Pediatr Blood Cancer 2004;42:74–83
Liver Transplantation for Hepatoblastoma: Results From the
International Society of Pe+diatric Oncology (SIOP) Study
SIOPEL-1 and Review of the World Experience{
J.B. Otte, MD,1* J. Pritchard, FRCP,7 D.C. Aronson, MD,2 J. Brown, MSc,3 P. Czauderna,
R. Maibach, PhD,5 G. Perilongo, MD,6 E. Shafford, MRCP,8 and J. Plaschkes, MD9
Background. For hepatoblastoma (HB) that
remains unresectable by partial hepatectomy
after chemotherapy, total hepatectomy with
orthotopic liver transplantation (LTX) has been
advocated as the best treatment option. The role
of LTX in the overall management of HB is still,
however, unclear. Procedure. The results of LTX
from the first study of HB by the International
Society of Pediatric Oncology, SIOPEL-1, were
analyzed. In addition, the world experience of
LTX for HB was extensively reviewed. Twelve
patients in the SIOPEL-1 study underwent a LTX.
Median (range) follow-up at Dec. 31, 2001 was
117 months (52–125) since LTX. Results. Over-
all survival at 10 years post-LTX was 85% for the
seven children who received a ‘‘primary LTX’’
and 40% for the 5 children who underwent a
‘‘rescue LTX’’ after previous partial hepatect-
omy. In the world experience (147 cases), the
Key words: childhood cancer; hepatoblastoma; liver malignancies; liver transplantation
INTRODUCTION
Hepatoblastoma (HB) is a rare malignancy but ac-
counts for 75% of primary liver tumors in childhood. The
5-year survival rate of children affected by HB and treated
with combination, Cisplatin-based chemotherapy and
surgical resection is now in the range of 60–80% which
represents at least a doubling of the survival rate reported
in the early 1980s [1]. Doxorubicin and Cisplatin have had
a major impact on prognosis, especially in those patients—
the majority—with initially unresectable disease [2–8].
—
1
—————
Department of Pediatric Surgery and Liver Transplantation, Université
Catholique de Louvain, Cliniques Saint-Luc, Brussels, Belgium
2 9
Pediatric Surgical Center of Amsterdam, Emma Children’s Hospital
AMC, Amsterdam, The Netherlands
3
Northern and Yorkshire Clinical Trials and Research Unit, University
of Leeds, United Kingdom
4
Department of Pediatric Surgery, Medical University of Gdansk,
Poland
5
Swiss Institute of Applied Cancer Research (SIAK) Coordinating
Center, Bern, Switzerland
6
Department of Pediatrics, University of Padua, Padua, Italy
7
Department of Surgery, Institute of Child Health, London and
Department of Oncology and Haematology, Royal Hospital for Sick
Children, Edinburgh, Scotland
ß 2003 Wiley-Liss, Inc.
DOI 10.1002/pbc.10376
MD,
4
overall survival rate at 6 year post-LTX was 82%
for 106 patients who received a ‘‘primary LTX’’
and 30% for 41 patients who underwent a
‘‘rescue LTX.’’ Multivariate analysis of patients
undergoing primary LTX showed that only
macroscopic venous invasion had a significant
impact (P-value: 0.045 with a hazard ratio of
2.96) on overall survival. Conclusions. Ortho-
topic LTX has added a new dimension to the
treatment of HB unresectable by partial hepa-
tectomy. Because of the rarity of the disease and
to optimize results, children with extensive HB
should be treated in centers with surgical
expertise in pediatric major liver resection and
LTX, in close collaboration with pediatric onco-
logists, radiologists, and histopathologists.
Pediatr Blood Cancer 2004;42:74–83.
ß 2003 Wiley-Liss, Inc.
Despite the crucial contribution of chemotherapy, com-
plete resection of the primary tumor is still a prerequisite
for cure. For those HBs that remain unresectable by partial
liver resection after appropriate chemotherapy, total hepa-
tectomy with orthotopic liver transplantation (LTX) has
been advocated as the best treatment option. However,
since experience with LTX for this disease is limited, its
overall place in the management of HB is still unclear.
The aims of this report are (a) to analyze the treatment
results of LTX achieved in those children enrolled into the
—
8
—————
Department of Pediatric Oncology, St. Bartholomew’s Hospital,
London, United Kingdom
Department of Pediatric Surgery, University of Bern, Switzerland
{
This manuscript was originally submitted to and accepted for
publication in Medical & Pediatric Oncology by its Editor-in-Chief,
Dr. G. D’Angio.
Grant sponsor: The Cancer Research Campaign (United Kingdom);
Grant sponsor: the Swiss Cancer League (Berne); Grant sponsor: the
Children’s Liver Tumor Parents’ organisation (United Kingdom).
*Correspondence to: J.B. Otte, Cliniques Universitaires Saint-Luc,
Avenue Hippocrate 10, B-1200 Brussels, Belgium.
E-mail: otte@chex.ucl.ac.be
Received 29 May 2002; Accepted 25 February 2003

