Impact of Preoperative a-Fetoprotein Level on Disease-FreeSurvival After Liver Transplantation for HepatocellularCarcinoma

Fabrice Muscari • Jean-Pascal Guinard •

Nassim Kamar • Jean-Marie Peron •

Philippe Otal • Bertrand Suc

Published online: 25 April 2012

� Societe Internationale de Chirurgie 2012

Abstract

Background Preoperative a-fetoprotein (AFP) levels may

have an influence on disease-free survival (DFS) of patients

after liver transplantation for hepatocellular carcinoma

(HCC) located on a cirrhotic liver.

Methods Between 2000 and 2009, two groups were dis-

tinguished according to preoperative AFP level: normal-

level group (\10 ng/ml) and increased-level group

([10 ng/ml). The increased-level group was further divi-

ded into three levels of preoperative AFP: 10–150,

150–500, and C500 ng/ml. DFS and recurrence rates were

compared. All patients underwent transplantation using the

preoperative 5/5 criteria.

Results Of the 122 patients in this study, 63 had normal

and 59 had increased preoperative AFP. There were no

differences between the two groups concerning periopera-

tive or pathologic data. Those with an increased preoper-

ative AFP level had a significantly shorter 5-year DFS, and

their recurrence rate was higher than that of the normal

AFP group. The 5-year DFS and recurrence rates were 71

and 4 %, respectively, for those with normal AFP; 57 and

10 %, respectively, for those with AFP 10–150 ng/ml; 46

and 24 %, respectively, for those with AFP 150–500 ng/

ml; and 28 and 62 %, respectively, for those with AFP

C500 ng/ml.

Conclusions This study shows the prognostic value of

preoperative AFP levels on DFS after a liver transplant for

HCC in a population of patients undergoing transplantation

with the same preoperative criteria.

Introduction

Hepatocellular carcinoma (HCC) on a cirrhotic liver is one

of the most common indications for liver transplantation

(LT). The overall 5-year survival rate for this procedure

ranges from 65 to 75 % [1–4]. These good results have

been achieved by using precise selection criteria for

patients. The Milan criteria [3, 5–8] are used as a reference

for LT teams and health systems and are currently used by

the United Network for Organ Sharing (UNOS). However,

during the last decade, the incidence of HCC has increased,

and thus more patients currently need treatment [9, 10].

Therefore, several LT teams have tried to extend the Milan

criteria with the objective of treating more patients [7, 11–

14]. At our center, we use the 5/5 criteria (B5 nodules,

B5 cm), which in a previous study showed good results in

terms of survival and recurrence [15]. These good results

have been confirmed by other teams [16, 17]. This criterion

(5/5) allows to patients to undergo transplantation [17] with

a low recurrence rate and good survival. It is important that

any extension of the HCC selection criteria does not

increase the recurrence rate after LT. The recurrence rate

F. Muscari (&) � J.-P. Guinard � B. Suc

Department of Digestive Surgery and Liver Transplantation,

CHU Rangueil, 1 Avenue Jean Poulhes, 31059 Toulouse Cedex,

France

e-mail: muscari.f@chu-toulouse.fr

F. Muscari

Department of Epidemiology and Inserm U1027,

Toulouse, France

N. Kamar

Department of Organ Transplantation and Nephrology,

CHU Rangueil, Toulouse, France

J.-M. Peron

Department of Hepatology, CHU Purpan, Toulouse, France

P. Otal

Department of Radiology, CHU Rangueil, Toulouse, France

123

World J Surg (2012) 36:1824–1831

DOI 10.1007/s00268-012-1587-z

needs to remain low to offer equity between all patients on

a waiting list, whatever their type of disease. Extensions to

the selection criteria have concerned only the number and

size of nodules [7, 11–15].

It has been shown that other criteria could influence the

recurrence rate after LT, particularly histologic criteria

(i.e., poor differentiation, satellite nodules, microvascular

invasion) [4, 18–22]. The main problem with the histologic

criteria is that they are difficult to obtain during the pre-

operative period as there is poor correlation between tumor

analysis performed on the preoperative biopsy and the final

analysis of the operative specimen. There is also a risk of

tumor seeding during percutaneous biopsy [19, 23]. Indeed,

only the analysis of a specimen at resection has a good

correlation with the histologic analysis of the liver explant

[19]. Thus, these criteria do not improve selection of

patients beyond the size and number of nodules, with the

exception of patients who have had a resection before LT.

