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

• ClinicalTrials.gov Identifier: NCT04678583
• Recruitment Status: Recruiting
• First Posted: December 22, 2020
• Last Update Posted: February 16, 2024
• Sponsor: Technische Universität Dresden
• Collaborators: KKS Dresden; German Cancer Research Center
• Information provided by (Responsible Party): Technische Universität Dresden

Tracking Information

• First Submitted Date: October 30, 2020
• First Posted Date: December 22, 2020
• Last Update Posted Date: February 16, 2024
• Actual Study Start Date: January 1, 2021
• Estimated Primary Completion Date: December 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2020)

Intrahepatic disease-free survival (iDFS) [ Time Frame: 24 months ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 1, 2023)

• Assessment of additional oncological and perioperative outcomes: Intraoperative blood loss [mL] [ Time Frame: During surgery ]
  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.
• Assessment of additional oncological and perioperative outcomes: Operating time [min] [ Time Frame: During surgery ]
  Time from skin incision until placement of last skin staple/suture.
• 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] [ Time Frame: 48 hours after surgery ]
  Administration of blood transfusions is documented for the intra- and postoperative period within 48 hours postoperatively.
• Assessment of additional oncological and perioperative outcomes: Duration of postoperative hospital stay [days] [ Time Frame: At day of discharge, assessed up to 90 days ]
  Postoperative day 1 until day of discharge
• Assessment of additional oncological and perioperative outcomes: Duration of postoperative intermediate/intensive care unit stay [days] [ Time Frame: At day of discharge, assessed up to 90 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
• Assessment of additional oncological and perioperative outcomes: Frequency of peri-operative morbidity after resection [ Time Frame: 90 days after surgery ]
  Frequency of peri-operative complications after resection of the primary tumor
• Assessment of additional oncological and perioperative outcomes: Kind of peri-operative morbidity after resection [ Time Frame: 90 days after surgery ]
  Kind of peri-operative complications after resection of the primary tumor
• Assessment of additional oncological and perioperative outcomes: 90-day mortality [ Time Frame: 90 days after surgery ]
  Death due to any cause within 90 days after surgery
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Platelet count [ Time Frame: pre-operatively, 5 days after surgery ]
  Platelet count will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Alanine-aminotransferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of alanine-aminotransferase (ALT) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: aspartate-aminotransferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of aspartate-aminotransferase (AST) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Gamma-glutamyl transferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of Gamma-glutamyl transferase (GGT) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: International normalized ratio [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of international normalized ratio (INR) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Total bilirubin [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of total bilirubin will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Albumin [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of albumin will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Frequency invasive re-interventions [ Time Frame: 30 days after surgery ]
  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
• Assessment of additional oncological and perioperative outcomes: Kind of invasive re-interventions [ Time Frame: 30 days after surgery ]
  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
• Assessment of additional oncological and perioperative outcomes: Number of patients with positive resection margins [ Time Frame: During surgery ]
  Detection of tumor at the resection margin will be counted as positive resection margin
• Assessment of additional oncological and perioperative outcomes: Frequency of Overall survival (OS) [ Time Frame: 24 month ]
  The overall survival of all patients is assessed between operation date to date of death of any cause
• Assessment of additional oncological and perioperative outcomes: Frequency of cancer-specific survival (CSS) [ Time Frame: 24 months ]
  The cancer-specific survival of all patients is assessed between operation date to date of death of colorectal cancer
• Assessment of additional oncological and perioperative outcomes: Frequency of disease-free survival (DFS) [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Administration of adjuvant therapy [y/n] [ Time Frame: 24 month ]
  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.
• Assessment of additional oncological and perioperative outcomes: Frequency of oncological Re-interventions [y/n] [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Kind of oncological Re-interventions [y/n] [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Assessment of "Quality of life" (QoL) [ Time Frame: 12 month ]
  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.

