Treatment of Non-resectable Bile Duct Cancer With Radiofrequency Ablation or Photodynamic Therapy (CARP)

Cholangiocarcinoma Treatment With Radiofrequency Ablation or Photodynamic Therapy: a Randomized Controlled Trial

Bile duct cancer is often diagnosed after curative options are no longer available. Stent therapy is used to keep the ducts open and can be combined with photodynamic therapy (PDT) to extend life expectancy. PDT requires an injection of photosensitizer after which light of a particular wavelength is applied endoscopically to kill the cancer cells. Drawbacks include not only high costs and poor availability, but foremost that patients have to avoid direct sunlight for a period of weeks. Radio frequency ablation (RFA) together with stent implantation constitutes an alternative by which the cancer cells are killed through heat, also applied endoscopically. The RFA technology is more widely available and easier to deploy. However, it has not been studied extensively and no randomized trials exist comparing the two methods. This trial will compare survival in patients with a particular bile duct cancer depending on whether they receive PDT or RFA. Moreover, data will be collected on side-effects and quality of life.

Study Overview

• Status: Recruiting
• Conditions: Hilar Cholangiocarcinoma
• Intervention / Treatment: Drug: Photosensitizer; Procedure: Radiofrequency ablation (RFA)

Detailed Description

Klatskin tumours are a form of bile duct cancer. They are generally not diagnosed until quite late and a curative operation is rarely a possibility. Their anatomic location usually results in bile duct obstruction and the aim of therapy is thus to keep the ducts open. This is accomplished through endoscopic retrograde cholangiopancreatography (ERCP) by implanting stents. Stent therapy combined with photodynamic therapy (PDT) extends life expectancy. PDT requires an injection of photosensitizer that is absorbed primarily by the cancer cells. Light of a particular wavelength is then applied with ERCP to kill the cancer cells. Drawbacks include not only high costs and poor availability, but foremost that patients have to avoid direct sunlight for a period of weeks. Radio frequency ablation (RFA) together with stent implantation constitutes an alternative by which the cancer cells are killed through heat applied during ERCP. The RFA technology is more widely available and easier to deploy. However, it has not been studied extensively and no randomized trials exist comparing the two methods. This trial will compare survival in patients with Klatskin tumours depending on whether they receive PDT or RFA. Moreover, data will be collected on side-effects and quality of life.

• Study Type: Interventional
• Enrollment (Estimated): 258
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Albrecht Hoffmeister, Prof.Dr.med.; Phone Number: +49-341-97-12240; Email: albrecht.hoffmeister@medizin.uni-leipzig.de
• Study Contact Backup: Name: Marcus Hollenbach, Dr. med.; Phone Number: +49-341-97-12362; Email: marcus.hollenbach@medizin.uni-leipzig.de

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • Uniklinik RWTH Aachen, Medizinische Klinik III
    • Contact: Karim Hamesch, PD Dr.; Phone Number: +49 241 80 80861; Email: khamesch@ukaachen.de
  • Augsburg, Germany, 86156
    • Not yet recruiting
    • Universitätsklinikum Augsburg; III. Med. Klinik
    • Contact: Tobias Weber, Dr.; Email: tobias.weber@uk-augsburg.de
  • Berlin, Germany, 10249
    • Not yet recruiting
    • Vivantes Netzwerk für Gesundheit GmbH, Klinikum Friedrichshain, Innere Medizin/Gastroenterologie
    • Contact: Thomas Brunk, Dr.; Email: thomas.brunk@vivantes.de
  • Bonn, Germany, 53127
    • Recruiting
    • Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I
    • Contact: Dominik Kaczmarek, Dr.; Phone Number: +49 228 287 -15263; Email: Dominik.Kaczmarek@ukbonn.de
  • Frankfurt, Germany, 60590
    • Not yet recruiting
    • Universitätsklinikum Frankfurt, Medizinische Klinik 1
    • Contact: Jörg Trojan, Prof. Dr.
  • Freiburg, Germany, 79106
    • Recruiting
    • Universitätsklinikum Freiburg, Medizinische Klinik II, Abteilung Gastroenterologie, Hepatologie, Endokrinologie & lnfektiologie
    • Contact: Armin Küllmer, Dr.
  • Greifswald, Germany, 17475
    • Recruiting
    • Universitätsmedizin Greifswald Klinik für Innere Medizin A
    • Contact: Ali Aghdassi, Prof.; Email: Ali.Aghdassi@med.uni-greifswald.de
  • Halle, Germany, 06120
    • Recruiting
    • Site: Martin-Luther-Universitat Halle-Wittenberg, Universitätsklinik und Poliklinik für Innere Medizin I
    • Contact: Jonas Rosendahl, Prof. Dr.; Phone Number: +49 345 557 2661; Email: jonas.rosendahl@uk-halle.de
  • Hanau, Germany, 63450
    • Recruiting
    • Klinikum Hanau; Klinik für Gastroenterologie, Diabetologie und Infektiologie
    • Contact: Likas Welsch, Dr.; Email: Lukas_Welsch@klinikum-hanau.de
  • Hannover, Germany, 30459
    • Recruiting
    • KRH Klinikum Siloah, Klinik für Gastroenterologie
    • Contact: Daniel Vidacek, Dr.; Phone Number: +49 511 927 2102; Email: Daniel.Vidacek@krh.de
  • Leipzig, Germany
    • Recruiting
    • University Hospital of Leipzig, Department of Gastroenterology
    • Contact: Albrecht Hoffmeister, Prof. Dr.; Phone Number: ++49 - 341 - 97 12240; Email: Albrecht.Hoffmeister@medizin.uni-leipzig.de
  • Leipzig, Germany, 04109
    • Not yet recruiting
    • Klinikum St. Georg gGmbH; Klinik für Gastroenterologie, Hepatologie, Diabetologie und Endokrinologie
    • Contact: Ingolf Schiefke, Prof.; Email: ingolf.schiefke@SanktGeorg.de
  • Ludwigsburg, Germany, 71640
    • Recruiting
    • RKH Kliniken Ludwigsburg- Bietigheim gGmbH, Klinik für Innere Medizin, Gastroenterologie, Hämato-Onkologie, Diabetologie und Infektiologie
    • Contact: Andreas Wannhoff, Dr.; Phone Number: +4971419967201; Email: andreas.wannhoff@rkh-kliniken.de
  • Mannheim, Germany, 68167
    • Recruiting
    • Universitätsmedizin Mannheim, II. Medizinische Klinik
    • Contact: Sebastian Belle, PD Dr.; Phone Number: +49 621 383-4642; Email: sebastian.belle@umm.de
  • Marburg, Germany, 35043
    • Not yet recruiting
    • Universitätsklinikum Gießen und Marburg GmbH (UKGM); Klinik für Innere Medizin mit den Schwerpunkten Gastroenterologie, Endokrinologie, Stoffwechsel und klinische Infektiologie
    • Contact: Ulrike Denzer, Prof.; Email: ulrike.denzer@uk-gm.de
  • München, Germany, 81377
    • Not yet recruiting
    • Klinikum der LMU München, Medizinische Klinik II, Campus Großhadern
    • Contact: Jörg Schirra, Prof. Dr.; Phone Number: +49 89 4400 73031; Email: joerg.schirra@med.uni-muenchen.de
  • Münster, Germany, 48149
    • Not yet recruiting
    • Universitlitsklinikum Munster Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische lnfektiologie)
    • Contact: Jonel Trebicka, Prof.; Phone Number: +492518343330; Email: Jonel.Trebicka@ukmuenster.de
  • Nürnberg, Germany, 90419
    • Recruiting
    • Klinikum Nürnberg Nord; Gastroenterologie/ Endokrinologie
    • Contact: Alexander Dechêne, Prof.; Email: Alexander.Dechene@klinikum-nuernberg.de
  • Stuttgart, Germany, 70376
    • Recruiting
    • Robert-Bosch-Krankenhaus (RBK) Stuttgart; Gastroenterologie, Hepatologie und Endokrinologie
    • Contact: Arthur Schmidt; Email: arthur.schmidt@rbk.de
  • Tübingen, Germany, 72076
    • Recruiting
    • Universitätsklinikum Tübingen, Medizinische Klinik I
    • Contact: Christoph Werner, Dr.; Phone Number: +49 7071 2982712; Email: christoph.werner@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Hilar cholangiocarcinoma (cytological or histological confirmation)
2. Surgery is not planned
3. Age ≥ 18 years
4. Written informed consent

Exclusion Criteria:

1. Tumour not accessible endoscopically
2. Known hypersensitivity to porphyrins or to any of the other ingredients of the photosensitizer chosen
3. Leukopenia (< 2000/mm3)
4. Thrombocytopenia (< 100,000 / mm³)
5. Severe, uncorrected coagulopathy (at the discretion of the physician)
6. Suspected erosion of major blood vessels, because of the risk of life-threatening mass haemorrhage exists
7. Porphyria (clinician's assessment) or other light-exacerbated diseases
8. Severely impaired liver and or kidney function (at the discretion of the physician)
9. Bedridden for more than 50% of the time (similar to ECOG (Eastern Cooperative Oncology Group) grade 3)
10. Planned surgical procedure within the next 30 days
11. Concurrent eye disease that will require a slit lamp examination within the next 30 days
12. Prior radiotherapy within the last four weeks
13. Previous PDT or RFA
14. Planned liver transplantation
15. Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects of the trial medication on contraception)
16. Participation in other interventional trials
17. Patients under legal supervision or guardianship
18. Pregnant or nursing women

