28 Prospectivo downstaging Ravaioli Am J Transpl 2008.pdf

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American Journal of Transplantation 2008; 8: 25472557Wiley Periodicals Inc.

C 2008 The AuthorsJournal compilation C 2008 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2008.02409.x

Liver Transplantation for Hepatocellular Carcinoma:Results of Down-Staging in Patients Initially Outside

the Milan Selection Criteria

M. Ravaiolia, G. L. Grazia,, F. Piscagliab,F. Trevisanib, M. Cescona, G. Ercolania,M. Vivarellia, R. Golfieric, A. DErrico Grigionid,I. Panzinie, C. Morellia, M. Bernardib, L. Bolondib

and A. D. Pinnaa

aDepartment of Liver and Multi-organ Transplantation,bDepartment of Gastroenterology and Internal Medicine,cDepartment of Radiology and dDepartment ofOnco-hematology, Pathology Division of the F. Addarii

Institute, Sant Orsola-Malpighi Hospital, University ofBologna, Bologna, ItalyeDepartment of Research and Innovation, Hospital ofRimini, Rimini, ItalyCorresponding author: Gian Luca Grazi,[email protected]; [email protected]

Conventional criteria for liver transplantation for pa-tients with hepatocellular carcinoma are single HCC 5 cm or less than or equal to three HCCs 3 cm.We prospectively evaluated the possibility of slightlyextending these criteria in a down-staging protocol,which included patients initially outside conventionalcriteria: single HCC 56 cm or two HCCs 5 cm orless than six HCCs 4 cm and sum diameter 12 cm,but within Milan criteria in the active tumors after thedown-staging procedures. The outcome of patientsdown-staged was compared to that of Milan criteriaafter liver transplantation and since the first evalua-tion according to an intention-to-treat principle. From2003 to 2006, 177 patients with HCC were consideredfor transplantation: the transplantation rate was com-parable between the Milan and down-staging groups:88/129 cases (68%) versus 32/48 cases (67%), respec-tively. At a median follow-up of 2.5 years after trans-plantation, the 1 and3 years disease-free survival rateswere comparable: 80% and 71% in the Milan group ver-sus 78% and 71% in the down-staging. The actuarialintention-to-treat survival was 27/48 patients (56.3%)

in the down-staging and 81/129 cases (62.8%) in theMilan group, p=n.s. The proposed down-staging crite-ria provide a comparable outcome to the conventionalcriteria.

Key words: Allocation, hepatocellular carcinoma, livertransplantation, MELD score, patient survival, selec-tion criteria, tumor recurrence

Received 12 March 2008, revised 30 June 2008 andaccepted for publication 02 August 2008

Introduction

Liver transplantation (LT) for hepatocellular carcinoma

(HCC) preoperatively meeting the Milan criteria (MC) is an

established effective treatment, with a tumor recurrence

rate and 5-year patient survival close to 10% and 75%,

respectively (13).

Patients with HCC not meeting the MC are generally ex-

cluded from LT (3,4), due to the poor results reported in the

past in comparison to patients transplanted for cirrhosis,and are managed with alternative treatments which offer

a lower survival than LT (5,6).

Several authors believe these criteria, which include single

nodule with a diameter 5 cm or multiple nodules up to

three with a diameter 3 cm, could be slightly expanded

without affecting the postoperative tumor recurrence rate

and patient survival (718). However, there are no prospec-

tive and comprehensive studies with new preoperative

selection criteria, intention-to-treat analysis, including all

tumor stages, and a median follow-up of more than

2 years.

The extension of the selection criteria based on postopera-

tive histological samples proposed in some studies should

be carefully evaluated, due to the discrepancy between

preoperative and postoperative tumor stages which may

affect the analysis of patient outcome (1,19,20).

Other debated issues are the type of priority on the wait-

ing list for each tumor stage which HCC patients should

receive and the management of these patients during the

waiting time to avoid tumor progression or death due to

liver failure (2128).

We performed a prospective study, applying a down-

staging protocol for patients initially outside the conven-tional tumor criteria and meeting them after preoperative

treatments (pre-Ts). The outcome of patients meeting the

Milan criteria at the beginning and the outcome of patients

included in the down-staging protocol were compared both

after LT and after the first evaluation of the patients in an

intention-to-treat analysis.

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Patients and Methods

Study design and patient population

From January 2003 to January 2006, we prospectively evaluated 177 pa-

tients considered forLT witha preoperativediagnosis of HCC. Thediagnosis

of HCC was made following the EASL and the AASLD guidelines (29,30).

Nodules between 1 and2 cm were considered HCCs when tworadiological

techniques among ultrasonography (US), computed tomography (CT) and

magnetic resonance imaging (MRI) showed a typical hypervascular pattern

with a washoutin thevenous phase.Noduleslessthan2 cmwithan equivo-

cal imaging pattern were biopsiedwhenever possible and, if the biopsy was

technically unfeasible, they were included in a US and CT scan surveillance

program (31).

The diagnosis of HCC was the only indication for LT in 15 cases (8.5%),

while in the remaining cases it was associated with liver failure.

During the waiting time, pre-Ts were decided in each patient by a mul-

tidisciplinary team according to the tumor stage, HCC location and liver

function. Patients with a single nodule or two nodules located in the same

segment and preserved liver function were treated by liver resection (LR)

and were listed for LT only if tumor recurrence within the MC or liver

failure occurred. Patients not suitable for LR were treated by transarterial

chemo-embolization (TACE) and/or alcohol injection (PEI) or percutaneousradiofrequency ablation (RFA) aimed at achieving complete tumor necrosis

(1,32,33).

