione Policlinico Universitario Agostino Gemelli Irccs
-
Contact:
- Felice Giuliante, MD PhD
-
Contact:
- Roberto Iezzie, MD PhD
-
Principal Investigator:
- Felice Giuliante, MD PhD
-
Principal Investigator:
- Roberto Iezzie, MD PhD
-
-
-
-
-
Amsterdam, Netherlands, 1081HV
- Recruiting
- Amsterdam Medical Centers, Location VUmc
-
Contact:
- Martijn R Meijerink, MD PhD
-
Contact:
- Evelien Schouten
-
Principal Investigator:
- Martijn R Meijerink, MD PhD
-
Principal Investigator:
- Geert Kazemier, Prof.
-
Sub-Investigator:
- Jan de Vries, MD PhD
-
Sub-Investigator:
- Evelien Schouten
-
Breda, Netherlands
- Recruiting
- Amphia
-
Contact:
- Farshad Imani, MD PhD
-
Principal Investigator:
- Farshad Imani, MD PhD
-
Principal Investigator:
- Paul Gobardhan, MD PhD
-
Eindhoven, Netherlands
- Recruiting
- Maxima Medisch Centrum
-
Contact:
- Wouter Leclercq, MD PhD
-
Principal Investigator:
- Wouter KG Leqlercq, MD PhD
-
Principal Investigator:
- Laurens van Baardewijk, MD PhD
-
Groningen, Netherlands, 9713 GZ
- Recruiting
- University Medical Center Groningen
-
Contact:
- Marieke T de Boer, MD PhD
-
Contact:
- Jan T Bottema
-
Principal Investigator:
- Marieke T de Boer, MD PhD
-
Principal Investigator:
- Koert P de Jong
-
Principal Investigator:
- Reinhoud PH Bokkers
-
Sub-Investigator:
- Jan T Bottema
-
Sub-Investigator:
- Leanne van der Plas - Kemper
-
Utrecht, Netherlands
- Recruiting
- Universitair Medisch Centrum Utrecht
-
Contact:
- Maarten LJ Smits, MD PhD
-
Principal Investigator:
- Maarten LJ Smits, MD PhD
-
Sub-Investigator:
- Jeroen Hagendoorn, MD PhD
-
Sub-Investigator:
- Inne HM Borel Rinkes, Prof.
-
Sub-Investigator:
- Rutger CG Bruijnen, MD PhD
-
-
Limburg
-
Maastricht, Limburg, Netherlands, 6229 HX
- Completed
- Maastricht University Medical Center+
-
-
Noord-Holland
-
Amsterdam, Noord-Holland, Netherlands, 1105 AZ
- Recruiting
- Amsterdam UMC, location AMC
-
Contact:
- Joris I Erdmann, MD PhD
-
Contact:
- Otto M van Delden, MD PhD
-
Principal Investigator:
- Joris I Erdmann, MD PhD
-
Principal Investigator:
- Otto M van Delden, MD PhD
-
-
Zuid-Holland
-
Rotterdam, Zuid-Holland, Netherlands, 3015
- Completed
- Erasmus Medical Center
-
-
-
-
-
Oslo, Norway, 0450 Oslo
- Completed
- Oslo University Hospital
-
-
-
-
-
Barcelona, Spain, 08036
- Recruiting
- Clinic de Barcelona
-
Contact:
- Constantino Fondevilla, MD PhD
-
Contact:
- Fernando Gómez, MD PhD
-
Principal Investigator:
- Constantino Fondevilla, MD PhD
-
Principal Investigator:
- Fernando Gómez, MD PhD
-
Sub-Investigator:
- Yiliam Fundora, MD PhD
-
Sub-Investigator:
- Silvia Fernandez
-
Zaragoza, Spain, 50009
- Recruiting
- University Hospital Miguel Servet
-
Contact:
- Alejandro Serrablo, MD PhD
-
Contact:
- Luis Sarria, Md PhD
-
Principal Investigator:
- Alejandro Serrablo, MD PhD
-
Principal Investigator:
- Joaquin Medrano, MD PhD
-
Principal Investigator:
- Luis Luis Sarria, MD PhD
-
-
Barcelona
-
Badalona, Barcelona, Spain, 08916 Badalona
- Completed
- University Hospital Germans Trias i Pujol
-
Sabadell, Barcelona, Spain, 08208
- Recruiting
- University Hospital Parc Taulí
-
Contact:
- Arantxa Gelabert, MD
-
Contact:
- Francisco J Garcia Borobia, MD
-
Principal Investigator:
- Arantxa Gelabert
-
Principal Investigator:
- Francisco J Garcia Borobia
-
Terrassa, Barcelona, Spain, 08221
- Completed
- Hospital Universitari Mútua Terrassa
-
-
Gerona
-
Girona, Gerona, Spain, 17007
- Recruiting
- Hospital Universitari Dr. Josep Trueta
-
Contact:
- Jaume Codina Font, MD PhD
-
Contact:
- Santi Lopez Ben
-
Principal Investigator:
- Jaume Codina font, MD PhD
-
Principal Investigator:
- Santi Lopez Ben, MD PhD
-
Sub-Investigator:
- Margarida Casellas, MD PhD
-
-
-
-
-
Linköping, Sweden, 581 85
- Completed
- Linköping University Hospital
-
Stockholm, Sweden, 14186
- Completed
- Karolinska University Hospital
-
-
-
-
-
Winterthur, Switzerland, 8401
- Completed
- Kantonsspital Winterthur (KSW)
-
-
Basel-Stadt
-
Basel, Basel-Stadt, Switzerland, CH-4058
- Completed
- Claraspital & Clarunis University Hospital Basel
-
-
-
-
-
Belfast, United Kingdom
- Recruiting
- Belfast Health and Social Care Trust
-
Contact:
- David Vass
-
Principal Investigator:
- David Vass, MD PhD
-
Principal Investigator:
- Ridchard Lindsay, MD PhD
-
Sub-Investigator:
- Mark Taylor, MD PhD
-
Sub-Investigator:
- Stephen McCain, MD PhD
-
Sub-Investigator:
- Peter Kennedy, MD PhD
-
London, United Kingdom
- Recruiting
- King's College Hospital NHS Foundation Trust
-
Contact:
- Krishna Menon
-
Principal Investigator:
- Krishna Menon, MD PhD
-
Principal Investigator:
- Praveen Peddu, MD PhD
-
Oxford, United Kingdom
- Recruiting
- Oxford University Hospitals Nhs Foundation Trust
-
Contact:
- Katherine Gordon-Quayle
-
Principal Investigator:
- Venkatesha Udupa, MD PhD
-
Principal Investigator:
- Andrew Macdonald, MD PhD
-
-
Hampshire
-
Southampton, Hampshire, United Kingdom, SO16 6YD
- Completed
- University Hospital Southampton
-
-
Merseyside
-
Liverpool, Merseyside, United Kingdom, L9 7AL
- Completed
- Aintree University Hospital
-
-
-
-
Connecticut
-
New Haven, Connecticut, United States, 06510
- Recruiting
- Yale School of Medicine
-
Contact:
- David C Madoff, MD PhD
-
Contact:
- Kristin DeFrancesco
-
Principal Investigator:
- David C Madoff, MD PhD
-
Sub-Investigator:
- Kristin DeFrancesco
-
-
Illinois
-
Chicago, Illinois, United States, 60612
- Recruiting
- Rush University Medical Center
-
Contact:
- Erik Schadde, MD PhD
-
Contact:
- Jordan C Tasse, MD PhD
-
Principal Investigator:
- Erik Schadde, MD PhD
-
Principal Investigator:
- Jordan C Tasse, MD PhD
-
Sub-Investigator:
- Sam G Pappas, MD PhD
-
Sub-Investigator:
- Bulent Arslan, MD PhD
-
Sub-Investigator:
- Ashiq Masood, MD PhD
-
Sub-Investigator:
- Karl Villanueva
-
Sub-Investigator:
- Karie Karolinski
-
-
New York
-
New York, New York, United States, 10065
- Recruiting
- Memorial Sloan Kettering Cancer Center
-
Contact:
- T. Peter Kingham, MD PhD
-
Contact:
- Juan C Camacho, MD PhD
-
Principal Investigator:
- T. Peter Kingham, MD PhD
-
Principal Investigator:
- Juan C Camacho, MD PhD
-
Sub-Investigator:
- Alicia N Lashley
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
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:
- 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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Portal and Hepatic Vein Embolization
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/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)
Other Names:
|
What is the study measuring?
