Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Nivolumab

Pembrolizumab

Tislelizumab

Immunomodulating Agents

Liver Extracts

Immunologic Factors

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.

Liver transplantation

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

Spots Global Cancer Trial Database for downstaging therapy