Patients not meeting the MC were included on the waiting list after com-

pleting the following down-staging protocol, drawn up by a multidisciplinary

team at our hospital including surgeons, hepatologists, radiologists and

pathologists, based on our previous experiences and studies (1,22,24

26,3234).

Down-stage protocol

(1) The criteria approved by the committee were a single HCC 8 cm or

bifocal HCCs 5 cm or multiple HCCs < 6 with a maximum diameter

4 cm and a total tumor diameter 12 cm.(2) All cases had to meet the MC after the down-staging procedures, con-

sidering the still active tumors. The radiological response to the pre-Ts

were evaluated in a blinded fashion by two different investigators and a

disagreementof lessthan 0.5 cm wasallowed during the measurement

of nodules.

(3) TACE, LR, PEIor RFA were applied according to case-by-case discussion

as described.

(4) After the pre-Ts, the nodules were considered active if contrast en-

hancement of any extent was present at imaging techniques. Among

the active nodules, the diameter of the whole lesion including the

necrotic portion was considered to establish the size to meet the MC.

Only active nodules were considered to meet the selection criteria and

the new nodules appearing during the waiting time were put together

with the treated nodules. Indeed, the total number of nodules, either

treated or not and either present at the beginning or developed subse-

quently, should not exceed the number approved for the protocol.

(5) A minimum follow-up of 3 months of meeting the conventional criteria

after the pre-Ts was considered necessary for patients to be included

on the waiting list. The alfa-feto protein level (AFP) had to remain


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Ravaioli et al.

Table 3: Preoperative tumor stage and preoperative treatments

129 patients 48 patients

177 patients Conventional criteria (CC) Bologna criteria with down-stage (BCDS) p

Any preoperative treatment 145 (81.9%) 97 (75.2%) 48 (100%)


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Bologna HCC Criteria for Liver Transplantation

0

20

40

60

80

100

0 12 24 36

Intention-to-treat survival (months)

%

C.C. B.C.D.S.

A

Actuarial intention-to-treat survival

Bologna criteria with down-stage (B.C.D.S.)

48 pts

Conventional criteria (C.C.)

129 pts

5 pts unable to complete

the protocol (all died)

43 pts listed for LT

8 pts excluded for

tumor progression

(3 pts still alive)2 pts died on list

from liver failure

1 pt still alive

on waiting list

32 pts had LT

23 alive after LT9 pts died after LT

27 pts alive

(56%)

129 pts listed for LT

15 pts excluded for

tumor progression

(2 pts still alive)

12 pts died on list

from liver failure

14 pt still alive

on waiting list

88 pts had LT

65 alive after LT23 pts died after LT

81 pts alive

(62.8%)

B

Figure 2: (A) Intention-to-treat survival since patient evaluation for liver transplantation according to the study group: conven-

tional criteria (CC) versus extended criteria with the down-staging protocol (BCDS). (B) Actuarial intention-to-treat outcome since

patient evaluation at every treatment steps according to the study group: conventional criteria (CC) versus extended criteria with the

down-staging protocol (BCDS).

the cases meeting the conventional criteria ab initio. All

patients were therefore given pre-Ts with the aim of al-lowing them to meet the conventional criteria (Figure 1).

An expert consensus was needed since there was very

little and only retrospective published evidence at the

time of protocol writing. According to practical experi-

ence, our selection criteria can be summarized by the

rule of six: single nodule with a maximum diameter 6

cm; multiple nodules 6 cm, even if our initial proposal included sin-

gle nodule up to 8 cm, as suggested by some authors

(11,13). The lack of these cases was probably due to our

surveillance policy for cirrhotic patients (34) and to our

surgical strategy favoring LR whenever possible (32,33).

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Ravaioli et al.

preoperative tumor stage assessment and reaching a me-

dian follow-up of more than 2 years.

In conclusion, the present prospective study advocates a

new patient selection based on slightly extended preoper-

ative staging and on the clinical response to pre-Ts, which

were validated to be effective and safe by the compara-

ble outcome according to both intention-to-treat analysis

and survival after LT. According to the proposed protocol,among the 48 patients believed to be beyond any curative

therapeutic strategy such as LT, the intention-to-treat sur-

vival at 3 years was close to 60%; this result opens new

prospectives for HCC patients respecting these criteria.

Acknowledgments

The author thank the colleagues of the University of Bologna, who gave

their support to the management of patients: Augusto Lauro, M.D.; Mas-

simo Del Gaudio, M.D.; Giovanni Varotti, M.D.; Gaetano Vetrone, M.D.;

Alessandro Cucchetti, M.D.; Giuliano La Barba, M.D.; Matteo Zanello, M.D.;

Alessandro Dazzi, M.D.; Francesco Tuci, M.D.; Chiara Zanfi, M.D.; Claudia

Sama, M.D.; Sonia Berardi, M.D.; Piero Andreone, M.D.; Maurizio Biselli,

M.D.; Paolo Caraceni, M.D.; Giorgio Ballardini, M.D.; Marco Lenzi, M.D.;

Maria Rosa Tame, M.D.; Giuseppe Mazzella, M.D.; Fabio Tumietto, M.D.;

Paolo Costigliola, M.D.; Marco Zoli, M.D.; Gian Paolo Bianchi, M.D.; Alberta

Cappelli, M.D.; Emanuela Giampalma, M.D.; Walter Franco Grigioni, M.D.;

Michelangelo Fiorentino, M.D.; Barbara Corti, M.D.

Conflict of Interest Statement

Statistical analysis was performed by I.P.

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28 Prospectivo downstaging Ravaioli Am J Transpl 2008.pdf