first international prospective cooperative study run by the
International Society of Pediatric Oncology—SIOPEL 1
study—who underwent LTX, (b) to analyze the world
experience, and (c) to suggest guidelines regarding the
indications for LTX.
SIOPEL 1 STUDY
Patients and Methods
The SIOPEL-1 study was an international, co-operative
single arm study open to children aged less than 16 years
with a histologically proven, previously untreated HB. A
new pre-treatment extent of disease system (PRETEXT
grouping), based on the radiological findings, was devel-
oped [6,9] to describe the extent of the primary tumor,
before and during therapy (Fig. 1). The aim of PRETEXT
grouping was to determine whether it would be possible,
preoperatively, to identify the patients in whom complete
tumor resection could be performed by means of a partial
hepatectomy. This system is quite different from those
Fig. 1. PRETEXT, Pre-treatment extent of disease system.
Liver Transplantation for Hepatoblastoma 75
developed by the Children’s Cancer Study Group [3,10]
and the German Cooperative Pediatric Liver Tumor Study
[4,5] in which the stage of disease is determined at the
initial surgical intervention, before chemotherapy starts.
Between January 1990 and February 1994, 154 chil-
dren were enrolled in SIOPEL-1 by 91 centers in 30
countries from five continents [7].
The treatment strategy adopted for the SIOPEL-1 study
was based on preoperative chemotherapy. Definitive
surgical resection of the primary tumor was carried out
after 4–6 courses of PLADO (Cisplatin and Doxorubicin).
This is different from what was recommended by the
North American [3,10] and German studies [5,11] in
which surgical resection of resectable tumors was carried
out at diagnosis and was then followed by chemotherapy.
The treatment plan, response to chemotherapy, timing, and
results of surgical resection and the main treatment results
of the SIOPEL-1 study have been reported elsewhere [6–
9,12]. To the best of our knowledge, the SIOPEL-1 trial is
the first major cooperative study in which LTX has been
suggested in the protocol as a valid treatment option. This
design provided an opportunity to assess retrospectively
the overall role of LTX in the treatment of HB.
Eligibility Criteria for LTX
When the tumor remained unresectable after six courses
of PLADO because it was judged still to be invading all
four sectors of the liver (PRETEXT group IV) or because
of too close proximity to either hepatic vein(s) or portal
vein precluded radical excision by partial hepatectomy
(centrally located HB), LTX was recommended as
primary surgery (‘‘primary LTX’’), provided that (a) there
had been at least a partial response to chemotherapy
(reduction of tumor size and serial fall of serum alpha-
feto-protein (AFP) level), and (b) there was no current
evidence of metastatic disease or extrahepatic tumor
deposits [7]. Also eligible for transplantation were (a)
patients with PRETEXT group I to IV tumors at pre-
sentation who had intrahepatic relapse after previous
partial hepatectomy if there was no current evidence of
metastatic disease or (b) those who had incomplete
resection (‘‘rescue LTX’’). Patients with lung metastases
at presentation were also eligible if, after chemotherapy, a
chest computed tomography (CT) showed that these
metastases had completely disappeared. The protocol did
not include a recommendation for thoracotomy to confirm
complete clearance of the lung metastases.
In case of persisting disease after the six planned
courses of PLADO, not amenable to surgical resection, the
decision to test further therapy (other than Cisplatin/
Doxorubicin) before considering LTX was left to the
judgement of the local center. Complete normalization
of serum AFP level was not required pretransplant. No
recommendations on the use of post-LTX chemotherapy
were formulated in the protocol.
76 Otte et al.
Post-Liver Transplant Immunosuppression
The protocol did not include recommendations regard-
ing this issue which was addressed according to local
practice in the treating institution because, as yet, there is
no standardized, agreed regimen either for induction or
maintenance immunosuppression in these patients. HLA
matching, which is not, in any case, relevant in LTX for
HB, was not studied.
Accuracy of Data and of Follow-Up
The study was based on analysis of the data collected in
the database of the Northern and Yorkshire Clinical Trials
and Research Unit (Leeds, UK).
The accuracy of the data and update of follow-up
(at December 31, 2001) was double-checked by the first
author (JBO) through direct contact with each of the
medical teams in charge of patients who received a liver
transplant.
Statistical Analysis
Overall survival from time of LTX was estimated by the
Kaplan–Meier method, and standard deviations estimated
by the Greenwood formula.
Results
Of the 138 children who received preoperative che-
motherapy as per protocol, 6 died after the start of PLADO
but before surgery, 1 was lost to follow-up, 115 had
delayed surgery, after PLADO chemotherapy, and the
tumor remained unresectable after PLADO in 16 others.
Among the 115 children who underwent surgery after
PLADO, 6 patients (nos. 66, 67, 99, 169, 186, and 225)
received a ‘‘primary LTX’’ because the tumor was still
judged unresectable by partial hepatectomy, there were 5
peri-operative deaths and 104 children underwent partial
liver resection. Of these latter 104 patients, 2 (nos. 58 and
168) received a ‘‘rescue LTX’’ after additional chemother-
apy because of intrahepatic recurrence of the disease and
another patient (no. 147) received a ‘‘rescue LTX’’
because of left hepatic vein obstruction after right
trisegmentectomy. Among the 16 children who had an
unresectable tumor after PLADO and who received
alternative chemotherapy, 3 received a LTX (patient nos.
35, 61, and 198), in one case as a ‘‘primary LTX’’ (patient
no. 61), in one case as a ‘‘rescue LTX,’’ because the tumor
resection was incomplete at partial liver resection (patient
no. 35) and in one case because an autograft of the
right posterior liver sector, performed after bench left
trisegmentectomy, failed due to arterial thrombosis
(patient no. 198). Of the other 13 patients whose tumor
remained unresectable post-PLADO, 3 were lost to
follow-up and 10 died without further attempts at curative
treatment.
In summary, LTX was performed in 12 patients (8%
of the total enrolled in the SIOPEL-1 study). Their ages
at presentation ranged from 7 months to 10.5 years
(median: 2.5 years) and at the time of LTX from 1.25 year
to 11.6 years (median: 3.8 years). There were seven boys
and five girls. These 12 children received a cadaveric liver
transplant in eight different centers (Birmingham, UK,
four patients (nos. 058, 066, 168, 169), Copenhagen, two
patients (nos. 099, 147), Sydney, two patients (nos. 035,
061) and one each in Brussels (no. 198), Helsinki (no.
067), London King’s College (no. 186), and Oslo (no.
225)). The procedure was performed as a ‘‘primary LTX’’
in seven children (58%) because the tumor remained
unresectable after PLADO in six, and after PLADO,
additional chemotherapy and radiotherapy in the remain-
ing one. The other five (42%) patients had ‘‘rescue LTX’’
after previous partial hepatectomy.
Regarding intrahepatic extent at diagnosis, eight
patients had PRETEXT IV tumors (Table I). Of these
eight children, six remained PRETEXT IV despite che-
motherapy (nos. 61, 66, 67, 99, 186, and 225); they all
received ‘‘primary LTX.’’ The two remaining patients
received a ‘‘rescue LTX’’ because of macroscopic residual
tumor after partial resection (no. 35) or intrahepatic
relapse after several partial liver resections (no. 168). Two
patients had PRETEXT III tumors. One of them (no. 169)
underwent ‘‘primary LTX’’ because of close proximity of
tumor to the hepatic veins (centrally located HB); the other
(no. 198) received a ‘‘rescue LTX’’ because an attempt at
segmental autograft failed. The final two patients were
PRETEXT II. Both received ‘‘rescue LTX,’’ one because
of intrahepatic relapse after three successive partial
resections (no. 58) and one due to occlusion of the left
hepatic vein, 5 weeks after right trisegmentectomy (no.
147). Of the 12 children, 6 patients had multifocal HB, 5
had lung metastases, 7 had macroscopic venous extension
and 1 had an extension outside the liver. Seven patients
who received PLADO only (4 to 7 courses) before LTX
(nos. 66, 67, 99, 147, 169, 186, 225) have been mentioned
in previous reports [6,7,9]. Five patients, not yet reported,
received additional chemotherapy before LTX (nos. 35,
58, 61, 168, 198); one also received radiotherapy.
Median (range) follow-up of this cohort of patients was
127 (101–135) months since diagnosis and 117 (52–125)
months since LTX for surviving patients. The overall
patient survival was 75% at 5 years and 66% at 10 years,
both since diagnosis and since LTX (Fig. 2). All eight
survivors were free of evidence of recurrent disease at the
time of reporting. One child (no. 35) developed unresect-
able adenocarcinoma of the ascending colon 9 years post-
LTX but was still surviving at the last follow-up (Dec. 31,
2001). Another patient (no. 66) was retransplanted 6 years
after his first LTX for biliary cirrhosis secondary to arterial
thrombosis. Finally, a further patient (no. 99) developed
HCV chronic hepatitis.
 Liver Transplantation for Hepatoblastoma 77
TABLE I. SIOPEL-1 Study

