Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging

NCT ID: NCT01387503

Last Updated: 2021-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-01-31
• Study Completion Date: 2019-07-31

Brief Summary

This clinical trial is aimed at extending the chance of liver transplantation, through downstaging procedures, to patients with hepatocellular carcinoma (HCC) exceeding conventional Milan Criteria.

Those patients that will achieve a sustained tumor response after downstaging will be randomized either to undergo liver transplantation or to proceed with conventional non-transplant treatments.

The aim of the study is to demonstrate unequivocally that liver transplantation may provide a survival benefit, with an acceptable survival rate of at least 60% at 5 years, to patients that demonstrate a radiological and sustained tumor response after downstaging. Noteworthy is that response is chosen rather than stage migration as endpoint of downstaging.

Detailed Description

1. Downstaging phase

Patients that will be considered eligible for the study will undergo downstaging procedures according their stage of disease and to Center's policies. Length and intensity of downstaging will be center specific and not centrally pre-determined, but should be inferior to 18 months. Downstaging procedures will be stopped when, according to the Investigators' judgement, the best possible tumor response has been achieved: at this timepoint a radiological evaluation of tumor response according to modified RECIST (mRECIST) criteria will be performed. Patients that have achieved a Complete or Partial Response (PR or CR) will proceed to Bridging Phase, while those with a Stable or Progressive disease (SD or PD) will drop-out from the study.

2. Bridging phase

Patients that achieved PR or CR after downstaging will receive systemic therapy with sorafenib for three months. After three months radiological response will be assessed according to mRECIST criteria. If a sustained response will be demonstrated patients will proceed to randomization. PD during bridging phase will cause drop-out from the study.

3. Randomization and study period

Patients will be randomized in a 1:1 ratio, using computer generated list stratified by Center and by compliance to sorafenib treatment (based on whether ≤50% or > 50% of the standard dosage (800 mg/day) has been administered).

1. The experimental group (Group 1 - transplant strategy) will be enlisted for transplantation and will undergo liver transplantation within 8 months unless major medical or oncological contraindications should occur.

2. The control group (Group 2 - non-transplant strategy) will continue with sorafenib until progression. Then they may be treated with either medical or locoregional/surgical therapies according to best practice and Centers' policy, excluding transplantation.

Conditions

Carcinoma, Hepatocellular; Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group 1 - Transplant strategy

Patients randomized to Group 1 will be enlisted for liver transplantation and will undergo liver transplantation within 8 months unless oncological (i.e. extrahepatic disease) or medical (i.e. cardiac insufficiency) will occur

Group Type: EXPERIMENTAL

Liver transplantation

Intervention Type: PROCEDURE

Once randomized to Group 1, patients will be enlisted for liver transplantation at the recruiting Center. Prioritization is encouraged as a waiting time of more than 8 months could cause patients' drop-out from the study

Group 2 - Non-transplant strategy

Patients randomized to Group 2 will continue to receive treatments according to their stage of disease, or will undergo only strict follow-up should a complete response after downstaging treatments have been achieved

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Liver transplantation

Once randomized to Group 1, patients will be enlisted for liver transplantation at the recruiting Center. Prioritization is encouraged as a waiting time of more than 8 months could cause patients' drop-out from the study

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Patient's age ≥ 18 yrs and ≤ 65 yrs
• Presence of cirrhosis of any etiology
• Child-Pugh class ≤ B7
• ECOG Performance Status ≤ 1
• Diagnosis of HCC either by biopsy or according to AASLD criteria
• HCC exceeding Milan Criteria with a 5-yr estimated survival after transplantation >50% according to the Metroticket calculator (http://www.hcc-olt-metroticket.org/calculator)
• Women of child bearing potential with a negative serum pregnancy test performed before enrolment
• Absence of general contraindications to sorafenib/molecular targeted therapies

