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Liver transplantation for the treatment of unresectable colorectal cancer liver metastasis

Living donor liver transplantation

YoungRok Choi, MD

YoungRok Choi, M.D.

Nam-Joon Yi, Ph.D.

Unlike hepatocellular carcinoma, liver transplantation in patients with liver metastasis from colorectal cancer is limited in only few centers. Previously, it was not generally implemented due to lack of organs and high recurrence rates after transplantation. However, due to progressive development in treatments, good results such as increased survival rates can be expected even in liver transplant patients with liver metastasis from colorectal cancer, which is known to have poor prognosis. Therefore, the purpose of this study is to analyze the efficacy of liver transplantation as an alternative treatment for liver metastasis from colorectal cancer.

Surgical treatment offers a distinct survival benefit in liver metastasis of colorectal cancer (CRC LM). However, it has been estimated that only 40% of patients are candidates for curative liver resection. Liver transplantation can be considered as one of a treatment option, since all evident disease is removed during procedure. However, it is limited in only few centers due to lack of organs and high recurrence rates after transplantation.

Currently, with help of development in treatments, prognosis after LT in CRC LM is improving. Recent study of LT for CRC LM from Norway demonstrated a 5-year survival of 56%. In addition, cohort study and randomized controlled trials are ongoing in Germany and Canada. Therefore, it seems to be necessary to verify the effectiveness of liver transplantation for CRC LM and to verify it as an alternative treatment if there is no other treatment. The purpose of this study is to analyze the efficacy of liver transplantation as an alternative treatment for liver metastasis from colorectal cancer.

Potential participants will be evaluated for liver transplantation and must also have a willing, healthy living donor. Unresectable metastasis should be limited to the liver and stable without no other treatment such as immunotherapy, chemotherapy, surgical resection, and radiofrequency ablation. The suitability of liver transplantation will be evaluated through a multidisciplinary assessment immediately before transplantation. Those participants who undergo liver transplantation will be followed for survival, disease-free survival, and recurrence for 3 years.

LT for Unresectable Colorectal Liver Metastasis

Effectiveness of Liver Transplantation for Unresectable Colorectal Liver Metastasis; Pilot Study

Seoul National University Hospital

Professor

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Antineoplastic Agents

Chlorotrianisene

29 HCC patients who had loco regional therapies for HCC were analyzed. Twenty patients met the Milan criteria (68.97%) \& 4 (13.8%) were beyond Milan but met UCSF criteria and 5 were exceeding UCSF criteria (17.2%).All patients underwent preoperative LRTs, The protocol of bridging/down staging, methods, duration of follow up, the number of the patients who were successfully down-staged before LT and their outcomes after LT were recorded.

29 HCC patients received locoregonal therapy as a bridging therapy for those who were within milan and as downstaging for those were initially beyond milan. The main LRT types used for our patients were TACE and or RFA and microwave ablation

loco regional therapies for HCC

This study aimed to analyze the outcomes of loco-regional treatment prior Living Donor Liver Transplantation in patients with HCC.

50 patients received LDLT at Ain Shams Centre for Organ Transplantation (ASCOT) over 1 year of whom data of 29 HCC patients were analyzed. Twenty patients met the Milan criteria (68.97%) \& 4 (13.8%) were beyond Milan but met UCSF criteria and 5 were exceeding UCSF criteria (17.2%).All patients underwent preoperative LRTs, The protocol of bridging/down staging, methods, duration of follow up, the number of the patients who were successfully down-staged before LT and their outcomes after LT were recorded.

Efficacy of Loco-regional Treatment for Hepatocellular Carcinoma Prior to Living Donor Liver Transplantation in Egypt

Loco-regional Treatment for HCC Patients

the success of loco-regional therapy for hepatocellular carcinoma in term of radiological complete or partial response in the last spiral triphasic abdominal CT and /or MRI before transpalantation

1. presence of viable tumour tissue in the explant pathology,
2. mictro vascular invasion
3. capsular or lymph node invasion the degree of accuracy between the last CT/ MRI and the pathology of explant

Ain Shams University

Associate profesor of tropical medicine , Ain Shams university

Two-stage hepatectomy combined with transplantation of left-lateral lobe from a living donor.

Living donor liver transplantation with two-staged hepatectomy.

Falk Rauchfuss, M.D., M.Sc.

Ulrike McCaulley, Study Nurse

Utz Settmacher, M.D.

Alfred Königsrainer, M.D.

Silvio Nadalin, M.D.

Nearly one third of patients with colorectal cancer develop liver metastases. It is well known that the achievement of a R0-situation is one of the most important factors for a positive long-term outcome. Despite further advantages in multimodal treatment concepts, only 20 - 30 % of the patients with metastases can be resected in curative intention.

Recent studies, especially from Norway, have shown that liver transplantation might be a feasible option in well selected patients since the complete hepatectomy with subsequent liver transplantation can be an option for the achievement of a R0 situation.

In this study, we pursue the strategy of two-stage hepatectomy combined with a left-lateral living donor liver transplantation.

Inclusion criteria are as follows: non-resectable liver metastases of a primary colorectal carcinoma with an assumed portal-venous drainage of the tumor and at least a "stable disease" after a period of eight weeks systemic chemotherapy. Patients are excluded from the study if there is an extrahepatic tumor burden (with the exception of resectable lung metastases) or if the patient is not suitable for liver transplantation due to co-morbidities.

The transplantation itself will be undertaken as a living donor liver transplantation where the left lateral liver lobe (liver segments 2 \& 3) from a healthy volunteer donor will serve as graft. Prior transplantation, a left hemihepatectomy in the recipient is performed and the left lateral graft will be transplanted in this position. At the end of the transplantation procedure, the right portal vein will be closed to induce a rapid growth of the graft. The second step, and therefore the completion of the operation is performed after a growth period of the transplanted left-lateral lobe: in this procedure, the right hemi-liver of the recipient will be removed and the patient is supposed to be free of tumor at this point in time.

Purpose

The purpose of the present study is to evaluate a two-stage hepatectomy with a left-lateral living donor liver transplantation and right portal vein ligation for treatment of otherwise irresectable liver metastases of colorectal carcinoma in curative intent.

Study setting

The study is an investigator-initiated, bi-institutional, one-arm trial. For ethical reasons, it was decided to perform no control group since the superiority of the liver transplantation procedure is to be expected. Therefore, it was decided to compare the transplantation cohort with a historic control group who has received the actual gold-standard of chemotherapy.

Endpoints Primary endpoint The primary endpoint is the overall patient survival 36 months after the 2nd step of liver transplantation in a two stage procedure.

This time point was chosen since the patient has to be regarded as "free of tumor" from this last step of tumor operation.

Secondary endpoints

Secondary endpoints are:

* the recurrence-free survival of the patients 36 months after second stage of hepatectomy.
* the morbidity of both donor and recipient, defined as complications ≥ IIIb according to the Clavien-Dindo classification.

Patient selection

All patients with irresectable colorectal liver metastases and no extrahepatic tumor burden (except resectable lung metastases) are potential candidates for study inclusion, if:

* the tumor burden is at least a "stable disease", according to the RECIST criteria at least after eight weeks of systemic chemotherapy
* an external, independent review board, composed of a surgeon, an oncologist and a radiologist, checked and approved the criteria for study inclusion.

Exclusion criteria

Patients are ineligible for study participation, if:

* there is an extrahepatic tumor burden, except resectable lung metastases
* no suitable donor available
* significant comorbidities that preclude transplantation
* there is a tumor progression during chemotherapy.

Treatment methods If the potential recipient fulfills the in- and exclusion criteria and has a potential suitable living donor, the patient will be admitted to a special transplantation ward, where the evaluation process for liver transplantation in this special setting begins according to the standard evaluation protocol of the specific centre. The procedure includes a PET-CT scan for tumor burden additional to the standard evaluation for liver transplantation.

If contraindications for liver transplantation are excluded, the potential recipient will be discussed in the transplantation board and subsequently listed as organ recipient at Eurotransplant waiting list.