Extrahepatic Timing of
extension transplantation Status and
follow-up
Age at Primary Rescue since LTX
Number Trial no. Gender diagnosis PRETEXT Multifocal V P E M LTX LTX Relapse (months)

1 35 f 17 mo IV No þ þ
þ X No ANED (115)
2 58 f 8 y 9 mo II No þ þ

X Yes DIED (24)
3 61 f 4 y 8 mo IV Yes
þ
þ X No ANED (120)
4 66 m 2 y 7 mo IV Yes



X No ANED (122)
5 67 m 10 y 6 mo IV Yes
þ

X No ANED (125)
6 99 m 2 y 4 mo IV Yes þ þ

X No ANED (119)
7 147 f 2 y 8 mo II No


þ X NA DIED (0.2)
8 168 m 3 y 9 mo IV Yes þ þ
þ X No ANED (52)
9 169 m 6 y 5 mo III No þ þ þ
X Yes, DIED (70)
lungs
10 186 m 2 y 5 mo IV No



X No ANED (98)
11 198 m 7 mo III No



X No DIED (48)
12 225 m 3 y 8 mo IV Yes


þ X No ANED (92)

PRETEXT, pre-treatment extent of primary tumor; V, extension to the vena cava and/or hepatic vein(s); P, extension to portal vein; E, extension
outside of the liver; M, lung metastases; NA, not appropriate; ANED, alive with no evidence of disease; y, year; mo, month; m, male; f, female.

Four children died. Two died from uncontrolled tumor
relapse 24 (no. 58) and 70 (no. 169) months post-
transplant, respectively. In patient no. 169, tumor probably
recurred in the lung almost 6 years post-LTX; histology of
the relapse was very similar to the original HB but was not
stained for AFP and the serum AFP concentration was
normal, so the precise diagnosis is uncertain. The re-
maining two patients died from treatment-related compli-
cations 6 days (no. 147, arterial thrombosis) and 4 years
(no. 198 biliary sepsis), respectively, post-LTX.
Of the seven patients who received a ‘‘primary LTX,’’
six (85.7%) survived and one died of recurrent disease. Of
the five patients who received a ‘‘rescue LTX,’’ two (40%)
survived and three died. All eight patients with PRETEXT
IV tumors and all six patients with multifocal HB were
alive and disease-free at the time of reporting. Of the seven
patients with macroscopic extension into the portal vein
and/or the hepatic veins/vena cava, two died of tumor
relapse while five (71.4%) became long term disease-free
survivors. The patient who had extrahepatic extension
died of recurrent disease. Complete clearance of lung
metastases present at diagnosis was obtained by che-
motherapy in four patients (no. 35, 61, 147, 225) who
became long-term, disease-free survivors with a follow-up
post-LTX of 115, 120, 119, 92 months, respectively. In one
patient (no. 147), the pulmonary deposits had apparently
cleared on CT-scan before transplant; he died from arterial
thrombosis 6 days post-LTX. At autopsy, four very small
metastases, 0.3 to 0.4 mm in diameter, were found in the
right lung.

Fig. 2. SIOPEL-1 study: overall survival of LTX patients from the
date of transplant.
WORLD EXPERIENCE
The current world experience of LTX for HB was
collected through an extensive review of the literature and
personal contacts made by the first author (JBO) with
teams around the world known to him as having
experience in this area.
Compilation of the data also aimed at detecting
duplicate reports and updating the previously reported
survival data. Seven patients from the SIOPEL-1 study
reported in this paper were not included in the analysis of
the world experience, whereas five cases registered in
SIOPEL-1 study were also included in publications from
individual centers. Chemotherapy given before or after
LTX varied too much between centers to be evaluated
separately with confidence.
78 Otte et al.

