Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Recurrence

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Disease Attributes

Early-Stage hepatocellular carcinoma From January 2014 to January 2015, a total of 139 patients with early HCC from the First Affiliated Hospital, the Second Affiliated Hospital and the Third Affiliated Hospital of the Third Military Medical University were prospectively recruited according after MESS-RFA

MESS-RFA

Yunhua Tan

The aim was to investigate the efficacy of radiofrequency ablation (RFA) with a multiple-electrode switching system (MESS) in the treatment of early hepatocellular carcinoma (HCC) and to evaluate the patterns and risk factors of intrahepatic recurrence of HCC after RFA.

Percutaneous RFA has become a particularly promising treatment for patients with early HCC. For HCC with a diameter less than 3cm, RFA is becoming an effective topical method for the goal of a complete cure. Although RFA is successful for small HCCs, for HCCs with a diameter larger than 3 to 5 cm, the complete ablation rate is reported to range from 61.3% to 82.5%. These results may be obsolete due to the further development of RFA techniques and instruments. For example, the use of clustered electrodes and an improved motor can provide a higher power, and the multiple-electrode switching system RFA (MESS-RFA) uses various methods to create a sufficient ablation zone, the investigators need to further update the management strategy of the RFA treatment of early HCC.

However, HCC recurrence after RFA is still a significant problem . the investigators divide the intrahepatic recurrence after RFA into local tumor progression (LTP) and intrahepatic distant recurrence (IDR); each type of recurrence has a different pathogenic mechanism and is thought to occur relatively independently . Understanding the pattern and risk factors of recurrence is very important for the development of RFA and its clinical application.

The objective of our multicenter prospective study was to evaluate the efficacy of MESS-RFA as a primary method for treating early HCC, to assess the pattern of intrahepatic recurrence according to the types of recurrence, and to determine the risk factors associated with tumor recurrence and survival.

Recurrence Risk Factors of Early-Stage Hepatocellular Carcinoma After Radio Frequency Ablation

Recurrence Risk Factors of Early-Stage Hepatocellular Carcinoma After Radio Frequency Ablation: a Multi-center Prospective Case-control Study

Southwest Hospital, China

Instructor

Rare Diseases

Fibrolamellar Carcinoma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Anti-Infective Agents

Hematinics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Prednisone

Lenograstim

Mycophenolic Acid

Tacrolimus

Liver Extracts

Antilymphocyte Serum

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Calcineurin Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Protective Agents

Patients receive living related donor partial liver transplantation performed according to standard practices. Patients will be maintained on tacrolimus, MMF, and prednisone after liver transplantation.

Upon recovery, patient must undergo eligibility screening for bone marrow transplantation (BMT).

If eligible, patients will begin:

Antithymocyte globulin (ATG): Day -16 to Day -14; fludarabine: Days -6 to Day -2 low-dose cyclophosphamide: Day -6 and -5. Tacrolimus, mycophenolate mofetil (MMF), and prednisone: day -7 and day -6. Total body irradiation on Day -1 Bone marrow infusion on Day 0. High dose cyclophosphamide plus MESNA: Day 3 and 4th Filgrastim, tacrolimus,MMF, and prednisone: Day 5 until neutrophil counts recover.

Patients followed up through post transplant day 60, then weekly following discharge.

HLA matched or haploidentical related living donor partial liver transplant followed by tacrolimus, prednisone, and MMF immunosuppression for \>3 wks

living related donor partial liver transplantation

200 cGy total body irradiation (TBI) on Day -1.

Total body irradiation

BMT using cells from the same Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor will be performed on Day 0

Bone marrow transplant from same donor

Pre-transplantation low dose cyclophosphamide given day -6 and -5 Post-transplantation high dose cyclophosphamide (PTCy; 50 mg/kg/day) will be administered on Days 3 and 4 with hydration

administered daily starting on Day 5 until absolute neutrophil count (ANC) recovery

Filgrastim

Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT

mycophenolate mofetil

Given from Day -16 to Day -14 prior to bone marrow transplantation on day 0

Antithymocyte globulin

fludarabine given from Days -6 to Day -2 before BMT

fludarabine

This trial is a phase II, single arm, open-label, single center study to assess a reduced-intensity conditioning regimen, bone marrow transplantation and high dose PTCy in recipients of a partial liver allograft from a Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor in patients with HCC.