Furthermore, the patient's history and all available imaging will be sent to an external review board, consisting of an experienced hepatobiliary surgeon, an oncologist and a radiologist, who will assess the individual case from their specialized field. Only if all three reviewer approve the study inclusion of the patient, the following steps are performed.

Now the potential donor will be evaluated for the living donation process. This includes an ultrasound, an MR scan for the visualization of the biliary tract and a CT scan. The latter ones will be analyzed with exact volumetric analyses of the donated and remaining liver parenchyma. Furthermore, the evaluation process includes a cardiologic examination and the premedication visit as well as a LiMAX test. Both, donor and recipient, will be interviewed by a clinical psychologist.

At the end of the evaluation procedure, the individual patient case will be judged by an independent living donation committee of the respective State Chamber of Physicians.

Operative procedure - Step 1 The transplantation procedure starts with an extensive exploration of the abdominal cavity of the recipient to exclude an extrahepatic tumor manifestation. If there is no extrahepatic tumor burden, a left hemihepatectomy is performed (the liver resection itself is undertaken using an appropriate device, e.g. Cavitron Ultrasound Aspirator), whereby the resection plane depends on the localization of the metastases and might vary between individual patients. For the subsequent reconstruction of the arterial inflow of the left lateral graft, a venous interposition graft (usually saphenous vein of the recipient) is established from the common hepatic artery.

Parallel, the donor procedure is started, whereby a left-lateral hepatectomy (resection of the segments II and III) is performed (also using standard devices for parenchymal transsection, e.g. Cavitron Ultrasound Aspirator).

The left-lateral graft is transplanted orthotopically. To induct a more rapid growth and regeneration of the graft, the right portal vein is ligated (according to an ALPPS procedure) while measuring the portal pressure. The reconstruction of the biliary tree of the graft is realized performing a bilio-enteric anastomosis. This allows an easier procurement of the right liver in step 2.

The immunosuppression is performed according to the following protocol:

* Intraoperative

  500 mg Methylprednisolone i.v.
* Early postoperative phase

Tacrolimus Target level 5 - 10 ng/ml

Mycophenolat-Mofetil 1000 mg twice daily

Basiliximab 20 mg i.v. on the day of the transplantation and on POD 4

Prednisolone 0,5 mg/kgBW/d from POD 1 - 10 and reduction of 0,1 mg/kgBW/d every 10 days

\* 3 months after the transplantation procedure

Everolimus in combination with Tacrolimus Both with a target level of around 5 ng/ml

Between both operative steps, continuous laboratory analyses as well as ultrasound investigations will be performed. Presumable after three weeks, a CT scan, a subsequent MEVIS analysis and a LiMAX test are performed. If a normal liver function is diagnosed, step 2 is scheduled for the following day.

Operative procedure - Step 2 In this operation, the remaining right liver will be removed. Hereby, additional parenchymal transsection is usually not necessary since both liver has been completely separated in Step 1.

Follow-up The follow-up is coordinated by the transplantation unit of the centers. It includes a CT scan of thorax and abdomen six, nine, 18 and 30 months after the finalization of the two-stage procedure (step 2). Furthermore, a PET-CT scan will be performed after three months and 1, 2 and three years after step 2. At these points in time, a LIMAX-test will also be performed to assess the liver function of the graft. Furthermore, the individual immunosuppressive regime is recorded. In case of an adjuvant chemotherapy, agents, duration and tolerance of the drug(s) will be registered.

Statistical methods The primary endpoint (overall survival) and the secondary endpoint "disease-free survival" are examined in a model using a Gray's test since they are competing events. For both events, the calculated hazard ratios are indicated with a confidence interval of 95 %.

All other secondary endpoints, reflecting the morbidity of donor or recipient, are compared using Fisher's exact test between the groups. The absolute and relative frequency of these adverse events per group will be reported.

The significance level for all tests is defined as α=0,05. The analysis is performed according to an "intention-to-treat"-principle. Subgroup analysis are not planned.

Centralized monitoring and the Data and Safety Monitoring Committee The data monitoring will be performed by the Center of Clinical Studies in Jena and Tübingen.