Statistical Analysis They were 87 males and 60 females. Their age at

diagnosis was <3 years in 92 cases, 3–<6 years in 32
Proportional hazards regression was used in a multi-
cases and 6–<19 years in 23 cases with a median age of
variate analysis to evaluate any possible association of
26 months (range: 2–223). Twenty-eight (19% of the
survival with gender, age (below vs. above 3 years), donor
total) patients presented with macroscopic venous inva-
(live related vs. post-mortem graft), presence versus
sion (data missing in 43 instances) and 12 (8%) with lung
absence of lung metastases at diagnosis, presence versus
metastases. One hundred six (72%) underwent a ‘‘primary
absence of venous invasion, pre-LTX versus pre- and post-
LTX’’ and 41 (28%) received a ‘‘rescue LTX’’, either for
LTX chemotherapy. The analyses for primary LTX and
incomplete resection with partial hepatectomy or for
for rescue LTX were carried out separately; the results
relapse after previous partial hepatectomy. Twenty-eight
were expressed in terms of the hazard ratio, a value >1
patients (19%) received a live related liver transplant and
signifying an increased risk of death with respect to the
119 (81%) received a post-mortem liver graft. Eighty-two
control group.
(55%) patients received chemotherapy before LTX.
Chemotherapy was given after LTX in 65 (44%) cases of
Patients
whom 61 (41% of the total) had also received chemother-
One hundred forty-seven cases were collected apy before LTX.
(Table II). Data were contributed by 24 centers; their
experience, gained mostly during the last decade, com-
Results
prised between 10 and 16 cases in six instances and
between 1 and 9 cases in 16 instances. The collective Median (range) follow-up since diagnosis for surviving
review of the early USA experience (12 cases) was in- patients was 38 months (1–211). Overall survival at 6-
cluded in the analysis. The patient characteristics and the year post-LTX was 82% (95% CI: 72–92%) for ‘‘primary
overall survival rates are detailed in Table III. LTX’’ and 30% (95% CI: 14–46%) for ‘‘rescue LTX’’

TABLE II. World Experience of Liver Transplantation in Hepatoblastoma

Reference No. of Primary Rescue Post-LTX Overall survival

Center (n ¼ 24) update Period patients LRLT LTX LTX chemotherapy (%)
USA—collective series [13] 1981–1988 12 — 7 5 8 50
Dallas [37]a 1984–2000 9 — 6 3 3 66
UCLA [38]b 1984–2001 16 — 8 8 14 75
Boston [39]c 1985 1 — — 1 1 100
Toronto [28–40]d 1986–1996 5 — 4 1 — 60
New Haven [41] 1986 1 — 1 — — 100
Omaha e 1986–1999 10 2 6 4 3 70
Madrid f 1986–2001 8 1 7 1 7 75
Brussels [42]g 1987–2001 10 7 7 3 — 70
Bergamo h 1988–2000 4 — 3 1 — 25
Leeds, UK [43]I 1 — 1 — — 100
Coop. German group j 1989–2001 4 — 4 — — 100
Pittsburgh [27]k 1989–1998 12 — 10 2 10 83
Kyoto l 1990–2001 8 8 4 4 6 62
Birmingham, UK [24-44]m 1991–2001 14 — 12 2 5 78
London, UK [26]n 1992–2001 13 4 12 1 — 92
Edmonton [33] 1992 1 1 1 — 1 100
San Francisco [46] 1992–1998 3 3 3 — 3 100
Padova o 1994–1999 5 1 5 — 3 80
Paris p 1996–2001 3 — 1 2 — 33
Torino q 1999 1 — 1 — — 100
Chicago r 1999–2001 2 — 1 1 — 50
Brisbane s 1999–2001 3 — 1 2 — 66
Boston t 2001 1 1 1 — 1 100
Total 147 28 106 41 65 72.8

LRLT, living related liver transplant; LTX, liver transplant.

The unpublished data and/or the update of follow-up in previously reported series were kindly provided by the following colleagues: (a) Dallas: G.
Klintmalm; (b) UCLA: S. Mc Diarmid; (c) Boston: B. Cosimi; (d) Toronto: R. Superina; (e) Omaha: A. Langnas; (f) Madrid: J. Tovar; (g) Brussels:
J.B. Otte (unpublished data); (h) Bergamo: D. Alberti; (i) Leeds UK: M. Stringer; (j) Cooperative German Group: D. von Schweinitz; (k) Pittsburgh:
J. Reyes; (l) Kyoto: F. Oike; (m) Birmingham: J. de Ville de Goyet; (n) London King’s College: M. Rela; (o) Padova: G. Perilongo; (p) Paris-Bicêtre:
C. Chardot; (q) Torino: F. Gennari; (r) Chicago: R. Superina; (s) Brisbane: R.W. Strong; (t) Boston: R.C. Jenkins.
 Liver Transplantation for Hepatoblastoma 79