Another factor is that the preoperative a-fetoprotein (AFP)

level seems to be well correlated with the recurrence of

HCC after LT. The AFP level is increased by 20 to 80 % in

patients with HCC and is strongly related to tumor

aggressiveness [24–26]. The AFP level also seems to be

related to survival and recurrence rates after LT [27–32].

The advantage of the AFP level is that it is easy to obtain

before surgery at all LT centers.

The aim of our study was to evaluate the influence of

preoperative AFP levels on DFS of patients undergoing

liver transplantation for HCC and to assess if this evalua-

tion meets the preoperative 5/5 criteria.

Patients and methods

Patients

Data from all HCC patients who received a full-size liver

graft from a deceased donor between 2000 and 2009 in our

department were enrolled in this study. Two groups of

patients were distinguished: one with normal preoperative

AFP levels (\10 ng/ml) and the other with increased pre-

operative levels ([10 ng/ml).

Inclusion criteria

All patients’ records were analyzed at a multidisciplinary

meeting before registration on to the LT waiting list. A

diagnosis of HCC was assigned in accordance with the

Barcelona criteria [33]. A preoperative biopsy was per-

formed in cases of atypical appearance of lesions on

imaging and/or when the size of the nodule was \2 cm.

Patients were registered for the waiting list if they fell

within the 5/5 criteria (i.e., up to five nodules with a

maximum size of 5 cm [15]) as assessed by imaging

studies. The serum AFP was determined at least once in all

patients before the LT. The last determination of AFP

before liver transplantation was considered in this study.

Data collection

Data were collected prospectively. (1) Perioperative crite-

ria were the recipient’s age, sex, blood type, underlying

liver disease, Child-Pugh score, preoperative AFP levels—

normal (\10), 10–150, 150–500 or [500 ng/ml—a pre-

operative biopsy or not, tumor size and number of nodules

found on imaging, pre-LT treatment (for alcoholization,

resection, radiofrequency, or transarterial chemoemboli-

zation), waiting time on list, donor age, number of preop-

erative red blood cells and frozen fresh-plasma

transfusions, use of perioperative autotransfusion, amount

of blood transfused, and duration of graft cold ischemia. (2)

Pathologic criteria were the size and number of nodules,

macroscopic vascular invasion, degree of tumor differen-

tiation, presence of microvascular invasion, and presence

of satellite nodules. (3) Postoperative criteria were com-

plications (during hospitalization), death (during hospital-

ization), and/or recurrence (including the date and site of

the recurrence and its treatment).

Follow-up

While on the waiting list, AFP was determined each month,

and morphologic examinations [computed tomography

(CT) or magnetic resonance imaging (MRI)] were per-

formed every 3 months. Treatment while on the waiting list

was decided upon during a multidisciplinary meeting on a

case-by-case basis, depending on blood group and expected

waiting time. Data collection was completed on June 1,

2010—one year after the first inclusion.

After transplantation, the same team of pathologists

(two persons) performed the explant analyses. Follow-up,

after transplantation, was done in the outpatient clinic

every 3 months for the first year and then every 6 months

in the absence of any adverse events. Standard laboratory

tests, liver function tests, and determination of residual

anticalcineurins were done each time. An AFP assay was

performed every 6 months after LT for HCC. Ultrasonog-

raphy (US) was performed at 1 month, 6 months, 1 year,

and then every 6 months thereafter. CT/MRI was not per-

formed routinely but was used liberally for follow-up of

biliary and arterial complications; it was also used if

recurrence of HCC was suspected on the basis of history,

physical examination, laboratory findings, or US imaging.

An HCC recurrence was diagnosed during a multidis-

ciplinary meeting that included the same radiologist,

World J Surg (2012) 36:1824–1831 1825

123

surgeons, and hepatologists who treated the patient. The

recurrence was established based on imaging studies, the

AFP value, and the histology of a percutaneous biopsy.

