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

Controlled Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging Procedures: a Randomized Trial (XXL Trial)

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular; Cirrhosis
• Intervention / Treatment: Procedure: Liver transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Bergamo, Italy, 24125
    • Ospedali Riuniti di Bergamo
  • Milano, Italy, 20162
    • Azienda Ospedaliera Ospedale Niguarda CA' Granda
  • Milano, Italy, 20133
    • Istituto Nazionale Tumori
  • Milano, Italy, 20122
    • Ospedale Maggiore di Milano Policlinico
  • Padova, Italy, 35128
    • Azienda Ospedaliera Universitaria di Padova
  • Palermo, Italy, 90133
    • Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)
  • Roma, Italy, 00133
    • Policlinico Tor Vergata
  • Roma, Italy, 00149
    • Ospedale "Lazzaro Spallanzani"
  • Roma, Italy, 00161
    • Ospedale Umberto Iº Policlinico di Roma
  • Torino, Italy, 10126
    • Ospedale Universitario Molinette S. Giovanni Battista di Torino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Procedure: 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
No Intervention: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant vs. non transplant strategy cost-benefit analysis	Comparison between the cost/benefit of a downstaging strategy followed by liver transplantation (treatment group) Vs the cost/benefit of convenional therapies (control group), analyzed according to the Quality Adjusted Life Years (QALY) gained in the treatment group	Approx. 1 year after the last patient randomized
Validation of modified RECIST criteria of radiological response to downstaging treatments	Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.	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	http://www.hcc-olt-metroticket.org/	Approx. 1 year after the last patient randomized

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Collaborators: Associazione Italiana per la Ricerca sul Cancro; Ministero della Salute, Italy; AISF (Associazione Italiana per lo Studio del Fegato); CNT (Centro Nazionale Trapianti); NITp (Nord Italia Transplant project); OCST (Organizzazione Centro Sud Trapianti); Basilicata Region
• Investigators: Principal Investigator: Vincenzo Mazzaferro, MD, Istituto Nazionale Tumori, Milano

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: Lancet Oncol. 2020 Aug;21(8):e373.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): March 31, 2015
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: July 1, 2011
• First Posted (Estimate): July 4, 2011

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 4, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; Sorafenib; Liver resection; Liver Transplantation; Trans-arterial chemoembolization (TACE); Radiofrequency ablation (RFA); Downstaging
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: INT 80/09