TABLE III. World Experience-Survival Data; Percentage Alive or for ‘‘primary LTX’’ and ‘‘rescue LTX’’. For ‘‘primary
Dead by Patient Characteristics LTX’’, the only parameter significantly related to overall
Alive (%) Dead (%)
survival was venous invasion (P value ¼ 0.04 with a
hazard ratio of 3 in univariate analysis; P value ¼ 0.045
Gender with a hazard ratio of 2.96 in multivariate analysis). For
Male (n ¼ 87) 71 29 ‘‘rescue LTX,’’ there was no correlation of any parameter
Female (n ¼ 60) 75 25
Age at diagnosis with overall survival, but the total number was too small to
Unknown (n ¼ 2) 50 50 draw valid conclusions.
0–<3 months (n ¼ 2) 100 —
3–<12 months (n ¼ 25) 80 20
1–<3 years (n ¼ 63) 75 25 Discussion
3–<6 years (n ¼ 30) 73 27
6–<12 years (n ¼ 21) 62 38 It is only since the advent of effective, Cisplatin-
>12 years (n ¼ 4) 50 50 containing chemotherapy that LTX has been considered as
<3 years (n ¼ 92) 76 24 a valid treatment option for children with HB [3,6–
3 years (n ¼ 55) 67 33 8,11,14]. The premises underlying this belief are that (a)
Lung metastases micrometastatic disease has genuinely been eliminated in
No (n ¼ 135) 74 26
Yes (n ¼ 12) 58 42 most cases (b) tumor shrinkage, via chemotherapy, makes
Venous invasion surgery easier and less dangerous, and (c) since che-
No (n ¼ 76) 78 22 motherapy does not usually eradicate ‘‘bulky’’ disease,
Yes (n ¼ 28) 54 46 that complete surgical resection of the primary tumor
Unknown (n ¼ 43) 77 23 remains a prerequisite for cure [9].
Timing of liver transplant
Primary (n ¼ 106) 86 14 The definition of ‘‘unresectability’’ of a liver tumor
Rescue (n ¼ 41) 39 61 depends on a correct interpretation of imaging obtained
Donor with advanced technology such as MRI with angioscan.
Post-mortem (n ¼ 119) 71 29 However, the distinction between real invasion beyond the
LRLT (n ¼ 28) 82 18 anatomic border of a given sector and displacement can be
Post-transplant chemotherapy
No (n ¼ 82) 70 30 very difficult indeed (Fig. 1). It also depends on surgical
Yes (n ¼ 65) 77 24 expertise. For instance, some tumors involving both liver
lobes can still be radically resected by trisegmentectomy
LTR, living related liver transplant. when one sector (left lateral or postero-lateral segment in
North American terminology) is disease-free whereas
(Fig. 3). Crude survival data with respect to gender, age, encasement of the retrohepatic vena cava does not
lung metastases, and venous invasion at presentation, preclude a radical removal since it can be resected ‘‘en-
timing of LTX, type of graft and post-LTX chemotherapy bloc’’ and replaced by either a prosthetic graft or a venous
are provided in Table III. allograft [15].
Univariate and multivariate proportional hazards re- When intrahepatic extent is limited (stage I in the
gression analyses of overall survival were done separately Pediatric Oncology Group Study [14], PRETEXT I and II
in the SIOPEL-1 study [16]), complete resection can be
achieved with a partial hepatectomy. When the tumor
involves the liver more extensively (stage II and III in the
POG study, PRETEXT III in SIOPEL-1 studies), pre-
operative chemotherapy can make resectable most of the
initially ‘‘unresectable’’ tumors [7–9,16,17]. However, in
a subgroup of PRETEXT III patients, close proximity of
the tumor to the main hepatic veins or the main intra-
hepatic portal branches (‘‘centrally located HB’’) can
make it genuinely unresectable, unless total hepatectomy
and LTX are performed. By contrast, PRETEXT IV
solitary or multifocal tumors invading all four sectors of
the liver are not usually regarded as being amenable to
complete resection by partial hepatectomy though, sur-
prisingly, the SIOPEL-1 study included nine such patients
whose tumor did become resectable after PLADO
Fig. 3. World experience of LTX in hepatoblastoma: overall patient chemotherapy [9]. Thus, caution is required in determin-
survival after ‘‘primary’’ or ‘‘rescue’’ liver transplant. ing the PRETEXT group from imaging studies at
80 Otte et al.
diagnosis. Since only the radiological reports and not the
imaging itself was reviewed centrally in SIOPEL-1 study,
there is serious doubt as to whether or not those 9 cases
really were PRETEXT IV at presentation. The displace-
ment of the anatomic borders separating the sectors of
the liver, due to compression by the tumor, can lead to the
mistaken classification of a PRETEXT III tumor as
PRETEXT IV. In some multifocal PRETEXT IV HB
invading all four sectors, downstaging to PRETEXT III
can apparently be achieved in some cases when one sector
clears completely after intensive chemotherapy, allowing
partial hepatectomy. Observations that such a sector still
contained microscopic tumor foci when ‘‘primary LTX’’
was performed (G. Perilongo, personal communication)
suggest that LTX is likely to be the optimal surgical choice
for this subcategory of PRETEXT IV, whatever the result
of chemotherapy may be.
In the SIOPEL-1 study, the overall survival rate of the
seven patients who received a ‘‘primary LTX’’ was 85%;
similarly, it was 82% for the 106 patients included in the
review of the world experience. The excellent outcome of
these high risk patients with a tumor that remains
unresectable after appropriate chemotherapy compares
favorably with the results obtained after partial hepatect-
omy in patients with a resectable tumor [4,5,10,16,18–
23]. These data therefore indicate that LTX may now
be regarded as a validated therapy for patients with
‘‘unresectable’’ tumors.
So far as the world experience goes, one can speculate
that either patients have been selected very carefully for
LTX or there might have been a bias towards publication
of series with favorable results. We think that the second of
these speculations is unlikely since 12 of the 24 series
(contributing 71/147 cases) included in this overview have
been courteously communicated, unpublished, to the first
author (JBO). (There could, of course, have been a bias in
the other 12 series that have been reported).
Incomplete tumor resection and intrahepatic recurrence
after partial hepatectomy are other potential indications
for LTX. Forty-one such cases were found in the review of
the world experience, with an overall survival rate of 30%.
These figures should alert physicians to the poor efficacy
of LTX in these situations. One can reasonably presume
that these patients would have died without LTX since
survival is most unlikely under these circumstances. On
the other hand, the far better survival rate obtained in
patients who received a ‘‘primary LTX’’ after good
response to chemotherapy also supports the strategy, first
recommended by the Birmingham, UK group [24], of
avoiding any attempt at partial hepatectomy when radical
resection seems difficult and unlikely. This is the case for
PRETEXT III tumors in close proximity to the main
vessels, because peeling the tumor off the vessels is likely
to leave malignant residue at the resection line. Never-
theless, an apparently contradictory preliminary observa-
tion made in both SIOPEL 1 and 2 studies—that
microscopic residual disease at the resection line after
partial liver resection does not impact on survival [9,25]—
is intriguing and requires further analysis. One possible
explanation of this finding is that microscopic residual
tumor is not necessarily viable [9].
Multifocality of the tumor at presentation may be a
poor prognostic factor for conventionally treated HB, as
suggested by univariate analysis of the results of the
SIOPEL-1 study [6]. However, in the LTX series reported
by the King’s College, London group [26], 10 of 13
patients became long-term survivors despite having
multifocal disease at diagnosis. Similarly, all six LTX
patients with multifocal disease in the SIOPEL-1 study
survived long-term with no evidence of disease.
In the world experience (Table III), the overall survival
was 78% in patients without, and 54% in patients with
venous invasion. The separate analysis for ‘‘primary
LTX’’ showed that venous invasion was associated with a
shorter overall survival. However, in the SIOPEL-1 study,
five of seven (71%) patients with macroscopic venous
invasion became long-term, disease-free survivors.
Similarly, in the Pittsburgh experience [27], seven of
nine patients who were TNM stage IVA or IV B, of whom
eight had major intrahepatic venous invasion, remained
alive and disease-free at 21 to 146 months after LTX.
These data suggest that macroscopic venous invasion
might be considered as a relative contraindication for LTX
in HB. The final answer to this issue will require more
experience and longer follow-up, however.
Should patients with lung metastases at presentation be
excluded from LTX? Such is the policy in some centers
[27], but not in others if the lung deposits appear to clear
after chemotherapy [26,28,45]. Of the 12 patients who
received a liver transplant in the SIOPEL-1 study, 5 had
lung metastases at presentation (Table I). Their lungs
cleared after chemotherapy and four of the five (80%) were
alive and disease-free with a follow-up of 92–120 months
since LTX, suggesting that these patients are likely cured.
In the world experience, 7 (58%) of the 12 patients with
lung metastases at presentation were surviving at the
time of publication. On the basis of these data, it appears
that LTX is a viable option for children presenting with
lung metastases if they are undetectable after chemo-
therapy; thoracotomy may be indicated for surgical ex-
cision of residual disease if any doubt persists [9,29–31].
The absolute necessity of chemotherapy before LTX is
obvious since these candidate patients present with
unresectable tumors. Not only does chemotherapy cause
tumor shrinkage and substantially reduce tumor cell viabi-
lity while patients await LTX, but it is also essential to
clear visible or invisible extrahepatic deposits. Response
to chemotherapy was not included as a prognostic factor
in the analysis of the SIOPEL-1 study [6] but in the
Birmingham, UK series [24] the quality of response to

