Anatomical Resection of Liver MetAstases iN patIents With RAS-mutated Colorectal Cancer (ARMANI)

the ARMANI trial will test the hypothesis, if an anatomic resection (AR) improves long-term outcome vs. a non-anatomical resection (NAR) in patients undergoing surgery for RAS-mutated colorectal liver metastasis (CRLM).

Study Overview

• Status: Recruiting
• Conditions: Colorectal Liver Metastasis
• Intervention / Treatment: Procedure: Resection of colorectal liver metastases

Detailed Description

Despite increasing application and success of personalized treatment in medical oncology, little progress has been made in personalized surgical cancer therapy. The ARMANI trial presents the first prospective, randomized trial to evaluate effectiveness and safety of molecular-guided resection in patients with colorectal liver metastasis (CRLM). While CRLM might be removed independently of the liver's segmental borders, retrospective data favor anatomic resections in the subgroup of patients with a mutation in the RAS oncogene. Therefore, the ARMANI trial will test the hypothesis, if an anatomic resection (AR) improves long-term outcome vs. a non-anatomical resection (NAR) in patients undergoing surgery for RAS-mutated CRLM. The trial will be carried out among 11 high-volume centers of hepato-biliary surgery in Germany. A total of 220 patients will be enrolled and randomized in a 1:1 ratio to undergo an AR vs. NAR. The primary endpoint is intrahepatic disease-free survival (iDFS). In addition, the study will provide important data on perioperative outcomes and quality of life for both surgical techniques. Given the trend among liver surgeons to aim for parenchymal-sparing operations to preserve liver parenchyma, a positive trial will be practice changing and present the first piece of high-level evidence on benefits of personalized surgical therapy guided by the tumor's mutational profile in patients with CRLM.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jürgen Weitz, Prof Dr med; Phone Number: +49-(0)351 458 4850; Email: juergen.weitz@ukdd.de

Study Locations

• Germany
  • Berlin, Germany
    • Recruiting
    • Department of General, Visceral and Vascular Surgery, Charité, University Medicine Berlin, Campus Benjamin Franklin Berlin
  • Bonn, Germany
    • Recruiting
    • Clinic and Polyclinic for General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn
  • Braunschweig, Germany
    • Recruiting
    • Surgical Clinic, Municipal Hospital Braunschweig gGmbH
  • Dachau, Germany
    • Recruiting
    • Cancer Center, Helios Amper-Hospital Dachau
  • Dresden, Germany
    • Recruiting
    • Clinic for General and Visceral Surgery, Municipal Hospital Dresden
  • Düsseldorf, Germany
    • Recruiting
    • Clinic for General, Visceral and Pediatric Surgery, University Hospital Düsseldorf
  • Erlangen, Germany
    • Recruiting
    • Surgical Clinic, University Hospital Erlangen
  • Frankfurt, Germany
    • Recruiting
    • Clinic for General, Visceral and Transplant Surgery, University Hospital Frankfurt, Goethe University Frankfurt am Main
  • Freiburg, Germany
    • Recruiting
    • Department for General and Visceral Surgery, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg
  • Gießen, Germany
    • Not yet recruiting
    • JLU Gießen, Department for General, Visceral, Thoracic and Transplant Surgery
  • Greifswald, Germany
    • Recruiting
    • Clinic and Polyclinic for General Surgery, Department of Gastrointestinal, Thoracic and Vascular Surgery, University Greifswald, University Hospital Greifswald
  • Göttingen, Germany
    • Recruiting
    • Clinic for General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University
  • Halle (Saale), Germany
    • Recruiting
    • University Hospital and Polyclinic for Visceral, Vascular and Endocrine Surgery, University Hospital Halle (Saale)
  • Hamburg, Germany
    • Recruiting
    • Department of Liver, Bile Duct and Pancreas Surgery, University Department of surgery, Asklepios Klinik Barmbek
  • Hamburg, Germany
    • Recruiting
    • Center for Surgical Medicine - Clinic and Polyclinic for General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf
  • Hannover, Germany
    • Recruiting
    • Medizinische Hochschule Hannover, Department of General, Visceral and Transplant Surgery
  • Heidelberg, Germany
    • Recruiting
    • Department of General, Visceral and Transplantation Surgery, University of Heidelberg
  • Jena, Germany
    • Recruiting
    • General Visceral and Vascular Surgery, Jena University Medical Center
  • Lübeck, Germany
    • Recruiting
    • Clinic for Surgery, University Hospital Schleswig-Holstein Lübeck Campus
  • Magdeburg, Germany
    • Recruiting
    • University Department of General, Visceral, Vascular and Transplant Surgery, Faculty of Medicine, Otto von Guericke University Magdeburg
  • Mainz, Germany
    • Recruiting
    • Clinic for General, Visceral and Transplantation Surgery, University Medical Center of the Johannes Gutenberg-University Mainz
  • Munich, Germany
    • Not yet recruiting
    • LMU Munich Hospital, Clinic for General, Visceral and Transplant Surgery
  • München, Germany
    • Recruiting
    • Department of Surgery, University Hospital rechts der Isar
  • München, Germany
    • Recruiting
    • Department Hepato-Pancreato-Biliary Surgery, Barmherzige Brüder gGmbH of the Hospital Barmherzige Brüder Munich
  • Münster, Germany
    • Recruiting
    • Clinic for General, Visceral and Transplant Surgery, University of Münster
  • Oldenburg, Germany
    • Recruiting
    • University Hospital for General and Visceral Surgery, Oldenburg Hospital
  • Tübingen, Germany
    • Recruiting
    • Department of General, Visceral and Transplant Surgery, University of Tübingen, Comprehensive Cancer Center
  • Ulm, Germany
    • Recruiting
    • Clinic for General and Visceral Surgery, Ulm University Medical Center
  • Wuppertal, Germany
    • Recruiting
    • General and Visceral Surgery, Helios University Medical Center Wuppertal, University Witten/Herdecke
  • Würzburg, Germany
    • Recruiting
    • Department for General, Visceral, Transplant, Vascular and Pediatric Surgery, Julius-Maximilian-University Würzburg, University Hospital Würzburg
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68167
      • Recruiting
      • Department of Surgery at the University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University
      • Contact: Nuh Rahbari, PD Dr. med.; Phone Number: +49-(0)621 383 3591
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Recruiting
      • Department of Gastrointestinal-, Thoracic and Vascular Surgery University Hospital Carl Gustav Carus Technische Universität Dresden
      • Contact: Jürgen Weitz, Prof Dr med
      • Contact: Secretary; Phone Number: +49-(0)351 458 4850

