Murawski 2016

Published Ahead of Print on January 25, 2016 as 10.1200/JCO.2014.60.
2250
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.60.2250
JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T
Hepatocellular Carcinoma in Children: Does Modified

Platinum- and Doxorubicin-Based Chemotherapy Increase
Tumor Resectability and Change Outcome? Lessons Learned
From the SIOPEL 2 and 3 Studies
Maciej Murawski, Vı́ola B. Weeda, Rudolf Maibach, