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

NCT01387503 | Completed

• 1 other identifier: INT 80/09
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 10

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.

Conditions

Carcinoma, Hepatocellular; Cirrhosis

Keywords

Hepatocellular Carcinoma; Liver Transplantation; Downstaging; Trans-arterial chemoembolization (TACE); Radiofrequency ablation (RFA); Liver resection; Sorafenib

Outcome Measures

Primary Outcomes (2)

• For Phase II - Time to Tumoral Event (TTE)

  TTE after randomization will be calculated as the interval between the randomization date and the date of tumour recurrence for tumor-free patients (either because of liver transplantation or complete response after downstaging procedures) or the date of tumour progression otherwise, with censoring at the date of last contact for event-free patients.

  Every 4 months

• For Phase III - Overall Survival

  Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients

  Every 4 months

Secondary Outcomes (3)

• Transplant vs. non transplant strategy cost-benefit analysis

  Approx. 1 year after the last patient randomized

• Validation of modified RECIST criteria of radiological response to downstaging treatments

  Approx. 8 months after the last patient randomized

• Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria

  Approx. 1 year after the last patient randomized

Study Arms (2)

Group 1 - Transplant strategy

EXPERIMENTAL

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

Procedure: Liver transplantation

Group 2 - Non-transplant strategy

NO INTERVENTION

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

Interventions

Liver transplantation 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 1 - Transplant strategy

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead
• AISF (Associazione Italiana per lo Studio del Fegato): collaborator
• CNT (Centro Nazionale Trapianti): collaborator
• NITp (Nord Italia Transplant project): collaborator
• OCST (Organizzazione Centro Sud Trapianti): collaborator
• Associazione Italiana per la Ricerca sul Cancro: collaborator
• Ministero della Salute, Italy: collaborator
• Basilicata Region: collaborator

Study Sites (10)

Ospedali Riuniti di Bergamo

Bergamo, 24125, Italy

Location

Ospedale Maggiore di Milano Policlinico

Milan, 20122, Italy

Location

Istituto Nazionale Tumori

Milan, 20133, Italy

Location

Azienda Ospedaliera Ospedale Niguarda Ca' Granda

Milan, 20162, Italy

Location

Azienda Ospedaliera Universitaria di Padova

Padua, 35128, Italy

Location

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

Palermo, 90133, Italy

Location

Policlinico Tor Vergata

Roma, 00133, Italy

Location

Ospedale "Lazzaro Spallanzani"

Roma, 00149, Italy

Location

Ospedale Umberto Iº Policlinico di Roma

Roma, 00161, Italy

Location

Ospedale Universitario Molinette S. Giovanni Battista di Torino

Torino, 10126, Italy

Location

Related Publications (5)

• 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.

  PMID: 19058754 BACKGROUND

• 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.

  PMID: 8594428 BACKGROUND

• 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.

  PMID: 18477802 BACKGROUND

• 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.

  PMID: 20175033 BACKGROUND

• 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.

  PMID: 32615109 DERIVED

Related Links

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

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Fibrosis

Interventions

Liver Transplantation

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Digestive System Surgical Procedures; Surgical Procedures, Operative; Organ Transplantation; Transplantation

Study Officials

• Vincenzo Mazzaferro, MD

  Istituto Nazionale Tumori, Milano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 30, 2011
• First Posted: July 4, 2011
• Study Start: January 1, 2011
• Primary Completion: March 31, 2015
• Study Completion: July 31, 2019
• Last Updated: October 11, 2021

Record last verified: 2021-10

Locations

IT (10)