The primary objective of this trial is to characterize recurrence-free survival at 1 year following bone marrow transplantation among recipients of prior partial liver transplantation from the same donor.

The purpose of this study is to characterize the safety and anti-tumor efficacy of sequential partial liver transplantation followed by bone marrow transplantation from the same living related donor. This treatment applies to patients whose cancer remains confined to the liver but is too widespread to be removed by surgery or treated by a liver transplant from a deceased donor. The purpose of this combined treatment is to reduce the risk of the cancer coming back after the liver transplant The bone marrow transplant may reduce the risk of cancer relapse in two ways. First, patients who have combined bone marrow and solid organ transplants may be able to get off all anti-rejection drugs, which inhibit the immune system from destroying cancer cells. Second, the donor's bone marrow contains cells of the immune system, which can attack any cancer cells that remain after the liver transplant.

This trial is a phase II, single arm, open-label, single center pilot study to assess a reduced-intensity conditioning regimen, bone marrow transplantation and high dose post-transplantation cyclophosphamide (PTCy) in recipients of a partial liver allograft from a Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor in patients with HCC. The trial includes analyses of tumor characteristics and the number and phenotype of tumor infiltrating lymphocytes in the explanted tumor. The trial also includes periodic monitoring of circulating hepatocytes to correlate with tumor response.

The study is expected to take two years to complete accrual of six patients, and the primary objective of this trial is to characterize recurrence-free survival at 1 year following bone marrow transplantation among recipients of prior partial liver transplantation from the same donor. Secondary objectives include documenting percentage of patients who become tolerant of the transplanted liver, i.e. off immunosuppression for \>6 months without biochemical evidence of liver rejection, and characterizing the relationship between donor chimerism and transplantation tolerance.

Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Hepatocellular Carcinoma (HCC)

Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Fibrolamellar or Non-fibrolamellar Hepatocellular Carcinoma (HCC) Including Fibrolamellar HCC

The proportion of transplanted participants who remain free of disease recurrence for 1 year post bone marrow transplantation

The proportion of participants who are off immunosuppression without GVHD or liver rejection at 1 year after bone marrow transplantation.

Disease-free is defined as the lack of radiographic evidence of recurrence by computed tomography or MRI.

Determine the cumulative incidences of acute grades II-IV, III-IV and chronic graft-versus-host disease

Proportion of transplanted participants who die

Determine the proportion of transplanted participants with liver allograft rejection demonstrated by a biopsy or clinically if a biopsy cannot be performed.

Fibrolamellar Cancer Foundation

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Death

2200 HCC cases from East and West centres enlisted for LT and then delisted or transplanted

630 HCC cases from a Western centre enlisted for LT and then delisted or transplanted

300 HCC cases from a Eastern centre enlisted for LT and then delisted or transplanted

Liver transplantation

The present study has been developed with multiple aims: 1) to refine available models for liver transplantation which would be able to cover the fate of HCC candidates from an ITT point of view; 2) to develop such an approach on cohorts coming from both Eastern and Western countries; 3) to maintain simplicity of use; 4) to provide individual prognostication taking into account different causes of death, through a competing-risk model; 5) to provide an external validation on cohorts coming from both Eastern and Western countries. All these aims converge at providing a comprehensive and useful assessment suitable for both candidates selection and allocation priority.

