Improving outcomes in patients with perihilar cholangiocarcinoma
Authors:   , Nooijen Lynn Eline 
Published: February 2024

The aim of this thesis was to investigate how to improve outcomes in patients with perihilar cholangiocarcinoma (pCCA). To achieve this, several topics including resection margin, lymph node status, additional resection, preoperative (chemo) therapy and follow-up methods were covered.

In Chapter 1, we gave an introduction on how to improve outcome in patients with pCCA. After imaging and defining resectability, the first step towards optimal surgical treatment is optimizing biliary drainage and preventing cholangitis, followed by securing adequate future liver remnant volume and/or function. The main goal of resection for pCCA is achieving radical resection and ultimately long-term survival.

In Chapter 2, we described the long-term outcomes of patients with initially resectable pCCA who were randomized between endoscopic (EBD) and percutaneous biliary drainage (PTBD) in the DRAINAGE trial. This study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA.

To date, the decision whether a patient seems resectable is based on expert opinion and decided by consensus. Resectability is based on preoperative imaging and actual resectability is determined during surgical exploration. Unfortunately, 10 to 30 % turns out to have unresectable disease during exploration due to more extensive disease than expected on imaging. Preoperative chemotherapy may downstage and convert unresectable tumors to resectable. However, in order to allocate patients for the best possible treatment, (e.g. resection, preoperative (chemo) therapy, or palliative (chemo) therapy) universal, widely implemented, and reproducible resectability criteria are needed. Therefore a study using the modified Delphi method, including Thirteen HPB-surgeons, from six tertiary referral centers in the Netherlands, was presented in Chapter 3.

In Chapter 4, a systematic literature review is described. In this study we aimed to investigate the efficacy and safety of systemic induction therapy in initially unresectable locally advanced pCCA and intrahepatic cholangiocarcinoma (iCCA) and summarized resectability criteria used across these studies.

In Chapter 5, a retrospective cohort study towards the potential of gemcitabine and cisplatin chemotherapy as future preoperative therapy for patients with unresectable locally advanced or borderline resectable iCCA, pCCA, and mid-cholangiocarcinoma is discussed.

Unresectable patients or patients with recurrent disease are treated with palliative chemotherapy consisting of gemcitabine and cisplatin. Unfortunately, a large variation in treatment response within these patients exists. In Chapter 6, we investigated the Human Equilibrative Nucleoside Transporter 1 (hENT1) biomarker. hENT1 is considered a potential predictive biomarker for chemotherapy efficacy, its prognostic value is however still under debate.

Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in pCCA on residual disease and oncological outcome remain uncertain. Therefore, in Chapter 7 a retrospective, multicenter, matched case-control study was performed.

Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival and poor recurrence-free survival for patients after resection for pCCA. Therefore the aim of the study described in Chapter 8 was to assess the prognostic value of positive lymph nodes and resection margin status on OS.

Currently, There is no evidence to support the structured use of imaging or biomarkers in the follow-up of patients after curative resection of biliary tract cancer (BTC). structured follow-up could cause recurrence to be noticed in an earlier stage. Which could ensure a better performance status of these patients, leading to a quick start with palliative chemotherapy ultimately prolonging survival. In Chapter 9 two follow-up strategies for resected BTC are investigated.