Participating institutions The German Medical Association approved the study protocol for the liver transplantation centers in Jena and Tübingen. During this study, it is not provided to enable other transplantation centers the study participation.

Living Donor Liver Transplantation With Two Stage Hepatectomy for Patients With Isolated, Irresectable Colorectal Liver Metastases

Overall survival three years after 2nd-stage of hepatectomy

Disease-free survival three years after 2nd-stage of hepatectomy

all complications \> grade IIIa according to the Clavien-Dindo classification

University Hospital Tuebingen

Jena University Hospital

Senior Surgeon

Hepatic Insufficiency

Liver Failure

In this group , patients will undergo biliary reconstruction using surgical loupe

In this group , patients will undergo biliary reconstruction using microscope

Biliary reconstruction will be performed using surgical loupe

Surgical Loupes

Biliary reconstruction will be performed using microscope

Microscope

Comparison of biliary complications in right lobe living donor liver transplantation patients undergoing biliary reconstructions using microscope versus surgical loupes .

Liver transplantation (LT) is the most effective treatment modality in patients with end-stage liver disease and it is also established as a viable treatment option in the field of oncology. Living donor liver transplantation (LDLT) using the right lobe (RL) is a major achievement despite its technical challenges, which has created a significant increase in graft supply. While a secure bile duct anastomosis is one of the basic principles of a successful liver transplant procedure, biliary reconstruction remains the Achilles' heel of LDLT because of the high incidence of posttransplant biliary complications associated with significant recipient morbidity and mortality. Some of these complications are related to technical difficulties due to multiple small biliary orifices, particularly in right lobe grafts. In our center, we have been using microsurgical reconstruction technique for duct-to-duct biliary anastomosis in such grafts. The routine use of this technique has been shown to significantly decrease biliary complications in single-center retrospective studies. However, prospective controlled studies comparing microsurgical and standard biliary reconstruction techniques are lacking. In this study, our objective is to compare posttransplant complications of the two techniques of biliary reconstruction in RL LDLT.

40 patients will be included in the study. They will be randomly allocated in the equal groups.İn group 1 biliary anastomosis will be performed using surgical loupes and İn group 2 biliary anastomosis will be performed using microscope. The patients will be followed for one year after the transplant to compare biliary complications.

The patients will be randomly allocated in the equal groups.İn group 1 biliary anastomosis will be performed using surgical loupes and İn group 2 biliary anastomosis will be performed using microscope.

Biliary Anastomosis Using Surgical Loupe Versus Microscope in Living Donor Liver Transplantation

Prospective Randomized Single-center Trial Comparing Biliary Anastomosis Using Surgical Loupe Versus Microscope in Living Donor Liver Transplantation

Incidence of biliary complications after living donor liver transplantation

Istanbul Medipol University Hospital

Primary researcher

The LDLT will be performed by the UW Division of Transplantation in accordance with the standard of care for this operation.

Living Donor Liver Transplantation

David P Al-Adra, MD, PhD

This study will test the safety and efficacy of living donor liver transplant after standard-of-care chemotherapy for participants with non-resectable liver metastases (LM) from colorectal cancer. 25 donor-recipient pairs will be enrolled (50 participants). Donors will be on study for 2 years and recipients will be on study for up to 5 years.

This study is a single center, open-label study available to male and female adults with CRC LM that are deemed to be "unresectable" and who are receiving standard of care chemotherapy. Participants will be worked up for LDLT while continuing to receive chemotherapy and, if deemed eligible for surgery, will stop chemotherapy 4 weeks prior to receiving a living donor transplant. Recipients will be followed for 5 years (for safety, survival and disease recurrence for purposes of study data collection). They will continue to be monitored for safety, survival and disease recurrence indefinitely as part of University of Wisconsin (UW) Health's Organ Transplant Program care standards. Living liver donors will be followed for 2 years after transplant surgery for safety monitoring as part of this study.