Methods

Liver transplantation

The procedure used for orthotopic liver transplantation was

inferior vena cava (IVC) conservation. The cava–caval

anastomosis was fashioned by either a side-to-side tech-

nique or the ‘‘piggy-back’’ technique, using the three main

hepatic veins, as described previously [34]. No systematic

temporary portocaval anastomosis was done. An intraop-

erative blood-salvage autotransfusion was done using a

Cell-Saver 5 (Haemonetics) with the addition of an an-

tiaggregate filter (the same as that used for massive

homologue transfusions). We decided to use the Cell Saver

because it does not appear to increase the risk of postop-

erative recurrence [35].

Immunosuppression protocol

At induction, patients received either rabbit anti-thymocyte

globulin (RATG) or antagonists of receptors for interleukin

2 (basiliximab and daclizumab), or they had no induction

therapy. For maintenance treatment, almost all patients

were given anticalcineurin therapy (tacrolimus or cyclo-

sporine A). From 2003, patients received mycophenolate

mofetil. When HCC recurrence was diagnosed before 2001

anticalcineurin doses were decreased, whereas after 2001

the therapy was switched to rapamycin.

Statistical analyses

Statistical analyses were done with Statview software.

Analyses to estimate survival used the Kaplan-Meier esti-

mation, and the log-rank test was used to compare survival

curves. The v2 test and Student’s t test were used to

compare data between groups of patients.

Results

Perioperative data

Between 2000 and 2009, a total of 122 patients, meeting

the preoperative 5/5 criteria received a liver graft for HCC.

In all, 80 patients (65 %) underwent transplantation after

January 1, 2005 and 42 (35 %) before that date. A total of

63 patients had a normal preoperative AFP level, and 59

patients had an increased AFP level. The perioperative

characteristics of these two groups of patients are listed in

Table 1. There were no significant differences between the

two groups, with the exception of a more advanced age for

patients who had normal preoperative AFP levels. The

mean size of the largest HCC nodule was greater in the

group with increased preoperative AFP levels, but this

difference did not reach significance.

Correlation between preoperative AFP level

and preoperative selection criteria

The numbers of patients with increased AFP levels before

surgery were similar regardless to the selection criteria

applied at the time of registration [Milan, University of

California at San Francisco (UCSF), and 5/5] (Table 1).

There was no difference in the levels of abnormal preop-

erative AFP levels between the patients subgrouped

according to the number and size of their largest tumor

(44 % for the subgroup with one nodule B3 cm versus

43 % for the subgroup with fewer than five nodules

B5 cm) (Table 2).

Pathologic data

The specimen analyses data are shown in Table 3. All

patients were shown to have HCC on specimen analysis.

The maximum size and number of HCC nodules were

significantly greater in patients with increased AFP levels

before surgery. Altogether, 29 patients (24 %) had disease

that was underestimated by the initial imaging technique,

so they were beyond the 5/5 criteria based on the final

specimen analysis.

Immunosuppressive protocol

In all, 25 % of patients underwent induction with RATG,

28 % received anti-interleukin-2 receptor blockers (basil-

iximab or daclizumab), and 47 % had no induction therapy.

Additionally, patients were treated with calcineurin inhib-

itors (CNIs); 87 % received tacrolimus to target trough

levels of 5 to 10 ng/ml until month 3 and from 5 to 8 ng/ml

thereafter; 23 % received cyclosporine A to target C2

levels of 1,000 to 1,200 ng/ml until month 3 and from 500

to 800 ng/ml thereafter. In addition, half received myco-

phenolate mofetil, and 84 % received steroids. If HCC

recurred before 2001, the CNI doses of were reduced. If

recurrence occurred after 2001, CNIs were switched to

sirolimus. No significant differences between the immu-

nosuppressive protocols were found according to preoper-

ative AFP levels.