For two decades, the Milan Criteria (MC) have represented the cornerstone in the selection of patients with hepatocellular cancer (HCC) as candidates for liver transplantation (LT). Since then, several Western and Eastern centres have tried to overcome MC stringency with the aim to expand the number of potentially transplantable patients without increasing the risk of post-LT tumour recurrence. Recently, variables correlated with HCC biology have been introduced to capture its aggressiveness and suitability for LT. Among the most commonly proposed, we can cite the alpha-fetoprotein (AFP) and the radiological response after neo-adjuvant loco-regional treatments (LRT). The effort to combine HCC morphology and biology is now emerging as the more promising approach for further refining the selection process of HCC candidates. The recently proposed prognostic indexes Metroticket 2.0, Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN), Model Of Recurrence After Liver transplant (MORAL) and French AFP-model represent the most promising results of such planned endeavours.

With the intent to be clinically useful, a prognostic system must achieve not only the most common performance metrics, such as discrimination and calibration, but also an adequate coverage of the population in which it would be applied. It can be argued that a prognostic system based only on criteria available at the moment of LT could not satisfy such a pre-requisite when the entire population of HCC patients waiting in the list for LT is taken into account, considering an intention-to-treat (ITT) point of view. In this sense, only the TRAIN system developed an ITT analysis, whereas the remaining were all based on pre-transplant information. The second quality that a clinically useful prognostic system should have is its immediacy. Thus, it should be based on commonly available information, not requiring additional analyses or exams if not justified by a substantial improvement in accuracy. Last but not least, a prognostic system should also provide for an individual prediction in addition to risk-stratification, with the intent to offer personalized prognostication for each different patient. To date, only the Metroticket 2.0 fulfils these two last requisites. A final important quality of the Metroticket 2.0 is that it applied a competing-risk analysis able to clean up the HCC-related cause of death from other non-tumour-related causes.

On this background, we developed the present study with multiple aims: 1) to refine available models which would be able to cover the fate of HCC candidates from an ITT point of view; 2) to develop such an approach on cohorts coming from both Eastern and Western countries; 3) to maintain simplicity of use; 4) to provide individual prognostication taking into account different causes of death, through a competing-risk model; 5) to provide an external validation on cohorts coming from both Eastern and Western countries. All these aims converge at providing a comprehensive and useful assessment suitable for both candidates selection and allocation priority.

A Worldwide Score for Hepatocellular Cancer and Liver Transplantation

A Worldwide Usable Scoring System for Patients With Hepatocellular Cancer Waiting for Liver Transplantation

Death for recurrence or other HCC-related causes

European Hepatocellular Cancer Liver Transplant Group

Principal investigator and Data manager of the EurHeCaLT Study Group

Chlorotrianisene

patients received immediate surgical hepatic resection

patients underwent transarterial chemoembolization (TACE) as initial treatments, and only patients who showed good response were subjected to surgical resection.

Chemoembolization and Response-Dependent Resection

patients received immediate surgical resection.

Immediate Resection

Ming Shi, MD

Rong Ping Guo, MD

The purpose of this study is to compare the survival outcomes between hepatic resection and transarterial lipiodol chemoembolization (TACE) used as the initial treatment in patients with Resectable Hepatocellular Carcinoma Beyond Milan Criteria.

For patients with large/multiple, and resectable hepatocellular carcinomas (HCCs) without macrovascular invasion or extrahepatic spread, the choice of treatment remains largely controversial. For these patients, transarterial lipiodol chemoembolization (TACE) is recommended as a palliative therapy.

On the other hand, many authors still believe that hepatic resection is the only potential curative treatment in these patients because it is still feasible to remove all macroscopic tumors safely at surgery. With advances in surgical techniques, more large/multiple HCCs are now resectable, and long-term results have been reported that ranged from 30% to 58% at 5 years; even patients with large bilobar multiple HCC could reach a survival rate of more than 20% at 5 years after hepatic resection.

Until now, there have been only a few studies that compared the outcomes of hepatic resection and TACE in the treatment of multiple HCCs, and these have reported controversial results. Some studies showed that hepatic resection had survival benefi t over TACE, but other studies showed the opposite result ( 11-15 ). Therefore, the investigators performed this prospective study in consecutive patients with large/multiple, and resectable HCCs to compare the outcomes in patients who underwent hepatic resection or TACE as the initial treatment.

Hepatectomy Versus Chemoembolization for Resectable Hepatocellular Carcinoma Beyond Milan Criteria

Hepatic Resection Versus Transarterial Chemoembolization as the Initial Treatment for Resectable Hepatocellular Carcinoma Beyond Milan Criteria

All severe adverse events for the entire course of treatment, including treatment for primary tumor and recurrent tumor.

First Affiliated Hospital, Sun Yat-Sen University

Third Affiliated Hospital, Sun Yat-Sen University

Kaiping Central Hospital

First People's Hospital of Chenzhou

Dongguan Shi People's Hospital

Sun Yat-sen University

Professor

Fluorodeoxyglucose F18

Imidacloprid

Milan-out, up-to-7-in, PET negative (≤1.15) HCC patients

Both groups will receive the same advantages on the LT waiting list (SE points)

Olivier Detry, MD PhD

Céline Lambrecht

Dirk Ysebaert, MD PhD

Thomas Vanwolleghem, MD PhD

Thierry Gustot, MD PhD

Valerio Lucidi

Hans Van Vlierberge, MD PhD

he, MD PhD

Frederik Berrevoet, MD PhD

Hans Van Vlierberghe, MD PhD

Chris Verslype, MD PhD

Jacques Pirenne, MD PhD

Frederik Nevens, MD PhD

Celine Lambrecht

Jean Delwaide, MD PhD

Ivan Borbath, MD PhD

Ivan Borbath

Geraldine Dahlqvist

Eliano Bonaccorsi

Hepatocellular carcinoma (HCC) is a rising public health concern with few curative options but liver transplantion (LT) in highly selected cases. LT could save many other HCC patients but organ shortage has lead to the necessity of selection of patients with the best survival chances, namely the Milan criteria. Hepatocellular carcinoma (HCC) is the fifth most common cancer, and the third cause of cancer related-death worldwide. HCC incidence is rising in Western countries including Belgium. There are more than 1,000 new HCC diagnoses in Belgium every year, but only 90 to 100 patients suffering from HCC are listed for liver transplantation (LT). In fact, the scarcity of organ donors has forced the development of strict criteria to limit LT to patients who are likely to have excellent outcomes. The universally accepted LT criteria for HCC are the Milan criteria (1 HCC nodule ≤5 cm or 3 nodules ≤3cm) that lead to a low rate of post-LT recurrence (\>80% of disease free recurrence at 5 years). The majority of patients suffering from HCC outside the Milan criteria at the time of diagnosis is not eligible for LT and is therefore limited to palliative care. It is however considered that some of these patients with HCC outside the Milan criteria may benefit from LT with an acceptable risk of recurrence and chances of long-term disease-free survival (DFS). This fact has led to the extension of LT criteria for HCC in some centres in different countries, as for example the University of California San Francisco (UCSF) criteria, the up-to-seven criteria or the Asan criteria.

The Belgian Liver-Intestine Allocation Committee (Be-LIAC) is a section of the Belgian Transplantation Society (BTS) composed of the 6 LT Belgian centres in charge of coordinating deceased LT activity in Belgium with the help of Eurotransplant. Be-LIAC has already built a retrospective HCC database that was successfully used for several scientific studies allowing international presentations and publications. Based on this successful experience, Be-LIAC is keen to continue with this national collaboration to initiate a prospective clinical observational database to better study the results of LT in Belgium and to evaluate potential of extension of LT criteria in HCC patients. Inclusion in this database will not change patient management or the allocation process of the liver grafts in Belgium. This project is financed by a 4-year (2019-2022) grant of the Belgian "Fondation contre le cancer" / "Stichting tegen Kanker".

All adult patients (\> 18 and \< 80 years) suffering from HCC and discussed for potential deceased or living related LT during multidisciplinary oncologic meetings in the 6 Belgian LT centres will be consecutively included in the prospective database after signing an informed consent form. Date of inclusion will be the date of discussion at the first multidisciplinary oncological meeting. All patients who are not contra indicated for LT due to general medical conditions (as presented in the exclusion criteria) or due to HCC staging (evidence of extrahepatic extension or cancerous macroscopic invasion of a liver vein at imaging) will be included in the database. These patients will be either directly listed on the Eurotransplant waiting list if considered within the local LT criteria by the given centre, or potentially listed after successful down-staging or HCC recurrence after a first attempt of curative management (ex: resection, radiofrequency ablation (RFA), ....).

A prospective, secured, anonymized (GDPR compliant), web-based database will be constructed with the help of an experienced company.

For LT listing, diagnosis of HCC will be based on international recommendations and Eurotransplant rules, either on biopsy or on imaging (AFP \>400 ng/mL and 1 positive result with hypervascularisation on CT and/or MRI), or AFP \< 400ng/mL and 2 positive results with CT and MRI). Hepatic lesions of \<1cm will not be considered for preoperative radiologic staging. All of the relevant liver images will be stored in a secured (GDPR compliant) web-based server and will be reviewed by a multicentre panel of expert radiologists in order to confirm the radiologic staging according to Milan and up-to-seven criteria.

Registration of HCC patients on the Eurotransplant waiting list will not be modified. Transplant candidates will be registered on the LT waiting list according to Eurotransplant and Be-LIAC allocation rules:

* 1 HCC nodule \> 2cm: labMELD score;
* HCC within the Milan criteria: (1 HCC nodule ≤ 5 cm or 3 nodules ≤ 3cm) exceptional standard exception (SE) MELD points;
* HCC outside the Milan criteria but successfully down-staged to inside Milan criteria: exceptional SE MELD points;
* HCC outside Milan criteria, within up-to-7 criteria, PET negative (≤ 1.15): exceptional SE MELD points;
* HCC outside Milan criteria, within up-to-7 criteria, PET positive (\> 1.15) or outside up-to-7 criteria: labMELD score.

Nodules ≤ 1 cm will be taken into account.

After transplantation, patients will undergo regular life-long immunosuppression according to the centre preferences. In the context of a malignant disease, the use of mTOR inhibitors will be encouraged but not mandatory, as suggested in the recent literature. The type of immunosuppression (induction therapy, calcineurin inhibitors, mTOR inhibitors, antimetabolites, steroids) will be recorded in the database. No adjuvant therapy will be performed in patients without evidence of recurrence.

Posttransplant tumour surveillance program will be standard for LT recipients with HCC and will consist in at least whole body CT every 6 months during the first 2 years, and AFP level measurement every 3-6 months during the entire follow-up period in patients with elevated pretransplant AFP. The date and site of recurrence will be recorded as well as survival data. Management of recurrence will be performed according to the centre policy and recorded in the database. As for other solid organ transplant recipients, all LT patients included in this study will be indefinitely followed by local transplant centres, allowing mid- and long-term (10 years) follow-ups.

Recorded data

* Patient's characteristics: Patient code generated by Eonix, internal patient code at the transplant center, Eurotransplant listing with the number and date of registration, ET listing criteria, country of residence, ethnicity, age, gender, blood group, BMI, viral status, cause of cirrhosis, diabetic status, smoking status, cancer status, history of liver and/or obesity surgery, cause of chronic liver disease, ascites and encephalopathy grade and Milan status at the Eurotransplant listing. If an HCC would have been treated in the past, more information will be required.
* HCC Data: - CT scan with the date, number of nodules and their sizes as well as their classification (TNM grade according to UICC 2018);