chemotherapy, rather than tumor size at presentation
(PRETEXT group), was the most important prognostic
factor, provided that a radical resection was performed.
The value of post-LTX chemotherapy is unclear, at least
in patients who have had a good response to chemotherapy
before LTX. Indeed, many resected tumors show extensive
necrosis pathologically, and metastatic relapse was un-
usual in the entire SIOPEL-1 study (only 5 patients of 115
who had delayed surgery relapsed in the lungs [7]), sug-
gesting that micrometastases were usually eradicated by
chemotherapy. In the review of the world experience, 65
patients received post-LTX chemotherapy (61 of the 65
had also received pre-LTX chemotherapy) while 82 did
not; the corresponding overall survival rates (77% and
70%, respectively) were not statistically different. Given
that post-LTX chemotherapy may add morbidity when
given together with immunosuppressants, the place of
post-LTX chemotherapy in the treatment plan is still
uncertain. This issue is one that might be settled by an
appropriately designed randomised international study.
Timing of LTX must be appropriate to avoid a long
delay between the completion of chemotherapy and LTX.
Every effort should be made to keep the waiting period as
short as possible but this policy supposes an expeditious
access to donor organs. If this cannot be achieved with
post-mortem donation, including liver graft splitting [32],
a live related donor provides a valuable alternative because
it allows optimal timing of the LTX, especially as some
centers and organ exchange organizations are still reluc-
tant to give priority on their waiting lists to recipients with
cancer [34,35]. Twenty-eight live related LTXs for HB
were found in the world experience review (Tables II
and III ) with an overall survival of 82% versus 71% of the
119 patients who received a post-mortem graft (NS).
To maximize the chance of complete tumor excision,
total hepatectomy for primary malignancies in children
should include removal of the retrohepatic inferior vena
cava [27]. This approach does not preclude a cadaveric
transplant provided with retrohepatic vena cava. In a live
related liver transplant not provided with vena cava,
reconstruction can be achieved either with a preserved
allogeneic iliac vein procured from a cadaveric donor or,
preferably, with the internal jugular vein procured from
the live liver donor [15,35].
The potential benefits of LTX must be balanced against
the inherent risks, related both to surgical complications
and life-long immunosuppression. Of the 12 patients of
SIOPEL-1, 2 died from technical complications and one
needed a second LTX for biliary cirrhosis related to
persistent cholangitis; the latter also developed nephro-
toxicity most likely induced by the additive effect of
cyclosporin and cisplatin. These complications might
reflect, at least partially, a lack of experience. In experi-
enced centers, life expectancy now exceeds 90% after
elective LTX and the incidence of technical compli-
Liver Transplantation for Hepatoblastoma 81
cations, e.g., arterial thrombosis, has been drastically
reduced [36]. Increasing experience with less toxic
immunosuppressive regimens (including tolerance induc-
tion protocols, as currently developed in Pittsburgh—USA
[T.E. Starzl, personal communication]) has the potential to
alleviate short- and long-term morbidity.
The results of the SIOPEL-1 study and our review of the
world experience clearly demonstrate that LTX has
become an integral part of the overall modern manage-
ment of HB with 8% of all patients in SIOPEL-1 receiving
a LTX. On the basis of these results, we propose the
following guidelines for early consultation with a
transplant surgeon when LTX is under consideration: (1)
patients with large solitary PRETEXT IV HB, involving
all four sectors of the liver at presentation as confirmed by
state-of-the art imaging, should be repeatedly assessed by
the pediatric oncologist and the transplant surgeon during
and after Cisplatin-based chemotherapy. Unless ‘‘down-
staging’’ is clearly demonstrated (as might be the case
when the anatomic border of the normal liver is com-
pressed without true malignant invasion), ‘‘primary LTX’’
seems to be the only appropriate option. (2) Multifocal
PRETEXT IV HB seems to be an acceptable indication for
LTX, so that complete resection is guaranteed. Since the
results of ‘‘primary LTX’’ are apparently superior, in terms
of patient survival, to those of ‘‘rescue LTX’’, heroic at-
tempts at partial hepatectomy surgery should be avoided.
Viable extrahepatic deposits persisting after full
chemotherapy and not amenable to surgical excision
represent an absolute contraindication. In order to prevent
new tumor growth after discontinuation of chemotherapy,
timing of LTX should not be long delayed after the last
course of chemotherapy. Entry on the cadaveric waiting
list is a good option if the access to a donor graft can be
expected soon; otherwise an intrafamilial live related liver
transplant should be considered. When tumor resection by
partial hepatectomy has been macroscopically incomplete
or when intrahepatic recurrence is observed after a
previous partial resection, the indication for ‘‘rescue
LTX’’ is controversial, because of the disappointing
results observed both in the SIOPEL-1 study and in the
world experience.
In conclusion, LTX has added a new dimension to the
treatment of HB. LTX should be considered for every child
presenting with unresectable disease due to involvement
of all four sectors of the liver or involvement of three
sectors when a complete tumor excision, by partial hepa-
tectomy, is unlikely. The only absolute contraindication to
LTX is the persistance of one or more ‘‘viable’’ extrahe-
patic deposits after chemotherapy that are not amenable to
surgical excision. Extension into the major liver vessels
might not contraindicate LTX so long as all tumors can be
excised at the time of hepatectomy. LTX is a valid option in
patients presenting with lung metastases if complete
clearance can be achieved by chemotherapy with or
82 Otte et al.
without surgical excision. Chemotherapy must be given
before LTX using drugs, including Cisplatin, with well-
established efficacy. There might be a place for completing