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.
Time Frame: 1 year/ 90 day mortality
|
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
Time Frame: 6 weeks
|
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
Time Frame: 1 year follow up
|
ion of patients proceeding to complete resection (=resection rate)
|
1 year follow up
|
Mortality assessment
Time Frame: 90 days
|
90-mortality after resection
|
90 days
|
Overall survival after PVE/HVE
Time Frame: 1 year follow up
|
Overall survival
|
1 year follow up
|
Oncological effectiveness of PVE/HVE
Time Frame: 1 year
|
Disease-free survival after 1 year
|
1 year
|
General complication assessment
Time Frame: 90 days
|
90-day complications, general (Clavien-Dindo)
|
90 days
|
Liver specific complication assessment
Time Frame: 90 days
|
90-day complications, liver specific (FABIB-classification)
|
90 days
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Ronald M van Dam, MD PhD, Maastricht University Medical Center
- Principal Investigator: Erik Schadde, MD FACS FEBS, Kantonsspital Winterthur/ Rush University Medical Center, Chicago
- Principal Investigator: Marc AH Bemelmans, MD PhD, Maastricht University Medical Center
- Principal Investigator: Christiaan van der Leij, MD PhD, Maastricht University Medical Center
- Principal Investigator: Christoph A Binkert, Prof.Dr.Med, Cantonal Hospital Winterthur
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
May 8, 2020
Primary Completion (Anticipated)
October 1, 2022
Study Completion (Anticipated)
October 1, 2022
Study Registration Dates
First Submitted
January 7, 2020
First Submitted That Met QC Criteria
February 14, 2020
First Posted (Actual)
February 17, 2020
Study Record Updates
Last Update Posted (Actual)
July 12, 2022
Last Update Submitted That Met QC Criteria
July 11, 2022
Last Verified
July 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NL71535.068.19
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Undecided
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Colorectal Cancer Liver Metastases
-
Mayo ClinicRecruitingColorectal Cancer | Colorectal Liver MetastasesUnited States
-
Shanghai Changzheng HospitalNot yet recruiting
-
Fondazione IRCCS Istituto Nazionale dei Tumori,...Completed
-
Fudan UniversityNot yet recruitingColorectal Cancer Liver MetastasesChina
-
Fudan UniversityUnknown
-
University Hospital, GhentCompletedColorectal Cancer | Metastatic Cancer | Liver Metastases | Liver Cancer
-
Humanitas Clinical and Research CenterCompletedColorectal Cancer | Liver Metastases | Immunotherapy | Colorectal Liver Metastases
-
Sun Yat-sen UniversityRecruitingColorectal Cancer Liver Metastases | RegorafenibChina
-
Ye XuUnknownResected Liver Metastases From Colorectal CancerChina
-
The Central Hospital of Lishui CityZhejiang Cancer Hospital; Zhejiang University; First Affiliated Hospital of Wenzhou...Not yet recruiting
Clinical Trials on Portal and Hepatic Vein Embolization
-
IRCCS San RaffaeleRecruitingHepatocellular Carcinoma | Metastatic Cancer | Primary Liver Cancer | Cholangiocarcinoma | Metastatic Gastric Cancer | Metastatic Pancreatic Cancer | Metastatic Colon CancerItaly
-
Karolinska University HospitalRecruiting
-
Asan Medical CenterCompletedProcedure-Related Complication | Degree of Liver RegenerationKorea, Republic of
-
Chinese University of Hong KongRecruitingGastrointestinal Cancer | Circulating Tumor CellHong Kong
-
Linkoeping UniversityKarolinska Institutet; Skane University HospitalCompletedPortal Vein Embolization, Liver, HypertrophySweden
-
Université de SherbrookeCompletedLiver Metastases | Liver Cancer
-
Hospital San Carlos, MadridCompletedColorectal CancerSpain
-
Imperial College LondonCompletedCancer | Liver ResectionUnited Kingdom
-
Assiut UniversityNot yet recruitingFluid Assessment by Doppler us Changes
-
University of ZurichTerminatedLiver Tumors Not Resectable in One Surgical ProcedureUnited States, Argentina, Switzerland