1826 World J Surg (2012) 36:1824–1831

123

Table 1 Perioperative data

Parameter All

patients

Normal

preop. AFP

Abnormal

preop. AFP

p

(n = 122) (n = 63) (n = 59)

Recipient age (years)a 58 58 55 0.030

Sex

Male 107 (88 %) 56 (89 %) 51 (86 %) 0.680

Female 15 (12 %) 7 (11 %) 8 (14 %)

Child–Pugh class

A 76 (62 %) 33 (53 %) 43 (73 %) 0.059

B 28 (23 %) 19 (30 %) 9 (15 %)

C 18 (15 %) 11 (17 %) 7 (12 %)

Meld scorea 18 17 18 0.653

Etiology of cirrhosis

Alcoholism 48 (39 %) 28 (44 %) 20 (34 %) 0.168

Viral C 49 (40 %) 24 (38 %) 25 (42 %)

Viral B 12 (10 %) 4 (7 %) 8 (14 %)

Others 7 (11 %) 6 (10 %)

Biopsy for HCC

Yes 36 (29 %) 17 (27 %) 19 (32 %) 0.661

No 86 (71 %) 46 (73 %) 40 (68 %)

Preoperative treatment

None 64 (52 %) 30 (48 %) 34 (58 %) 0.443

TACE 44 (36 %) 25 (40 %) 19 (32 %)

RFA 10 (9 %) 6 (9 %) 4 (7 %)

Resection 4 (3 %) 2 (3 %) 2 (3 %)

Size of nodule (cm)* 2.7 2.4 3 0.057

No. of nodule(s)a 2 2 2 0.728

Preoperative selection criteria

Milan criteria

Yes 89 (73 %) 42 (48 %) 47 (42 %) 0.158

No 33 (27 %) 21 (64 %) 12 (36 %)

UCSF criteria

Yes 98 (80 %) 52 (53 %) 46 (47 %) 0.882

No 24 (20 %) 11 (46 %)

AFP (ng/ml)

10–150 15 (12 %) – 15 (25 %)

150–500 27 (22 %) – 27 (46 %)

C 500 17 (14 %) – 17 (29 %)

Time on waiting

list (months)a2.7 3.0 2.5 0.483

Donor age (years)a 46 46 45 0.623

Cold ischemia

time (min)

472 478 465 0.601

No. of RBCsa 3.6 3.6 3.6 0.978

No. of FFPsa 5 5 6 0.381

IBSA

Yes 65 (53 %) 32 (51 %) 33 (56 %) 0.936

No 57 (47 %) 31 (49 %) 26 (44 %)

Table 2 Percentage of patients with abnormal preoperative AFP

levels ([10 ng/ml) according to the size and number of preoperative

HCC tumors

No. of

nodules

No. of patients with abnormal preop. AFP levels, by size

of largest nodule

B3.0 cm B4.5 cm B5.0 cm

1 11/25 (44 %),

AFP 229a22/38 (58 %),

AFP 204

27/44 (61 %),

AFP 180

B3 31/70 (44 %),

AFP 78

44/94 (47 %),

AFP 150)

52/106 (49 %),

AFP 136

B5 37/80 (46 %),

AFP 78

50/107 (47 %),

AFP 51

52/122 (43 %),

AFP 229

HCC hepatocellular carcinomaa Median of AFP measurements (ng/ml) in the subgroup

Table 3 Pathology data

Parameter All

patients

Normal

preop. AFP

Abnormal

preop. AFP

p

(n = 122) (n = 63) (n = 59)

Size of largest

nodule (cm)a3.3 2.8 3.7 0.016

No. of nodulesa 3.2 2.7 3.8 0.032

Differentiation

Poor 7 (6 %) 3 (4 %) 4 (7 %) 0.519

Middle 58 (46 %) 30 (48 %) 28 (47 %)

Good 44 (36 %) 25 (40 %) 19 (33 %)

Necrosis 13 (12 % 5 (8 %) 8 (13 %)

Microscopic

vascular

invasion

29 (24 %) 13 (21 %) 16 (27 %) 0.400

Satellite nodules 21 (17 %) 10 (10 %) 11 (19 %) 0.440

Selection criteria

5/5 93 (86 %) 52 (83 %) 41 (70 %) 0.901

[ 5/5 29 (24 %) 11 (17 %) 18 (30 %)

a Median

Table 1 continued

Parameter All

patients

Normal

preop. AFP

Abnormal

preop. AFP

p

(n = 122) (n = 63) (n = 59)