chemotherapy after LTX. Timing of LTX must be
optimized to prevent regrowth of the disease while the
child is awaiting transplantation. Live related LTX is a
valid option that guarantees optimal timing of surgery.
Because of the rarity of the disease, children with
extensive HB should be treated in centers with surgical
expertise in major pediatric liver resection and LTX, in
close collaboration with pediatric radiologists, oncolo-
gists, and histopathologists. International prospective
studies with an evidence-based protocol should be under-
taken to address unresolved issues.
ACKNOWLEDGMENT
The authors are very grateful to all colleagues listed
under Table II for their substantial contribution to the
review of the world experience. They also express their
warm thanks to Mrs C. Vuylsteke for her superb secretarial
assistance.
REFERENCES
1. Evans AE, Land VJ, Newton WA, et al. Combination chemother-
apy (vincristine, adriamycin, cyclophosphamide, and 5-fluorour-
acil) in the treatment of children with malignant hepatoma. Cancer
1982;50:821–826.
2. Shafford E, Pritchard J. Hepatoblastoma—a bit of a success story?
Eur J Cancer 1994;30A:1050–1051.
3. Ortega JA, Douglass EC, Feusner JH, et al. Randomized
comparison of Cisplatin/Vincristine/Fluorouracil and Cisplatin/
continuous infusion Doxorubicin for treatment of pediatric
hepatoblastoma: A report from the Children’s Cancer Group and
the Pediatric Oncology Group. J Clin Oncol 2000;18:2665–2675.
4. Von Schweinitz D, Hecker H, Burger D, et al. Surgical therapy of
childhood hepatoblastoma. Langenbeckx Archiv für Chirurgie
1995;380:315–320.
5. Von Schweinitz D, Byrd DJ, Hecker H, et al. Efficiency and toxicity
of ifosfamide, cisplatin and doxorubicin in the treatment of
childhood hepatoblastoma. Study Committee of the Cooperative
Paediatric Liver Tumour Study HB89 of the German Society for
Paediatric Oncology and Haematology. Eur J Cancer 1997;33:
1243–1249.
6. Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic
factors for children with hepatoblastoma—results from the Inter-
national Society of Paediatric Oncology (SIOP) study SIOPEL 1.
Eur J Cancer 2000;36:1418–1425.
7. Pritchard J, Brown J, Shafford E, et al. Cisplatin, doxorubicin,
and delayed surgery for childhood hepatoblastoma: A successful
approach—results of the first prospective study of the International
Society of Pediatric Oncology. J Clin Oncol 2000;18:3819–
3828.
8. Perilongo G, Shafford E, Plaschkes J. SIOPEL trials using pre-
operative chemotherapy in hepatoblastoma—A successful ap-
proach. Lancet Oncol 2000;1:94–100.
9. Schnater JM, Aronson D, Plaschkes J, et al. Surgical view of the
treatment of patients with hepatoblastoma. Results from the first
prospective trial of the International Society of Pediatric Oncology
Liver Tumor Study Group (SIOPEL-1). Cancer 2002;94:1111–
1120.
10. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of
unresectable or metastatic hepatoblastoma with cisplatin and
continuous infusion doxorubicin chemotherapy: A report from
the Children’s Cancer Study Group. J Clin Oncol 1991;9:2167–
2176.
11. Von Schweinitz D, Hecker H, Harms D, et al. Complete resection
before development of drug resistance is essential for survival from
advanced hepatoblastoma—A report from the German Coopera-
tive Pediatric Liver Tumor Study HB-89. J Pediatr Surg 1995;30:
845–852.
12. Plaschkes J, Perilongo G, Pritchard J. Pre-operative chemother-
apy—Cisplatin (PLA) and doxorubicin (DO) PLADO for the
treatment of hepatoblastoma and hepatocellular carcinomas—
Results after 2 years’ follow-up. Med Pediatr Oncol 1996;27:
209.
13. Koneru B, Flye MW, Busuttil RW, et al. Liver transplantation for
hepatoblastoma. The American experience. Ann Surg 1991;213:
118–121.
14. Douglass EC, Reynolds M, Finegold M, et al. Cisplatin,
Vincristine, and Fluorouracil therapy for hepatoblastoma: A
Pediatric Oncology Group Study. J Clin Oncol 1993;11:96–99.
15. Chardot C, Saint-Martin C, Gilles A, et al. Living related liver
transplantation and vena cava reconstruction after total hepatect-
omy including vena cava for hepatoblastoma. Transplantation
2001;72:1–3.
16. Stringer MD, Hennayake S, Howard ER, et al. Improved outcome
for children with hepatoblastoma. Br J Surg 1995;82:386–391.
17. Reynolds M, Douglass EC, Finegold M, et al. Chemotherapy can
convert unresectable hepatoblastoma. J Pediatr Surg 1992;27:
1080–1083.
18. Filler RM, Ehrlich P, Greenberg ML, et al. Preoperative
chemotherapy in hepatoblastoma. Surgery 1991;110:591–596.
19. Gururangan S, O’Meara A, MacMahon C, et al. Primary hepatic
tumours in children: A 26-year review. J Surg Oncol 1992;50:
30–36.
20. Ehrlich P, Greenberg ML, Filler RM. Improved long-term survival
with preoperative chemotherapy for hepatoblastoma. J Pediatr Surg
1997;32:999–1003.
21. Carceller A, Blanchard H, Champagne J, et al. Surgical resection
and chemotherapy improve survival rate for patients with
hepatoblastoma. J Pediatr Surg 2001;36:755–759.
22. Okada A, Fukuzawa M, Oue T, et al. Thirty-eight years experience
of malignant hepatic tumors in infants and childhood. Eur J Pediatr
Surg 1998;8:17–22.
23. Seo T, Ando H, Watanabe Y, et al. Treatment of hepatoblastoma:
Less extensive hepatectomy after effective preoperative chemo-
therapy with cisplatin and adriamycin. Surgery 1998;123:407–
414.
24. Pimpalwar AP, Sharif K, Ramani P, et al. Strategy for hepato-
blastoma management: Transplant vs. non-transplant surgery.
J Pediatr Surg 2002;37:240–245.
25. Brugières L, Phillips A, Rondelli R, et al. Hepatoblastoma with
microscopic residual disease after surgery: Data from SIOPEL 1
and 2 studies. Med Pediatr Oncol 2000;35:177.
26. Srinivasan P, McCall J, Pritchard J, et al. Orthotopic liver
transplantation for unresectable hepatoblastoma. Transplantation
2002;74:652–655.
27. Reyes JD, Carr B, Dvorchik I, et al. Liver transplantation and
chemotherapy for hepatoblastoma and hepatocellular cancer in
childhood and adolescence. J Pediatr 2000;136:795–804.
28. Bilik R, Superina R. Transplantation for unresectable liver tumors
in children. Transpl Proc 1997;29:2834–2835.
29. Passmore SJ, Noblett HR, Wisheart JD, Mott MG. Prolonged
survival following multiple thoracotomies for metastatic hepato-
blastoma. Med Pediatr Oncol 1995;24:58–60.