Recruitment will be done in two stages. The first stage will be a pilot study of 5 recipients to determine if LDLT is a suitable treatment for patients with non-resectable LM. If, after 3 years of follow-up, the overall survival is greater than 60%, stage two recruitment will commence. Thus, an interim analysis will be done for the first 5 recipients prior to requiring a larger number of subjects. Stage two recruitment will focus on accruing a total of up to 20 additional recipients to be analyzed.

The control group will consist of any potential recipients that sign the informed consent and are enrolled in the study but do not undergo LDLT due to a lack of an eligible donor. These participants will be referred back to their medical oncologists to receive standard of care chemotherapy, and will continue to be followed as the control group.

Patients who sign the informed consent and are enrolled in the study with an eligible live donor but do not undergo LDLT due to disease progression or a contraindication is established for undergoing LT (exclusion criteria) will also be referred back to their medical oncologists to receive standard of care chemotherapy. This group will be followed as part of the intent to treat cohort.

single-center, open-label, two-stage recruitment

* pilot study of 5 recipients to determine if LDLT is a suitable treatment for patients with non-resectable LM with 3 years of follow-up, if Overall Survival greater than 60%, then
* stage two recruitment focusing on accruing additional recipients will commence.
* control group of participants that sign the informed consent and are enrolled in the study but do not undergo LDLT due to a lack of an eligible donor

Living Donor Liver Transplantation for CRC Liver Metastases

Neo-adjuvant Chemotherapy Plus Living Donor Liver Transplantation (LDLT) for Non-Resectable Liver Metastases From Colorectal Cancer (CRC)

Overall survival, defined as length of time from the start of (neoadjuvant) chemotherapy that subjects diagnosed with colorectal liver metastases are still alive.

DFS, defined as length of time after LDLT during which no disease is found according to RESIST v1.1 criteria.

Patterns of recurrence will be investigated, assessed by standard of care chest, abdominal and pelvis imaging.

Surviving number of recipients who receive LDLT vs. control subjects will be assessed at 1-, 3-, and 5-years.

Quality of life is measured at 1-, 3-, and 5-years using the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire). The questionnaire assesses multi-item scales, each item scoring from 1 to 4, with higher scores representing a higher level of symptomatology or problems.

Quality of life is measured at 1-, 3-, and 5-years using the EORTC QLQ-LMC21 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire). The questionnaire assesses multi-item scales, each item scoring from 1 to 4, with higher scores representing a higher level of symptomatology or problems.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LT for Unresectable Colorectal Liver Metastasis	NCT04874259	Liver Metastasi...	Living donor li...	19 Years -	Seoul National University Hospital
Efficacy of Loco-regional Treatment for Hepatocellular Carcinoma Prior to Living Donor Liver Transplantation in Egypt	NCT02990351	Hepatocellular ... Living Donor Li...	loco regional t...	18 Years - 65 Years	Ain Shams University
Living Donor Liver Transplantation With Two Stage Hepatectomy for Patients With Isolated, Irresectable Colorectal Liver Metastases	NCT03488953	Colorectal Canc... Liver Metastase...	Living donor li...	18 Years -	Jena University Hospital
Biliary Anastomosis Using Surgical Loupe Versus Microscope in Living Donor Liver Transplantation	NCT04618692	Liver Failure Liver Diseases Liver Cancer Liver Neoplasms Liver Dysfuncti...	Surgical Loupes Microscope	18 Years - 75 Years	Istanbul Medipol University Hospital
Biliary Anastomosis Using Surgical Loupe Versus Microscope in Living Donor Liver Transplantation	NCT04618692	Liver Failure Liver Diseases Liver Cancer Liver Neoplasms Liver Dysfuncti...	Surgical Loupes Microscope	18 Years - 75 Years	Istanbul Medipol University Hospital
Living Donor Liver Transplantation for CRC Liver Metastases	NCT05175092	Liver Metastasi...	Living Donor Li...	18 Years - 65 Years	University of Wisconsin, Madison
Living Donor Liver Transplantation for CRC Liver Metastases	NCT05175092	Liver Metastasi...	Living Donor Li...	18 Years - 65 Years	University of Wisconsin, Madison

Spots Global Cancer Trial Database for living donor liver transplantation