IBSA (ml)a 553 607 500 0.622

AFP a-fetoprotein, TACE transarterial chemoembolizationm, RFA radio-

frequency ablation, USCF University of California at San Francisco, RBCsred blood cells, FFP frozen fresh plasma, IBSA intraoperative blood sal-

vage autotransfusiona Median

World J Surg (2012) 36:1824–1831 1827

123

Postoperative data

The postoperative mortality rate (3 months) was 6 % (7/

122). Causes of death were fungal infection, cerebral

infarction, intraabdominal hemorrhage, and mesenteric

infarction. The postoperative morbidity rate was 34.5 %

(42/122). Causes of morbidity were surgical in 21 cases

and medical in 21 cases. There was no difference in terms

of mortality and morbidity according to the AFP level.

Follow-up period

The median follow-up time of patients was 38 months

(1–123 months): 39 months for normal preoperative AFP

level patients and 38 months for increased preoperative

AFP level patients.

The HCC recurred in 16 patients (13 %) after LT. There

was no significant difference in recurrence before or after

2005: 16 versus 11 % (p = 0.406). Recurrence was sig-

nificantly more frequent in patients who had an increased

preoperative AFP level compared to those with a normal

level: 22 % (n = 13) versus 4 % (n = 3) (p = 0.003).

Depending on the threshold level of preoperative AFP

studied, we observed a 10 % recurrence rate when preop-

erative AFP levels were 10 to 150 ng/ml, 24 % when levels

were 150 to 500 ng/ml, and 62 % with AFP levels

[500 ng/ml.

The median time from a LT to recurrence was

20 months for patients with normal preoperative AFP

levels and 22 months for patients with increased AFP

levels (p = 0,849). The median time until death after

diagnosis of recurrence was 7 months (1–19 months) with

no difference between the two groups.

The treatments of HCC recurrence were symptomatic

for 11 cases, palliative chemotherapy (sorafenib) in 2

cases, surgical resection in 2 cases, and alcoholization in 1

case.

At the end of the study period, 83 patients were alive

without recurrence (68 %), 4 patients were alive with

recurrence (3 %), and 35 patients had died (28 %). Causes

of death for the 35 patients were HCC recurrence (n = 12),

fungal and bacteria infection (n = 15), other neoplasm

induced by immunosuppressive treatment (n = 4), hepatic

(loss of graft) (n = 2), cardiac arrest (n = 2).

Disease-free survival

The DFS rates at 1, 3, and 5 years, for the entire popula-

tion, were, respectively, 91.5, 67.0, and 60.0 %. There

were no significant differences in the 5-year DFS before

and after 2005: 64 versus 57 % (p = 0.398).

The DFS according to the ‘‘classic’’ selection criteria

(Milan criteria and UCSF criteria) was not significantly

different. The 5-year DFS was 63.5 % within the preop-

erative Milan criteria (n = 89) and 50 % beyond them

(n = 33) (p = 0.164). The 5-year DFS was 58 % within

the preoperative UCSF criteria (n = 98) and 66 % beyond

them (n = 24) (p = 0.914).

The DFS was significantly decreased in patients with

increased AFP levels, with a significant decrease at 5 years

according to the different threshold levels of preoperative

AFP (Fig. 1): 71 % for normal preoperative AFP levels,

57 % for AFP levels of 10 to 150 ng/ml, 46 % for AFP

levels of 150 to 500 ng/ml, and 28 % for AFP levels

[500 ng/ml. The recurrence rate was higher and the delay

to recurrence was shorter, depending on the preoperative

AFP levels (Fig. 2).

0

,2

,4

,6

,8

1

Sur

vie

Cum

.

0 10 20 30 40 50 60

p = 0.045

Patients at risk:1.2. 3.4.

63 53 33 28 26 18 30 15 21 10 8 6 6

6 4 1

(1)

(2)

(3)

(4)

Time (months)

419910

2 1

29 2116 12

8 6

Fig. 1 Disease-free survival according to preoperative a-fetoprotein

(AFP) levels. (1) Normal preoperative AFP (\10 ng/ml) (n = 63). (2)

Preoperative AFP 10–150 ng/ml (n = 30). (3) Preoperative AFP

150–500 ng/ml (n = 21). (4) Preoperative AFP [500 ng/ml (n = 8)

0

,2

,4

,6

,8

1

1,2

1,4

Tau

x d’

Evé

n C

um.

