STUDY PROTOCOL

 OBJECTIVE                                                                                                                                 

To conduct a retrospective multicenter cohort study to define benchmark values for best achievable outcomes following transplantation for perihilar cholangiocarcinoma (PHC). A secondary aim will be to identify the minimal follow-up necessary to properly assess morbidity associated with transplantation for PHC.

 INTRODUCTION                                                                                                                              

With the growing complexity and costs of modern surgical practice, convincing and unbiased quality assessment becomes mandatory. The notion of quality assessment is widely recognized and used in the world of business and manufacturing. A possible tool of quality assessment is benchmarking. Benchmarking is a process of measuring performance in order to enable for outcome comparison and improvement within a specific domain. In the surgical community, however, such standard outcome measures and multicenter comparison of results have been poorly developed and benchmarking for the best possible results for specific procedures is lacking.

Major liver resection due to a perihilary cholangiocarcinoma is a high-risk procedure still associated with significant mortality (6-12%) and very high severe morbidity (50-65%) (Franken et al., Surgery, 2019). And this is also true, in particular, in benchmark patients without known risk factors like severe cardiovascular disease, high BMI or diabetes (Mueller et al., Ann Surg, 2021). With this follow-up study, we aim to benchmark important outcome measures for transplant patients in case of PHC.

To identify the best possible outcome (i.e. benchmarking), data from high-volume centers in low risk patients will be analyzed. These benchmark outcomes will serve as “controls” for comparison with any future analyses of transplantation for PHC.

 POLICY SECURING                                                                                                                          

Confidential center specific data: No center-specific data will be published. Instead, all complications or adverse outcomes will be anonymously reported, as fractions of the total study population. Each center, of course, will be free to publish their own data, as they wish.

Authorship: No data will be submitted or published without authorization from each participating center. Each center will be represented by its contributors.

In the ideal case there will be one junior author who will coordinate data collection with Dr. Matteo Mueller and Dr. Eva Breuer (coordinators of the study from Zurich).

Further use of cohort data: Future studies based on the collected data will hopefully emerge from this multicenter study.

METHODS                                                                                                                                       

Benchmark Values:

  1. Mortality
  2. Morbidity
    • Renal replacement therapy
  3. Transplant-specific complications
    • Biliary complications
    • Hepatic artery thrombosis (HAT)
    • Acute or chronic rejection
    • Primary nonfunction and graft-loss
    • Retransplantation
  4. Operation characteristics
    • Duration of surgery
    • Blood loss
    • R0 resection
    • Transplantation technique
  5. Length of stay (ICU), length of stay (hospital)
  6. Readmission
  7. Center characteristic: volume per year
  8. Disease free survival (DFS) and Overall survival (OS) (reported at one year)

Study period

  • 1st Jan 2014-Dec 31st 2018 (5 years)

Center eligibility

  • Consider largest program in the respective countries
  • ≥ 50 liver transplantations (all indications) per year or ≥ 250 transplantations within 5 years (i.e. the study period)
  • Published in the area of transplantation
  • Prospective database available

Patient eligibility (benchmark cases criteria)

Please note that, at this stage, the study will include all cases.

Inclusion criteria:

  1. Adults ≥ 18 years
  2. Scheduled for liver transplantation for unresectable perihilar cholangiocarcinoma 
  3. Neoadjuvant chemoreadiotherapy according Mayo protocol or modified Mayo protocol (Heimbach et al.; 2004)

Benchmark criteria:

  1. Liver transplantation according (modified) Mayo protocol
  2. Distant or intrahepatic metastases (based on final pathology)
  3. PHC with distal extension with need for pancreaticoduodenectomy (PD)?
  4. Co-morbidities:
    • ASA ≥ 3
    • BMI ≥ 35 (Sánchez-Velázquez et al., Ann Surg, 2019)
    • Cardiac disease (Tran et al., HPB, 2016)
      • Congestive heart failure (CHF) onset or exacerbation in 30 days prior to surgery
      • History of angina pectoris within 1 month of surgery
      • Myocardial infarct within 6 months prior to surgery
      • History of percutaneous coronary intervention or cardiac surgery.
      • Atrial fibrillation (Kazaure et al., World J Surg, 2015)
      • Ad Note: arterial hypertension is not considered as cardiac disease.
    • Chronic renal failure: ≥ stage 3 (GRF<60ml/min per 1.73 m2 or Creatinine > 1.8 mg/dl or 160 μmol/l)
    • Use of anti-coagulation: Non-vitamin K antagonist oral anticoagulants (NOACs) and Vitamin K antagonist and clopidogrel. Note: patients under Aspirin 100mg should not been excluded (Kristensen et al., Eur Heart J, 2014).
    • Lung disease: chronic obstructive pulmonary disease with FEV1<80% (Fields et al., Surgery, 2016).
    • Diabetes: when use more than 2 oral antidiabetes drugs or insulin

Governance

Data will be collected via a secure; password protected, and encrypted online data management system, provided by the University Hospital of Zurich. This platform uses a data entry management system (DEMS) to meet international standards for online databases including fully anonymous data. Data will not be published with hospital identifiers.

Data Collection

Local collaborators: Most hospitals will have two local investigators; a senior and a junior investigator. The junior collaborator will be in regular contact with the study coordinators in Zurich (Dr. Matteo Mueller; Dr. Eva Breuer). The junior investigator will be responsible for:

  • Gaining local research ethics approval
  • Identifying and including all eligible patients
  • Accurately collect baseline and follow-up data
  • Submit data to the online DEMS database