30. Feusner JH, Krailo MD, Haas JE, et al. Treatment of pulmonary
metastases of initial stage-1 hepatoblastoma in childhood. Report
from the Childrens Cancer Group. Cancer 1993;71:859–864.
31. Perilongo G, Brown J, Shafford E, et al. Hepatoblastoma presenting
with lung metastases: Treatment results of the first cooperative,
prospective study of the International Society of Paediatric
Oncology on childhood liver tumors. Cancer 2000;89:1845–
1853.
32. Otte JB. Is it right to develop living related liver transplantation? Do
reduced and split livers not suffice to cover the needs? Transpl Int
1995;8:69–73.
33. Dower NA, Smith LJ. Liver transplantation for malignant liver
tumors in children. Med Pediatr Oncol 2000;34:136–140.
34. Colombani PM, Lau H, Prabhakaran K, et al. Cumulative
experience with pediatric living related liver transplantation.
J Pediatr Surg 2000;35:9–12.
35. Martinez JA, Rigamonti W, Rahier J, et al. Preserved vascular
homograft for revascularization of pediatric liver transplant: A
clinical, histological, and bacteriological study. Transplantation
1999;68:672–677.
36. Evrard V, Otte JB, Sokal E, et al. Impact of surgical and immu-
nological parameters in pediatric liver transplantation. Annals of
Surgery, in press.
37. Molmenti EP, Wilkinson K, Molmenti H, et al. Treatment of
unresectable hepatoblastoma with liver transplantation in the
pediatric population. Am J Transplant 2002;6:535–538.
Liver Transplantation for Hepatoblastoma 83
38. Olthoff KM, Millis M, Rosove MH, et al. Is liver transplantation
justified for the treatment of hepatic malignancies? Arch Surg
1990;125:1261–1266.
39. Jenkins RL, Pinson CW, Stone MD. Experience with transplanta-
tion in the treatment of liver cancer. Cancer Chemother Pharmacol
1989;23:104–109.
40. Superina R, Billik R. Results of liver transplantation in children
with unresectable liver tumors. J Pediatr Surg 1996;31:835–839.
41. Barton JW, Keller MS. Liver transplantation for hepatoblastoma in
a child with congenital absence of the portal vein. Pediatr Radiol
1989;20:113–114.
42. Otte JB, Aronson D, Vraux H, et al. Preoperative chemotherapy,
major liver resection, and transplantation for primary malignancies
in children. Transplant Proc 1996;28:2393–2394.
43. Lockwood L, Heney D, Giles GR, et al. Cisplatin-resistant meta-
static hepatoblastoma: Complete responseto carboplatin,etoposide,
and liver transplantation. Med Pediatr Oncol 1993;21:517–520.
44. Al Qabandi W, Jenkins HC, Buckels JA, et al. Orthotopic liver
transplantation for unresectable hepatoblastoma: A single center’s
experience. J Pediatr Surg 1999;34:1261–1264.
45. Dower NA, Smith LJ, Lees G, et al. Experience with aggressive
therapy in three children with unresectable malignant liver tumors.
Med Pediatr Oncol 2000;34:132–135.
46. Renz JF, Rosenthal P, Roberts JP, et al. An approach to pediatric
liver transplantation for hepatoblastoma. Hepatology 1998;28:
737A.