Simultaneous vs. Staged Resection of Colorectal Cancer With Synchronous Liver Metastases (SYLMET)

Simultaneous vs. Staged Resection of Colorectal Cancer With Synchronous Liver Metastases - A Multicentre Randomized Controlled Trial

The SYLMET Trial is a randomized trial to compare simultaneous and two-staged resection of primary colorectal and synchronous liver metastases. This is an investigator-initiated, multicentre, randomized controlled trial to assess complications (primary endpoint), survival, cost-effectiveness, and quality of life (secondary endpoints).This trial will include patients with resectable primary tumour in the colon or upper rectum with less than five liver metastases that is possible to treat with surgical resection and/or ablation (RFA/MWA) at time of evaluation.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Liver Metastases; Liver Metastasis Colon Cancer; Colorectal Neoplasms Malignant
• Intervention / Treatment: Procedure: Staged resection; Procedure: Simultaneous resection

Detailed Description

Colorectal cancer (CRC) represents the second most common cause of cancer and cancer death in Norway, and the incidence is increasing (Cancer in Norway, 2021, Cancer Registry of Norway). The liver is the most common site of metastasis from CRC. More than 4500 individuals are diagnosed with CRC in Norway each year, and approximately 20% of patients present with liver metastases at time of diagnosis (synchronous metastases). Resection of both the primary tumor and liver metastases is considered the only curative treatment, and has been shown to improve long-term survival, and is considered standard of care. However, the optimal timing of surgical resection of synchronous liver metastases in relation to the primary tumor is not well defined. Traditionally, staged resection has been preferred (i.e., resection of the primary tumour and liver metastases on separate admissions with a period of recovery between the two operations), whereas simultaneous resection is appealing (i.e., resection of both primary and metastases in one operative session). Despite a lack of randomized controlled trials comparing these two surgical approaches, the number of simultaneous resections has increased at several institutions. The evolvement of both liver and colorectal surgery in the last decades has led to reduced complications, making simultaneous resections more feasible. Previous retrospective cohort studies and meta-analyses suggest that simultaneous and staged approach carry similar postoperative complication and perioperative mortality rates as well as long-term survival. A recently published prospective observational study on staged or simultaneous surgery, reported similar outcomes in selected patients. To date, there is only one published randomized controlled trial which was aborted after inclusion of half of the sample size, after an accrual time of 10 years18. Due to lack of evidence, the majority of surgical societies worldwide still treats this patient group with staged resections, resulting in two hospital admissions, two rounds of general anaesthesia and surgery, and finally two episodes of postoperative recovery and rehabilitation. If this trial demonstrates that simultaneous surgery is safe, feasible, and cost-effective, it will potentially have a practice-changing impact worldwide.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sheraz Yaqub, MD PhD; Phone Number: +47-23073296; Email: shya@ous-hf.no
• Study Contact Backup: Name: Frida B Hansen; Email: frbhan@ous-hf.no

Study Locations

• Norway
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital
    • Contact: Frida B Hansen; Email: frbhan@ous-hf.no
    • Contact: Sheraz Yaqub, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-80 years old.
• Both CRC and liver metastases in situ at time of evaluation.
• Resectable primary tumor in the colon or upper rectum.
• Less than 5 liver metastases, evaluated by the multidisciplinary tumor board meeting as possible to treat with surgical resection and/or ablation (RFA/MWA).

Exclusion Criteria:

• Unresectable primary tumor.
• Locally advanced primary tumor (T4).
• Primary tumor in the lower rectum with indication for abdominoperineal resection.
• Acute or imminent bowel obstruction.
• Perforation or major bleeding from the primary tumor.
• Pre-treatment of the primary tumor with a colon stent.
• Liver resection requiring resection of more than 2 adjacent segments (Couinaud).
• Liver metastases planned treated with irreversible electroporation (IRE).
• Non-resectable lung metastases.
• Metastases outside of liver (besides resectable lung metastases).
• Eastern Cooperative Oncology Group (ECOG) Performance status ≥ 3.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Staged resection; Resection of the primary colorectal carcinoma and liver metastases in two separate surgeries.	Procedure: Staged resection; Patients randomized to staged resection will be operated according to the decision made by the tumor board meeting (liver or colorectal cancer first, based on tumor burden and symptoms), but both resections have to be done within a time period of 4-12 weeks.; Other Names: Two-staged resection; Sequential resection
Experimental: Simultaneous resection; Resection of both the primary colorectal carcinoma and the liver metastases in one surgical procedure.	Procedure: Simultaneous resection; In cases with simultaneous surgery, the liver resection is performed prior to colon resection in order to keep a low central venous pressure during the first part of the surgical procedure and to avoid congestion of the anastomosis line owing to possible Pringle manoeuvre.; Other Names: Combined resection; Synchronous resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comprehensive Complication Index, CCI	The CCI is calculated as the sum of all complications that are weighted for their severity (multiplication of the median reference values from patients and physicians). The final formula yields a continuous scale to rank the severity of any combination of complications from 0 to 100 in a single patient.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Economics	Cost-effectiveness calculated by incremental cost effectiveness ratio (ICER)	1 year
Overall survival	Survival	3 and 5 years
Clavien Dindo Complications	Scale from 1 to 5. Higher score meaning more severe complication.	90 days
Quality of Life: EQ-5D	EQ-5D is an instrument which evaluates the generic quality of life developed in Europe and widely used. The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The scale range from -0.224 to 1; with 0, 1, and negative values corresponding to death, full health, and health states worse than death, respectively.	Pre-operative, 30-days, 90-days, 6 months, 12 months
Quality of Life: EORTC QLQ-30	The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. Score from 1-100.	Pre-operative, 30-days, 90-days, 6 months, 12 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University of Oslo; Helse Stavanger HF; Haukeland University Hospital; St. Olavs Hospital; University Hospital, Akershus
• Investigators: Principal Investigator: Sheraz Yaqub, MD, PhD, Oslo University Hospital

Publications and helpful links

General Publications

• Kleive D, Aas E, Angelsen JH, Bringeland EA, Nesbakken A, Nymo LS, Schultz JK, Soreide K, Yaqub S. Simultaneous Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: Contemporary Practice, Evidence and Knowledge Gaps. Oncol Ther. 2021 Jun;9(1):111-120. doi: 10.1007/s40487-021-00148-2. Epub 2021 Mar 23.
• Siriwardena AK, Serrablo A, Fretland AA, Wigmore SJ, Ramia-Angel JM, Malik HZ, Stattner S, Soreide K, Zmora O, Meijerink M, Kartalis N, Lesurtel M, Verhoef C, Balakrishnan A, Gruenberger T, Jonas E, Devar J, Jamdar S, Jones R, Hilal MA, Andersson B, Boudjema K, Mullamitha S, Stassen L, Dasari BVM, Frampton AE, Aldrighetti L, Pellino G, Buchwald P, Gurses B, Wasserberg N, Gruenberger B, Spiers HVM, Jarnagin W, Vauthey JN, Kokudo N, Tejpar S, Valdivieso A, Adam R; Joint E-AHPBA/ESSO/ESCP/ESGAR/CIRSE 2022 Consensus on colorectal cancer with synchronous liver metastases. The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE. HPB (Oxford). 2023 Sep;25(9):985-999. doi: 10.1016/j.hpb.2023.05.360. Epub 2023 Jul 13.
• Yaqub S, Margonis GA, Soreide K. Staged or Simultaneous Surgery for Colon or Rectal Cancer with Synchronous Liver Metastases: Implications for Study Design and Clinical Endpoints. Cancers (Basel). 2023 Apr 6;15(7):2177. doi: 10.3390/cancers15072177.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 28, 2023
• First Posted (Actual): January 11, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Neoplasms; Colorectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Neoplasms, Second Primary
• Other Study ID Numbers: 201644

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No