0 10 20 30 40 50 60

p = 0.045

(1)

(3)

(4)

(2)

Time (months)

Fig. 2 Recurrence of hepatocellular carcinoma according to preop-

erative AFP levels. See Fig. 1 for explanation of the curves

1828 World J Surg (2012) 36:1824–1831

123

Overall survival

The overall survival (OS) rates for the entire population at

1, 3, and 5 years were, respectively, 91.5, 67.5, and 62 %.

There was no significant difference in the 5- year OS rates

after and before 2005: 64 versus 61 % (p = 0.601).

The OS according to the ‘‘classic’’ selection criteria

(Milan criteria and UCSF criteria) was not significantly

different. The 5-year OS was 66 % within the preoperative

Milan criteria (n = 89) and 50 % beyond them (n = 33)

(p = 0.102). The 5-year OS was 61 % within the preop-

erative UCSF criteria (n = 98) and 66 % beyond them

(n = 24) (p = 0.914).

The OS rates were worse in patients with increased AFP

levels before surgery, whereas there was no significant

difference according to the various thresholds of the pre-

operative AFP levels (Fig. 3). However, we did observe a

significant difference in terms of OS when the preoperative

AFP levels were [150 ng/ml, with the 5-year OS rates of

40 % when it was [150 ng/ml versus 66 % when it was

\150 ng/ml (p = 0.032) (Fig. 4).

Discussion

Our study shows that in a population of patients with the

same radiologic preoperative criteria the preoperative AFP

level was significantly associated with a change in DFS

after LT for HCC. This impact seems to be related to the

preoperative AFP level, resulting in a change in 5-year

DFS that ranges from 71 % when the level was normal

(\10 ng/ml) to 28 % when AFP was [500 ng/ml.

We observed that increased AFP levels before surgery

did not correlate with the size and number of HCC nodules

(Table 2). Indeed, 44 to 61 % of patients had increased

AFP levels before surgery regardless of the chosen selec-

tion criteria of the number of nodules and size of the largest

tumor. This probably helps to explain the recurrence rate of

10 % after LT as reported for the Milan criteria [3, 5–8] but

also the stable results in terms of survival and recurrence

rates observed using extensive selection criteria with

regard to number and size of the tumors [7, 11–15]. This

means that the restriction of selection criteria in terms of

size and number of HCC tumors does not decrease the

number of patients with an increased AFP level and

therefore does not improve the DFS.

All patients in this study underwent transplantation

within the 5/5 criteria (B5 nodules, B5 cm) and we have

recently reported the results obtained using the 5/5 criteria

in terms of recurrence and survival compared to the Milan

criteria [15]. In the population of patients reported here, we

determined three thresholds of prognostic preoperative

AFP levels: 10 to 150 ng/ml with a 5-year DFS of 57 %;

150 to 500 ng/ml with a DFS of 46 %;[500 ng/ml with a

5-year DFS of 28 %. Differences in DFS observed between

these three levels were statistically significant. The recur-

rence rate was 4 % when the preoperative AFP was normal

and ranged from 10 to 62 % depending on the elevation of

the AFP levels before surgery. The higher the AFP level,

the earlier did a recurrence appear. Our data confirmed that

AFP can be used as a serum marker for tumor aggres-

siveness [24–26, 29–32]. This marker is correlated with the

presence of histologic markers of poor prognosis, such as

microscopic vascular invasion, presence of satellite nod-

ules, or a poorly differentiated tumor [24–27]. In our study,

the number of patients presenting with poor histologic

criteria was higher in the group with increased preoperative

AFP levels, but this difference was not significant probably

because of the small number of patients in the ‘‘elevated

AFP-level group.’’ However, our patients with abnormal

preoperative AFP levels had significantly more nodules and

larger size of nodules on histologic analyses, which are

well known to be poor prognostic factors. This marker,

0

,2

,4

,6

,8

1

Sur

vie

Cum

.