  - MRI with the date, the numbers of nodules and their size and their classification (TNM grade); - tumour biopsy with date and characteristics (differentiation, invasion) if performed; - FDG-PET / CT with the characteristics SUV max (\> 1.15) or SUV max (≤1.15); Medium SUV; the ratio between max SUV of the tumour with max SUV of a "normal" liver .
* Pre-transplant visits every 3 months: date, hemoglobin, platelets, white cells, neutrophils, lymphocytes, monocytes, international normalized ratio (INR), total bilirubin, creatinin, C-reactive protein (CRP), AFP, CA19-9, albumin and natrium. Lab-MELD score, encephalopathy and ascites grade, allowing determining Child Pugh score, CT scan/MRI every 3 to 4 months to monitor the nodules and their evolution. In addition, in some patients, blood samples will be stored in the biobank center. Additional informed consent will need to be signed by the patient to allow to retain vital biological data for future research. Standard neo-adjuvant HCC management (also called "bridge-to-transplant") will be performed according to the local multidisciplinary team decision, including resection, RFA, chemoembolization, radioembolization, Sorafenib, stereotaxic radiotherapy or no therapy. These informations will be included in the database. While on the LT waiting list, patients will be followed by CT/MRI and AFP level every 3 to 4 months, allowing the evaluation of the evolution of the tumour size and the ΔAFP. Response to neo-adjuvant therapy will be determined according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST): complete-response (CR), partial-response (PR), stable-disease (SD) and progressive-disease (PD).
* Liver transplant data: Recipients pretransplant last lab values: hemoglobin, platelets, white cells, neutrophils, lymphocytes, monocytes, INR, total bilirubin, creatinine, CRP, AFP, albumin, natrium, encephalopathy and ascites grade, waiting time before transplant, lab and exceptional MELD score at LT, Eurotransplant donor number, age of donor, type of donor, type of graft, graft origin, donor total bilirubin, ET donor risk index (ET-DRI), graft biopsy, time of ischemia, blood transfusion during surgery and after, need renal support, transaminase peak, total bilirubin at day 7, number of days in ICU, number of hospitalisation days.
* Pathology of explanted livers. Number of nodules and their sizes as well as their classification (TNM grade according to UICC 2018). These samples will be stored in the center's biobank to allow for further analyses needed for research in liver oncology. A consent must be signed by the patient.
* Follow up visits after LT: 1 month, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 66 months, 72 months, 78 months, 84 months, 90 months, 96 months, 102 months, 108 months, 114 months, 120 months:

Biology at follow up: AFP, tacrolimus level, everolimus level. Recorded informations: immunosuppression, graft survival, cause of transplant failure, the date of retransplantation, cause of patient death, recurrence of HCC and its location and planned treatment. A body CT will be performed at 6 months, 12 months, 18 months, 24 months, 32 months, 44 months and 60 months.

The HCC liver explant stored in the local biobank of the transplant center.

Value of Negative 18FDG PET/CT in Milan Out, Up-to-seven in, HCC Transplant Candidates

Extension of Liver Transplantation Opportunity to Patients Suffering From Milan-out, Up-to-7-in, Hepatocellular Carcinoma: a Prospective Belgian Study of the Value of Negative 18FDG PET/CT

Intention-to-treat (at LT waiting list registration) and post LT disease-free (DFS), recurrence-free (RFS) and overall survivals (OS)

Comparison of FDG-PET/CT to the other prognostic HCC prognostic factors, as the radiologic and pathologic Milan criteria, the UCSF criteria, the up-to-seven criteria, the Asan criteria and the AFP model

Evaluation of the value of positive or negative FDG-PET/CT in Milan-in HCC patients listed for LT and the impact on outcome in these patients

University Hospital, Ghent

Free University of Brussels

University Hospital, Antwerp

Universitaire Ziekenhuizen KU Leuven

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

University of Liege

Associate professor, Surgical head of the liver transplantation program

Heart and Blood Diseases

Hypertension

Hypertension, Portal

Adequate remnant liver volume was 30% for HCC patients without cirrhosis, and \>50% for HCC patients with chronic hepatitis, cirrhosis, or severe fatty liver.