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Colorectal cancer with RAS mutation (KRAS or NRAS)
• Colorectal liver metastases (single or multiple)
• Planned R0 resection of liver metastases (and primary tumor, if present)
• Anatomical and non-anatomical liver resection technically feasible
• Male and female patients, age ≥ 18 years
• Written informed consent

Exclusion Criteria:

• Extrahepatic metastases
• Planned staged liver resection (e.g. two-stage hepatectomy)
• Diagnosis of another cancer < 5 years prior to randomization Exceptions: curatively treated in situ cervical cancer, curatively resected non-melanoma skin cancer
• Expected lack of compliance
• Addiction or other illnesses which do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A - Anatomical resection; removal of the entire, tumor-bearing liver segment(s)	Procedure: Resection of colorectal liver metastases; Comparison of two liver surgery methods
Active Comparator: B - Non-anatomical resection; metastasectomy with a margin of healthy liver tissue irrespective of segmental borders	Procedure: Resection of colorectal liver metastases; Comparison of two liver surgery methods

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intrahepatic disease-free survival (iDFS)	Time from operation date to date of disease recurrence in the liver, followed up at intervals of three months for a maximum duration of 24 months or until death. Any new, solid lesion in the liver after resection of all CRLM that fulfils imaging criteria (CT, MRI) of a metastasis is counted as an iDFS event.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of additional oncological and perioperative outcomes: Intraoperative blood loss [mL]	Intraoperative blood loss presents the amount of blood lost from skin incision until skin closure. Spilling water and ascites will be subtracted. Swabs will be squeezed and their content will also be sucked and added to the fluid collected in the suction containers.	During surgery
Assessment of additional oncological and perioperative outcomes: Operating time [min]	Time from skin incision until placement of last skin staple/suture.	During surgery
Assessment of additional oncological and perioperative outcomes: Transfusion of blood, transfused packed red blood cells (PRBC), fresh frozen plasma (FFP) and / or platelet concentrate (PC) [units]	Administration of blood transfusions is documented for the intra- and postoperative period within 48 hours postoperatively.	48 hours after surgery
Assessment of additional oncological and perioperative outcomes: Duration of postoperative hospital stay [days]	Postoperative day 1 until day of discharge	At day of discharge, assessed up to 90 days
Assessment of additional oncological and perioperative outcomes: Duration of postoperative intermediate/intensive care unit stay [days]	Days on the intermediate care unit (IMC) or intensive care unit (ICU) after surgery. Patient's stay in the recovery room exceeding 24 hours is counted as ICU stay	At day of discharge, assessed up to 90 days
Assessment of additional oncological and perioperative outcomes: Frequency of peri-operative morbidity after resection	Frequency of peri-operative complications after resection of the primary tumor	90 days after surgery
Assessment of additional oncological and perioperative outcomes: Kind of peri-operative morbidity after resection	Kind of peri-operative complications after resection of the primary tumor	90 days after surgery
Assessment of additional oncological and perioperative outcomes: 90-day mortality	Death due to any cause within 90 days after surgery	90 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Alanine-aminotransferase	Levels of alanine-aminotransferase (ALT) will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: aspartate-aminotransferase	Levels of aspartate-aminotransferase (AST) will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Gamma-glutamyl transferase	Levels of Gamma-glutamyl transferase (GGT) will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: International normalized ratio	Levels of international normalized ratio (INR) will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Total bilirubin	Levels of total bilirubin will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Albumin	Levels of albumin will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery
Assessment of additional oncological and perioperative outcomes: Frequency invasive re-interventions	Invasive re-interventions such as placement of interventional drains, Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement, chest tube placement, and re-laparotomy within 30 days after the index operation or during patients' initial hospital stay	30 days after surgery
Assessment of additional oncological and perioperative outcomes: Kind of invasive re-interventions	Invasive re-interventions such as placement of interventional drains, Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement, chest tube placement, and re-laparotomy within 30 days after the index operation or during patients' initial hospital stay	30 days after surgery
Assessment of additional oncological and perioperative outcomes: Number of patients with positive resection margins	Detection of tumor at the resection margin will be counted as positive resection margin	During surgery
Assessment of additional oncological and perioperative outcomes: Frequency of Overall survival (OS)	The overall survival of all patients is assessed between operation date to date of death of any cause	24 month
Assessment of additional oncological and perioperative outcomes: Frequency of cancer-specific survival (CSS)	The cancer-specific survival of all patients is assessed between operation date to date of death of colorectal cancer	24 months
Assessment of additional oncological and perioperative outcomes: Frequency of disease-free survival (DFS)	The disease-free survival of all patients is assessed from operation date to the date of either progressive or recurrent disease, or death of any cause	24 month
Assessment of additional oncological and perioperative outcomes: Administration of adjuvant therapy [y/n]	Adjuvant therapy is not recommended. However, the decision for adjuvant therapy is left at discretion of the local oncologist. The administration of adjuvant therapy and kind of chemotherapy protocols used will be documented for both groups.	24 month
Assessment of additional oncological and perioperative outcomes: Frequency of oncological Re-interventions [y/n]	Frequency of interventions for treatment of intra- and/or extrahepatic disease recurrence will be documented. These interventions include: Chemotherapy, Surgical resection, Local ablation (e.g. radiofrequency or microwave ablation, stereotactic irradiation), Selective internal radiotherapy (SIRT), other	24 month
Assessment of additional oncological and perioperative outcomes: Kind of oncological Re-interventions [y/n]	Kind of interventions for treatment of intra- and/or extrahepatic disease recurrence will be documented. These interventions include: Chemotherapy, Surgical resection, Local ablation (e.g. radiofrequency or microwave ablation, stereotactic irradiation), Selective internal radiotherapy (SIRT), other	24 month
Assessment of additional oncological and perioperative outcomes: Assessment of "Quality of life" (QoL)	Quality of life is measured preoperatively and at 90 days (± 7 days) and 12 months (± 7 days) postoperatively using the EORTC QLQ-C30 questionnaire (European Organisation for Research and Treatment of Cancer; Questionnaire for the assessment of Quality of Life of Cancer patients with the module dedicated to colorectal liver metastases (EORTC QLQ-LMC21); the questionnaire assesses multi-item scales, each item scoring from 1 to 4, a high score represents a high level of symptomatology or problems.	12 month
Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Platelet count	Platelet count will be measured preoperatively and on postoperative day 5	pre-operatively, 5 days after surgery

Collaborators and Investigators

• Sponsor: Technische Universität Dresden
• Collaborators: German Cancer Research Center; KKS Dresden
• Investigators: Principal Investigator: Jürgen Weitz, Prof Dr med, Department of Gastrointestinal-, Thoracic and Vascular Surgery, University Hospital CGC; Principal Investigator: Nuh Rahbari, Prof Dr med, Allgemein- und Viszeralchirugie, University Hospital Ulm

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: October 30, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 22, 2020

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neoplastic Processes; Neoplasm Metastasis; Liver Neoplasms
• Other Study ID Numbers: VTG-08

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