0 10 20 30 40 50 60

(1)

(2)

(3) (4)

Patients at risk:1. 63 18 2. 303. 214.

p = 0.325

Time (months)

29 21 1553 42 33

16 12 10 8 6 6 2 1 1

28 26

6 48 6

10 10 9

Fig. 3 Overall survival according to preoperative AFP levels. See

Fig. 1 for explanation of the curves

0

,2

,4

,6

,8

1

Sur

vie

Cum

.

0 10 20 30 40 50 60

p = 0.032

AFP < 150 ng/ml (n = 101)

AFP > 150 ng/ml (n = 21)

Patients at risk: < 150 ng/ml. 101 69 53 42 83 30> 150 ng/ml. 21

Time (months) 8616 12 9 6 4 4

Fig. 4 Overall survival according to preoperative AFP levels greater

or less than 150 ng/ml

World J Surg (2012) 36:1824–1831 1829

123

however, was not related to preoperative size or number of

HCC nodules in our study because there was probably an

underestimation of these parameters during the preopera-

tive imaging studies. This underestimation of size and

number of HCC nodules was previously reported by many

studies and for all preoperative selection criteria [8, 11, 15,

36, 37]. In this context, the preoperative AFP value could

balance the radiologic preoperative underestimation of size

and number.

The predictive value of the AFP level for survival after

LT for HCC has been described in previous studies, with

preoperative AFP levels varying from 8.5 to 1000 ng/ml

[11, 29, 30, 32, 38–43]. Even with intention-to-treat anal-

ysis, it has been shown that high AFP levels are associated

with more patients dropping out of the waiting list [38, 39].

It has also been shown [28] that preoperative AFP levels of

[400 ng/ml that are associated with a tumor volume

\115 cm3 had a poor prognosis. Recently, studies [27, 31]

demonstrated that progression of preoperative AFP at [15

or [50 ng/ml per month was associated with worse sur-

vival and a higher risk of recurrence. AFP level also seems

to be a good marker of tumor response to various treat-

ments, including transarterial chemoembolization [44–46].

Until now, no study has compared increased AFP with the

preoperative cutoff in terms of survival and recurrence.

The mean weakness of our study was our long period of

inclusion. However, analysis of periods before and after

2005 did not find any significant difference for recurrence,

DFS, or OS. The choice of 2005 as a cutoff was justified by

our liver transplantation activity for HCC that was twice as

large (65 %) during 2005–2009 than during 2000–2004

(35 %). We could not analyze the effect of treatments on

the waiting list regarding the AFP level because this test

was not available to all patients before this time. The

heterogeneity of immunosuppressive protocols could be

explained by our long period of study. None of the various

immunosuppression protocols seemed to promote recur-

rence of HCC after transplantation. There was no differ-

ence in the use of anticalcineurin agents or the use of

induction therapies, whether by thymocyte globulin or

monoclonal antibodies, in this study (data not shown).

Rapamycin was used in our study only when recurrence of

HCC was suspected. We have not used other prognostic

markers (e.g., PIVKA-II, des-c-carboxyprothrombin)

because they were not easily available in our hospital.

Another limitation of our work was the absence of routine

CT or MRI for looking at HCC recurrence after orthotopic

liver transplantation. In our hospital, all liver transplant

patients are regularly followed and reviewed by the doctors

of the organ transplantation department. No patient was

lost to follow-up. The only distinctive feature of patients

who underwent transplantation for HCC was more regular

US examinations and AFP assays. In fact, we have

considered that there was no real benefit for the patient to

detect an early recurrence because therapeutic resources

are poor. Thus, the recurrence in our work was not

underestimated but was probably detected not early. In the

end, however, the recurrence rate is the same. In recent

studies on this topic, routine surveillance imaging has used

as well as US imaging [47].

Conclusions

This study confirms the prognostic value of preoperative

AFP levels on determining the DFS after LT for HCC.

With the objective of respecting equity among patients

waiting for LT for benign or malignant disease, it seems

necessary to us to select those HCC patients who are most

likely to benefit from LT. Therefore, it seems important to

consider preoperative AFP levels, which are easy to obtain.

One of the problems could be how to integrate the AFP

preoperative level with classic selection criteria for HCC—

how the preoperative AFP level could influence indications

for treatment while on the waiting list and possibly treat-

ment to downstage before LT.

Conflict of interest None.

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