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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Anatomical Resection of Liver MetAstases iN patIents With RAS-mutated Colorectal Cancer

Conditions
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Colorectal Liver Metastasis

Intervention / Treatment
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* Procedure: Resection of colorectal liver metastases


Participation Criteria
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Eligibility Criteria
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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

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: Randomized, controlled, patient and observer-blinded, confirmatory trial
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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: Platelet count | Platelet count 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: 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 |