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
Experimental: Photodynamic therapy (PDT); The index procedure in all patients at baseline includes stenting, using an endoscopic retrograde cholangio-pancreatography (ERCP) procedure. The Intervention is at least one PDT at baseline according to the clinical routine of the trial site.	Drug: Photosensitizer; A photosensitizer, which is absorbed preferentially by tumour cells, is administered 24 - 48 hours prior to PDT. Light of a particular wavelength is then applied during endoscopic retrograde cholangiopancreatography (ERCP) to kill primarily cancer cells locally within the stenosis. Immediately after PDT treatment, new stents are inserted into all treated segments if needed.; Other Names: Photodynamic therapy (PDT)
Experimental: Radiofrequency ablation (RFA); The index procedure in all patients at baseline includes stenting, using an endoscopic retrograde cholangio-pancreatography (ERCP) procedure. The Intervention is at least one RFA at baseline according to the clinical routine of the trial site.	Procedure: Radiofrequency ablation (RFA); RFA is also carried out as part of an ERCP. The RFA-probe is placed within the tumour stenosis and electrical current is applied. New stents are inserted into all treated segments if needed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Hazard ratio from a Cox regression model will be used to compare randomization arms. Covariates will be stratification variables, classification of local inoperability, use of prophylactic antibiotics, Bismuth type and time between diagnosis and beginning RFA/PDT.	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (complementary perspective: median survival time)	Estimates of the difference in median survival time between the groups will be based on the method of Chen and Zhang (PMID: 26983640).	through study completion, an average of 1 year
Overall survival (complementary perspective: two-year overall survival)	Kaplan-Meier estimates will be used.	up to two years
Overall survival (complementary perspective: restricted mean survival on a time horizon of two-years)	Kaplan-Meier estimates will be used (see e.g. PMID: 15690989)	through study completion, an average of 1 year
Days alive and out of hospital up to two years	This constitutes a basic and easy to understand measure of quality of life. Only in-hospital stays will be included in this endpoint and the day of arrival and dismissal will each be counted. The source of data will be the hospital records, epicrisis and patient disclosure.	up to two years
Quality of Life (QoL) measured using QLQ-C30 at various points in time after randomization (V2 (14 days), V3 (ca. 3 months), as a function of time after 6 months, adjusting for the baseline value)	Prolonging life is especially worthwhile if QoL is sufficiently good. The established cancer-specific Core Quality of Life questionnaire QLQ-C30 from the EORTC (European Organisation for Research will be used. Shortly after the index therapy (V2, V3), the difference between arms will be assessed. The requirement to stay indoors may affect QoL. At later points in time, a description per arm is of interest and will be based on a weighted mean of all available questionnaires, weighting according to calendar time.	through study completion, an average of 1 year
Quality of Life (QoL) measured using FACT-Hep at various points in time after randomization (V2 (14 days), V3 (ca. 3 months), as a function of time after 6 months, adjusting for the baseline value)	Prolonging life is especially worthwhile if QoL is sufficiently good. The Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) questionnaire, containing the hepatobiliary-specific cancer subscale, will be used as a second instrument for assessing QoL. Shortly after the index therapy (V2, V3), the difference between arms will be assessed. The requirement to stay indoors may affect QoL. At later points in time, a description per arm is of interest and will be based on a weighted mean of all available questionnaires, weighting according to calendar time.	through study completion, an average of 1 year
Quality-adjusted life years (QALYs)	Using QALYs, a weighted measure of survival will be compared between RFA and PDT that takes QoL into account. The details will be provided in a Statistical Analysis Plan.	through study completion, an average of 1 year
Stent patency based on clinician's assessment (e.g. cholangitis, cholestasis, ultrasound)	Stent patency provides one measure of the burden of the disease and efficacy of the treatment. Mean time to stent closure/replacement/death after last stent replacement will be analysed.	through study completion, an average of 1 year
Laboratory parameter (leucocytes)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (haematocrit)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (haemoglobin)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (bilirubin)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (albumin)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (CA 19-9)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (CRP)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (ALT)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Laboratory parameter (GGT)	Changes in laboratory parameters after index treatment (V3) and as a function of time will be analysed and compared between randomization arms.	through study completion, an average of 1 year
Pruritus as reported by patients on a scale from 0 ("no itching") to 10 ("worst imaginable itching").	Pruritus will be analysed as a function of time.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: University of Leipzig
• Collaborators: Zentrum für Klinische Studien Leipzig
• Investigators: Principal Investigator: Albrecht Hoffmeister, Prof.Dr.med., Universitätsklinikum Leipzig; Bereich Gastroenterologie

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2023
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: September 8, 2022
• First Submitted That Met QC Criteria: September 20, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Hilar Cholangiocarcinoma; Radiofrequency ablation (RFA); Bile Duct Cancer; Photodynamic therapy (PDT); Photosensitizer; Klatskin Tumor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Klatskin Tumor; Dermatologic Agents; Photosensitizing Agents
• Other Study ID Numbers: CARP; 2022-500107-50-00 (Other Identifier: EU CT Number (EMA)); 434336116 (Other Grant/Funding Number: Deutsche Forschungsgemeinschaft (DFG))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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