Original Secondary Outcome Measures (submitted: December 16, 2020)

• Assessment of additional oncological and perioperative outcomes: Intraoperative blood loss [mL] [ Time Frame: During surgery ]
  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.
• Assessment of additional oncological and perioperative outcomes: Operating time [min] [ Time Frame: During surgery ]
  Time from skin incision until placement of last skin staple/suture.
• 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] [ Time Frame: 48 hours after surgery ]
  Administration of blood transfusions is documented for the intra- and postoperative period within 48 hours postoperatively.
• Assessment of additional oncological and perioperative outcomes: Duration of postoperative hospital stay [days] [ Time Frame: At day of discharge, assessed up to 90 days ]
  Postoperative day 1 until day of discharge
• Assessment of additional oncological and perioperative outcomes: Duration of postoperative intermediate/intensive care unit stay [days] [ Time Frame: At day of discharge, assessed up to 90 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
• Assessment of additional oncological and perioperative outcomes: Frequency of peri-operative morbidity after resection [ Time Frame: 90 days after surgery ]
  Frequency of peri-operative complications after resection of the primary tumor
• Assessment of additional oncological and perioperative outcomes: Kind of peri-operative morbidity after resection [ Time Frame: 90 days after surgery ]
  Kind of peri-operative complications after resection of the primary tumor
• Assessment of additional oncological and perioperative outcomes: 90-day mortality [ Time Frame: 90 days after surgery ]
  Death due to any cause within 90 days after surgery
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Platelet count [ Time Frame: pre-operativley, 5 days after surgery ]
  Platelet count will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Alanine-aminotransferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of alanine-aminotransferase (ALT) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: aspartate-aminotransferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of aspartate-aminotransferase (AST) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Gamma-glutamyl transferase [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of Gamma-glutamyl transferase (GGT) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: International normalized ratio [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of international normalized ratio (INR) will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Total bilirubin [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of total bilirubin will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Liver biochemical tests: Albumin [ Time Frame: pre-operatively, 5 days after surgery ]
  Levels of albumin will be measured preoperatively and on postoperative day 5
• Assessment of additional oncological and perioperative outcomes: Frequency invasive re-interventions [ Time Frame: 30 days after surgery ]
  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
• Assessment of additional oncological and perioperative outcomes: Kind of invasive re-interventions [ Time Frame: 30 days after surgery ]
  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
• Assessment of additional oncological and perioperative outcomes: Number of patients with positive resection margins [ Time Frame: During surgery ]
  Detection of tumor at the resection margin will be counted as positive resection margin
• Assessment of additional oncological and perioperative outcomes: Frequency of Overall survival (OS) [ Time Frame: 24 month ]
  The overall survival of all patients is assessed between operation date to date of death of any cause
• Assessment of additional oncological and perioperative outcomes: Frequency of cancer-specific survival (CSS) [ Time Frame: 24 months ]
  The cancer-specific survival of all patients is assessed between operation date to date of death of colorectal cancer
• Assessment of additional oncological and perioperative outcomes: Frequency of disease-free survival (DFS) [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Administration of adjuvant therapy [y/n] [ Time Frame: 24 month ]
  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.
• Assessment of additional oncological and perioperative outcomes: Frequency of oncological Re-interventions [y/n] [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Kind of oncological Re-interventions [y/n] [ Time Frame: 24 month ]
  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
• Assessment of additional oncological and perioperative outcomes: Assessment of "Quality of life" (QoL) [ Time Frame: 12 month ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Anatomical Resection of Liver MetAstases iN patIents With RAS-mutated Colorectal Cancer
• Official Title: Anatomical Resection of Liver MetAstases iN patIents With RAS-mutated Colorectal Cancer
• Brief Summary: 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).
• 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
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized, controlled, patient and observer-blinded, confirmatory trial

Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Colorectal Liver Metastasis

Intervention

Procedure: Resection of colorectal liver metastases

Comparison of two liver surgery methods

Study Arms

• Experimental: A - Anatomical resection
  removal of the entire, tumor-bearing liver segment(s)
  Intervention: Procedure: Resection of colorectal liver metastases
• Active Comparator: B - Non-anatomical resection
  metastasectomy with a margin of healthy liver tissue irrespective of segmental borders
  Intervention: Procedure: Resection of colorectal liver metastases

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 16, 2020): 240
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2027
• Estimated Primary Completion Date: December 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04678583
• Other Study ID Numbers: VTG-08
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Technische Universität Dresden
• Original Responsible Party: Same as current
• Current Study Sponsor: Technische Universität Dresden
• Original Study Sponsor: Same as current

Collaborators

• KKS Dresden
• German Cancer Research Center

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

• PRS Account: Technische Universität Dresden
• Verification Date: February 2024