Exclusion Criteria

• Presence of extra-hepatic tumor spread
• Presence of macrovascular invasion
• Sorafenib therapy started > 2 months before enrolment
• Concurrent cancer, distinct from HCC (except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors)
• Previous history of any cancer, even if curatively treated, < 5 years prior to entry
• Active intra-venous or alcohol abusers
• HIV infection
• History of serious cardiac disease
• Severe pulmonary hypertension not treatable by medical therapy
• Patients with a life expectancy of less than 3 months due to HCC or less than 6 months due to any other disease

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AISF (Associazione Italiana per lo Studio del Fegato)

UNKNOWN

Sponsor Role: collaborator

CNT (Centro Nazionale Trapianti)

UNKNOWN

Sponsor Role: collaborator

NITp (Nord Italia Transplant project)

UNKNOWN

Sponsor Role: collaborator

OCST (Organizzazione Centro Sud Trapianti)

UNKNOWN

Sponsor Role: collaborator

Associazione Italiana per la Ricerca sul Cancro

OTHER

Sponsor Role: collaborator

Ministero della Salute, Italy

OTHER

Sponsor Role: collaborator

Basilicata Region

UNKNOWN

Sponsor Role: collaborator

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

OTHER

Sponsor Role: lead

Responsible Party

Vincenzo Mazzaferro

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vincenzo Mazzaferro, MD

Role: PRINCIPAL_INVESTIGATOR

Istituto Nazionale Tumori, Milano

Locations

Ospedali Riuniti di Bergamo

Bergamo, , Italy

Ospedale Maggiore di Milano Policlinico

Milan, , Italy

Istituto Nazionale Tumori

Milan, , Italy

Azienda Ospedaliera Ospedale Niguarda Ca' Granda

Milan, , Italy

Azienda Ospedaliera Universitaria di Padova

Padua, , Italy

Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)

Palermo, , Italy

Policlinico Tor Vergata

Roma, , Italy

Ospedale "Lazzaro Spallanzani"

Roma, , Italy

Ospedale Umberto Iº Policlinico di Roma

Roma, , Italy

Ospedale Universitario Molinette S. Giovanni Battista di Torino

Torino, , Italy

Countries

Italy

References

Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL, Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De Carlis L, Cillo U, Burroughs AK, Troisi R, Rossi M, Gerunda GE, Lerut J, Belghiti J, Boin I, Gugenheim J, Rochling F, Van Hoek B, Majno P; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009 Jan;10(1):35-43. doi: 10.1016/S1470-2045(08)70284-5. Epub 2008 Dec 4.

Reference Type: BACKGROUND

PMID: 19058754 (View on PubMed)

Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693-9. doi: 10.1056/NEJM199603143341104.

Reference Type: BACKGROUND

PMID: 8594428 (View on PubMed)

Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008 May 21;100(10):698-711. doi: 10.1093/jnci/djn134. Epub 2008 May 13.

Reference Type: BACKGROUND

PMID: 18477802 (View on PubMed)

Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60. doi: 10.1055/s-0030-1247132. Epub 2010 Feb 19.

Reference Type: BACKGROUND

PMID: 20175033 (View on PubMed)

Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, Colledan M, Salizzoni M, Romagnoli R, Antonelli B, Vivarelli M, Tisone G, Rossi M, Gruttadauria S, Di Sandro S, De Carlis R, Luca MG, De Giorgio M, Mirabella S, Belli L, Fagiuoli S, Martini S, Iavarone M, Svegliati Baroni G, Angelico M, Ginanni Corradini S, Volpes R, Mariani L, Regalia E, Flores M, Droz Dit Busset M, Sposito C. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020 Jul;21(7):947-956. doi: 10.1016/S1470-2045(20)30224-2.

Reference Type: DERIVED

PMID: 32615109 (View on PubMed)

Related Links

http://www.hcc-olt-metroticket.org/

The system will calculate the 3 and 5 year predicted survival of a given patient with HCC undergoing liver transplantation

Other Identifiers

INT 80/09

Identifier Type: -

Identifier Source: org_study_id