Protocol

Predictors of early disease recurrence and overall survival following clearance of bilobar colorectal liver metastases – An International Collaborative Study

Click here to download the PDF version of the study protocol.

Summary

BACKGROUND: Presence of bilobar liver metastases from primary colorectal cancer (BiCRLM) is considered a relatively poor prognostic indicator of long-term survival. However, with careful pre-operative planning and selected operative +/- ablative interventions, including the two-stage resections, surgeons can offer resection for an increased number of patients with bilobar liver disease. Some of these procedures are associated with a high risk of postoperative morbidity and mortality rates. Therefore, it is essential to risk stratify and identify the patients who will benefit from such interventions.

RATIONALE: This study aims to assess the clinical and pathological determinants of liver-specific recurrence and overall survival in patients undergoing surgical treatment of BiCRLM. It will help in risk-stratification that, in turn, will allow the selection of patients for appropriate treatment.

METHODS: A retrospective international multicenter cohort study 

Eligibility criteria: 

Patients should have had at least two lesions on the anatomical right, and two lesions on the anatomical left side.

- Patients should have been considered for clearance of liver disease by any combination of surgical and radiological procedures.

- Patients who had clearance of of BiCRLM and those who failed to progress to the completion of surgical pathway (such as drop-outs after 1st stage procedures) should also be included.

Data collection: Patients who had surgery between January 2012 to December 2018 should be recruited. Predefined electronic case report forms will be available for the BiCRLM.org website for all the participating centers. Participants in the study are responsible for the data collection from the individual centers. 

Primary outcomes: The primary outcome is liver-specific recurrence at three months, six months, 1-, 2-, 3- and 5-year period. 

Secondary outcomes: Secondary outcomes are overall survival, the disease-free interval at three months, six months, 1-, 3- and 5-year period, time trends in the management options during the study period, postoperative events including 90-day major morbidity (Clavien-Dindo ≥ 3a), the length of postoperative hospital stay, 90-day mortality, readmission rates, and drop-out rates for two-stage hepatectomies.

STRENGTHS: The multicentre study will involve many European (and non-European) centers and assess outcomes amongst patients treated for bilobar CRLM. This, in turn, will help identify patients at risk of early recurrence and enable the patients and surgeons to balance the risk-benefits of the interventions offered.

LIMITATIONS: Because the study sample groups are from different sources, selection-bias may be a problem. Secondly, the accuracy of the measurement of outcomes is potentially limited by the variation in various centers' follow-up protocols.

AUTHORSHIP: Each participating center will be eligible for three authorship positions. The BiCRLM team members will be listed individually, followed by the group authorship in alphabetical order as the 'E-AHPBA Bilobar Colorectal Liver Metastases study group'.  The last authorship position is reserved for the principal investigator. Any publication, presentation, or abstract on collected data will be delegated to all authors. Each center remains the possessor of their data, and additional reports on data collected will only be conducted in case of written permission.

 

Protocol

Introduction

Approximately 50% of patients develop liver metastases in their course of the disease. Surgical resection is the only treatment that offers a chance of cure and long-term survival, with 5- and 10-year survival rates at around 40% and 25%, respectively. Patients with bilobar liver metastases and multiple lesions are at higher risk of early disease recurrence (within six months). With the advances in perioperative care and surgical techniques, liver resection surgery outcomes have improved significantly over the past decade. This allowed surgeons worldwide to extend the treatment of bilobar liver metastases by innovative combinations of anatomical, non-anatomical liver resection, extended liver resection, and two-staged procedures. The postoperative morbidity and mortality of some of the treatment options are well-reported and debated. It is crucial to identify how far the patient selection criteria for surgical interventions can be stretched while balancing the oncological and postoperative outcomes.

Objectives

This study aims to assess the clinical and pathological determinants of liver-specific recurrence and overall survival in patients undergoing surgical treatment of  BiCRLM. Such a risk stratification might allow the selection of patients with better long-term oncological outcomes for more aggressive treatment options.

Methods

Study Design

This is a pan-European retrospective multicentre study supported by European-African Hepato-Pancreato-Biliary Association. We will also invite and encourage centers outside Europe to participate.

Study period and data collection

Patients who had surgery between January 2012 to December 2018 should be recruited.

Study will be open for recruitment from 1st November 2020 to 31st March 2021.

Each registered center will appoint one dedicated contact person who will register their details on the BiCRLM.org website. Each center will subsequently receive login codes and passwords for logging into the website, and access to the online case report form (CRF)

Predefined electronic case report forms will be available for the BiCRLM.org website for all the participating centers. A registered contact person is responsible for data collection from the individual centers. 

Participants

Eligibility criteria: 

  • Patients should have had at least two lesions on the anatomical right, and two lesions on the anatomical left side.
  • Patients should have been considered for clearance of liver disease by any combination of surgical and radiological procedures.
  • Patients who had clearance of BiCRLM and those who failed to complete the surgical pathway (such as drop-outs after 1st stage procedures) can also be included.

Primary outcomes: The primary outcome is liver-specific recurrence at three months, six months, 1-, 2-, 3- and 5-year period. 

Secondary outcomes: Secondary outcomes are overall survival, the disease-free interval at three months, six months, 1-, 3- and 5-year period, time trends in the management options during the study period, postoperative events including 90-day major morbidity (Clavien-Dindo ≥ 3a), the length of postoperative hospital stay, 90-day mortality, readmission rates, and drop-out rates for two-stage hepatectomies.

Definitions used

Status of the liver resection margin:

R0 = tumor-free margin 1mm from the metastatic lesion

R1 = <1mm margin from the lesion

R2 resection = macroscopically positive margin

For patients with multiple resected lesions, the highest margin status needs to be recorded. If lesion 1=  R0, Lesion 2=R1, Lesion 3=R2; please record margin status as R2

TNM staging of primary:

Please use 7th or 8th edition of the AJCC cancer staging manual

Postoperative complications are scored and classified using the Clavien-Dindo classification of surgical complications. Major complications are defined as Clavien-Dindo grade IIIa or higher.

Statistical analysis

Student’s t, Mann Whitney U, Chi-square, or Fisher’s exact tests will be used as appropriate. Categorical data will be presented as frequency and percentage. Continuous data will be presented either as mean and standard deviation or as median and interquartile range depending on the distribution of the data. The relationship between several clinicopathological factors and the disease recurrence rates will then be assessed using Kaplan-Meier curves, with Log-Rank tests. Factors found to be significant in the univariable analysis or clinically relevant will then be analyzed using a multivariable Cox regression model using a forward stepwise entry method. A prognostic index to risk stratify the patients based on the coefficients of the Cox regression model.

Authorship and publication policy

Each participating center will be eligible for three authorship positions. The BiCRLM team members will be listed individually, followed by the group authorship in alphabetical order as the 'E-AHPBA Bilobar Colorectal Liver Metastases study group'.  The last authorship position is reserved for the principal investigator. Any publication, presentation, or abstract on collected data will be delegated to all authors. Each center remains the possessor of their data, and additional reports on data collected will only be conducted in case of written permission.

 

Approvals

It is the responsibility of the registering centers to obtain the required institutional audit, research, and ethical approvals.

 

References

Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, Alexander DD, Choti MA, Poston G. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol. 2012;4:283–301.

Viganò L, Capussotti L, Lapointe R, Barroso E, Hubert C, Giuliante F, Ijzermans JN, Mirza DF, Elias D, Adam R. Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. Ann Surg Oncol. 2014 Apr;21(4):1276-86

Click here to download the PDF version of the study protocol.