RFA is performed in less than one week after clinical diagnosis.

Indications for HR are the presence of appropriate residual liver volume determined by volumetric computed tomography.

Hepatic Resection

Radiofrequency Ablation

Jian-Hong Zhong, MD

The purpose of the investigators' study is to prospectively compare the safety and efficacy of hepatic resection to radiofrequency ablation for hepatocellular carcinoma in patients with portal hypertension.

Cirrhosis is common among patients with hepatocellular carcinoma (HCC); in China, for example, it occurs in approximately 80% of HCC patients. Another common comorbidity of HCC is clinically significant portal hypertension (PHT), which occurs in 25-55% of patients with both HCC and cirrhosis. PHT correlates with the severity of cirrhosis, and it can complicate HCC treatment by increasing the risk of perioperative hemorrhage and liver failure.

Hepatic resection (HR) is a widely used radical therapy for HCC. Although HR is often suitable for HCC patients with cirrhosis, it is widely regarded as unsuitable for HCC patients with PHT because of the potential for postoperative hepatic decompensation. In fact, the absence of PHT is the best predictor of excellent HR outcomes. Guidelines of the American and European Associations for the Study of Liver Disease do not recommend HR as an option for HCC patients with PHT. Several studies, however, have reported that HCC patients with and without clinically significant PHT showed similar short- and long-term outcomes after HR. This controversy is important to resolve because more than 25% of cirrhotic patients with HCC also present with PHT.

Actually, official guidelines recommend liver transplatation for patients with HCC and PHT. However, implementation of liver transplantation is restricted by the lack of liver donation and the high cost of the procedure in many countries, especially China. However, as a minimally invasive therapy, radiofrequency ablation (RFA) is a popular treatment modality for patients with HCC within Milan Criteria. Moreover, randomized controlled trials have validated and proposed its clinical usage.

So here, we plan to address the safety and efficacy of HR comparing with RFA for HCC patients with PHT using a population from Guangxi province of China, where the population shows the highest HCC incidence in the world.

HR Versus RFA for HCC in Patients With PHT

Hepatic Resection Versus Radiofrequency Ablation for Patients With Hepatocellular Carcinoma and Portal Hypertension

Guangxi Medical University

Affiliated Tumor Hospital

Nivolumab

Pembrolizumab

Tislelizumab

Immunomodulating Agents

Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study.

Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously according to the manufacturer's instruction. Other combination regimens, such as locoregional therapies or targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.

Downstaging procedures containing immunotherapy

Patients with successful downstaging therapy at the end of the observation phase will enroll and undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Li PANG, PhD

Leibo Xu, PhD

Leibo XU, PhD

Chao LIU, PhD

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and the third leading cause of cancer death worldwide. Due to the shortage of donor organs and the risk of tumor recurrence after transplantation, the restrictive Milan criteria is the standard guideline for liver transplantation (LT) in patients with HCC and liver cirrhosis. The XXL study (Mazzaferro et al, 2020) is the first prospective trial validating that effective and sustained downstage therapy could expand the selection criteria and improve the prognosis of recipients with HCC beyond Milan criteria. However, the optimal DT protocol is poorly defined, especially in the Asian population. Recently, immunotherapies such as immune-checkpoint inhibitors (ICIs) are revolutionizing the management of advanced HCC, the combination of the ICI and other treatment regimens (Anti-VEGF, locoregional therapies et al) produced superior results in patients with advanced-stage HCC compared to those with traditional therapeutic regimens. Therefore, we hypothesize an intensive downstage regimen containing immunotherapy could expand the selection criteria for HCC LT

This will be a single-arm, open-label, non-randomized phase II study aiming to access the efficacy and safety of the downstage protocol containing immunotherapy for HCC beyond Milan Criteria. This study contains 4 phases:

