Liver Transplantation for Non-resectable Perihilar Cholangiocarcinoma

Brief Title

Liver Transplantation for Non-resectable Perihilar Cholangiocarcinoma

Official Title

Liver Transplantation for Non-resectable Perihilar Cholangiocarcinoma: a Prospective Exploratory Trial

Brief Summary

      The study will investigate whether liver transplantation provides increased survival, low
      side effects and good quality of life in patients with bile duct cancer where the tumor
      cannot be removed by normal surgery. Analyzes of blood and tissue samples from the tumor will
      be investigated to see if the analyzes can indicate who may have recurrence of the disease
      after liver transplantation. Furthermore, the effect of chemotherapy on normal liver and
      tumor tissues in the liver that are removed during transplantation will be investigated.
    

Detailed Description

      Liver transplantation (Lt) is an established method of treatment for acute and chronic liver
      failure. One and five- year survival after Lt is approximately 90% and 80%, respectively.
      Currently, Lt is a treatment option for selected patients with primary carcinomas in the
      liver and in patients with liver metastases from neuroendocrine tumors. The prerequisite is
      that there is no extra-hepatic tumor growth and that the primary tumor is removed. Lt for
      cancer comprises of 14% of all Lts in Europe (www.etlr.org). Types of primary carcinomas
      eligible for transplantation today include hepatocellular carcinoma (HCC), hepatoblastoma,
      hemangioendothelioma, and perihilar cholangiocarcinoma (pCCA), the latter in clinical
      protocols. The most common secondary hepatocarcinomas are neuroendocrine tumours (carcinoid
      tumours and gastrinomas). The International Registry of Hepatic Tumors in Liver
      Transplantation show that survival of HCC patients after transplantation is above 70% and 60%
      at 1 and 5 years, respectively. Recent studies on HCC and liver transplantation have shown
      even better results when patients are treated with an immunosuppressive regimen containing
      the antiproliferative agent rapamycin. For hepatoblastoma (children) and malign
      hemangioendotheliaoma the five-year survival is between 50-60% and for intestinal sarcomas
      and neuroendocrine tumours it is approximately 35-40%. In patients transplanted for pCCA
      using a multimodal approach utilizing neoadjuvant radiation, chemotherapy and liver
      transplantation (Mayo protocol) 5-year patient survival of >80% in selected patients compared
      to a corresponding 21% five-year survival in liver resection.

      Malignancy of the biliary tree (cholangiocarcinoma, CCA) is a rare cancer with an annual
      incidence around 150 cases in Norway. Cholangiocarcinoma can be subdivided into distal,
      perihilar, and intrahepatic according to their anatomical location5. Although rare,
      intrahepatic cholangiocarcinoma (iCCA) constitutes the second most common primary liver
      cancer after hepatocellular carcinoma, and the worldwide incidence of iCCA is increasing.
      Despite improvements in multidisciplinary management, patients with CCA have a poor outcome
      and only 20% of patients are eligible for surgical resection, with 5-year overall survival of
      less than 10% for all patients. The only potentially curative treatment option is surgical
      resection with complete excision of tumor with negative margins.

      An Irish study with liver transplantation for patients with unresectable hilar CCA who
      received neoadjuvant chemoradiotherapy had 1- , 3- and 5-year survival of 81%, 69% and 62%
      respectively, of the transplanted patients. We have recently started a prospective
      exploratory study, TESLA trial, investigating Lt in non-resectable iCCA with stable disease
      on oncological treatment.

      Building on these results in addition to our own experience with liver transplantation for
      non-resectable colorectal liver metastases, we want to investigate in the TESLA-II trial the
      role of Lt in selected patients with unresectable pCCA, who fulfill the inclusion criteria.
    


Study Type

Interventional


Primary Outcome

Overall survival

Secondary Outcome

 Overall survival from time of relapse

Condition

Perihilar Cholangiocarcinoma

Intervention

Liver transplant

Study Arms / Comparison Groups

 Liver transplant
Description:  The patients will be transplanted according to standard procedures by the institutional protocol. Median time of surgery is 7 hours and 20 minutes. Each surgical procedure will be performed by specialists at the Rikshospitalet liver transplantation team, which consists of seven specialists at the unit. The transplantation procedure is initiated by an exploratory laparotomy with clinical assessment and frozen section of the lymphnodes in the hepatoduodenal ligament and along the common hepatic artery/coeliac axis. Complete clearance of the lymphatic tissue around the hepatoduodenal ligament. Frozen section is obtained from the distal end of the common bile duct. Evidence of disease dissemination to these regional lymph nodes will be an absolute contraindication to transplantation.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

15

Start Date

September 1, 2021

Completion Date

May 31, 2045

Primary Completion Date

May 31, 2035

Eligibility Criteria

        Inclusion criteria

          -  Radiologically strong suspicion of pCCA

          -  Tumor can involve intrahepatic portal vein without thrombosis of extrahepatic portal
             vein

          -  Tumor can involve hepatic artery distal to gastroduodenal artery or involve replaced
             hepatic artery

          -  First time pCCA

          -  Disease deemed not eligible for liver resection based on tumor location or underlying
             liver dysfunction

          -  No extrahepatic disease, or lymph node involvement detected on imaging

          -  No signs of extrahepatic metastatic disease according to PET-CT scan

          -  No signs of extrahepatic metastatic disease according to CT or MR
             (chest/abdomen/pelvis) scan within 4 weeks prior to the faculty meeting at the
             transplant unit

          -  At least 18 years of age

          -  Good performance status, Eastern Cooperative Oncology Group (ECOG) score: 0 or 1

          -  Satisfactory blood tests Hb >10g/dl, neutrophiles >1.0 (after any G-CSF), TRC >50,
             Bilirubin<3 x upper normal level, ASAT, ALAT<5 x upper normal level, Creatinine <1.5 x
             upper normal level. Albumin above lower normal level, Normal IgG4 levels

          -  Signed informed consent and expected cooperation of the patients for the treatment and
             follow up must be obtained and documented according to GCP, and national/local
             regulations

          -  Received chemotherapy for at least 6 months with at least 10% response according ti
             RECIST criteria and with no progression of disease at time of Lt

          -  At least 10 months from diagnosis

          -  Patient must be accepted for transplantation before progressive disease

          -  Twelve months or more time span from the diagnosis of pCCA and date of being listed
             for liver transplantation

        Exclusion criteria

          -  Tumor involving common hepatic artery, celiac trunck or superior mesenteric artery the
             tumor

          -  Tumor involving main portal vein

          -  Tumor involving inferior vena cava

          -  Perforation of the visceral peritoneum

          -  Weight loss >15% the last 6 months

          -  Patient BMI > 30

          -  Other malignancies, except curatively treated more than 5 years ago without relapse

          -  Known history of human immunodeficiency virus (HIV) infection

          -  Prior history of solid organ or bone marrow transplantation

          -  Substance abuse, medical, psychological, or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study results

          -  Known hypersensitivity to rapamycin

          -  Prior extrahepatic metastatic disease

          -  Women who are pregnant or breast feeding

          -  Any reason why, in the opinion of the investigator, the patient should not participate
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, +4723073296, [email protected]

Location Countries

Norway

Location Countries

Norway

Administrative Informations


NCT ID

NCT04993131

Organization ID

270331


Responsible Party

Principal Investigator

Study Sponsor

Oslo University Hospital


Study Sponsor

, , 


Verification Date

August 2021