1. Screening and Downstaging phase Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study.

   Criteria for Successful Downstage

   Patients that meet 1-4 criteria are considered to have achieved the downstaging goal, otherwise, the downstaging treatment is considered to have failed within 12 cycles of downstaging treatment:
   * CR or PR evaluated by iRECIST/mRECIST after at least 2 cycles of downstaging treatment.
   * Patients with onset AFP\<400ng/ml: AFP \<400ng/ml at the end of downstaging therapy; Patients with onset AFP\>400ng/ml: AFP levels decrease more than 30%, and must be less than 1000ng/ml at the end of downstage therapy.
   * Estimated 5-year overall survival ≥60% at the end of downstaging therapy according to the Metroticket model (http://www.hcc-olt-metroticket.org/calculator).
   * For patients with portal vein tumor thrombus (PVTT1-3), tumor thrombus needs to retract above the bifurcation of the main portal vein, and portal vein anastomosis is feasible during liver transplantation according to the surgeons' judgment.
2. Observation phase Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase ≥ 3 months. Patients at this phase can optionally receive TKIs (sorafenib, lenvatinib et al), and other anti-tumor treatments (such as locoregional therapies, surgery, and immunotherapies et al) are not allowed at this phase. Patients with a sustained response and whose tumors still meet the Criteria for Successful Downstage at the end of the observation phase will be enrolled in the waiting list for liver transplantation, while patients with tumor progression (PD) and their tumors fail to meet the Criteria for Successful Downstage at the end of observation phase will drop out from the study.
3. Waiting and Bridging phase During the waiting period before liver transplantation, patients can optionally receive a non-immunotherapy protocol as bridging treatment determined by the multidisciplinary team (MDT). Surgery is not allowed at this phase.
4. Liver transplantation and post-transplantation phase Patients will undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Eligible patients will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.

Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

A Prospective, Single-arm Study of Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

From the date of transplantation to the date of tumor recurrence or the date of tumor progression otherwise, with censoring at the date of death or last contact for event-free patients.

The time elapsed from the liver transplantation to death during the 2-year follow-up period.

The probability of survival from the beginning of treatment to the end of 1-year and 2-year follow-up.

Number of recipients developing EAD after liver transplantation

Number of recipients developing allograft rejection after liver transplantation

Number of patients reaching the successful downstaging criteria for liver transplantation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Recurrence Risk Factors of Early-Stage Hepatocellular Carcinoma After Radio Frequency Ablation	NCT02046356	Hepatocellular ...	MESS-RFA	18 Years - 70 Years	Southwest Hospital, China
Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Hepatocellular Carcinoma (HCC)	NCT02702960	Fibrolamellar H... Hepatocellular ... Hepatocellular ...	living related ... Total body irra... Bone marrow tra... Cyclophosphamid... Mesna Filgrastim Tacrolimus mycophenolate m... Prednisone Antithymocyte g... fludarabine	16 Years - 65 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
A Worldwide Score for Hepatocellular Cancer and Liver Transplantation	NCT03595345	Liver Cancer Dropout, Patien... Recurrence	Liver transplan...	18 Years -	European Hepatocellular Cancer Liver Transplant Group
Hepatectomy Versus Chemoembolization for Resectable Hepatocellular Carcinoma Beyond Milan Criteria	NCT02138981	Resectable Hepa...	Chemoembolizati... Immediate Resec...	18 Years - 70 Years	Sun Yat-sen University
Value of Negative 18FDG PET/CT in Milan Out, Up-to-seven in, HCC Transplant Candidates	NCT05276037	Hepatocellular ...	Liver transplan...	18 Years - 80 Years	University of Liege
HR Versus RFA for HCC in Patients With PHT	NCT02192671	Carcinoma, Hepa... Liver Neoplasms Neoplasms, Glan...	Hepatic Resecti... Radiofrequency ...	18 Years - 75 Years	Guangxi Medical University
Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation	NCT05475613	Liver Transplan... Hepatocellular ...	Downstaging pro... Liver transplan...	18 Years - 75 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

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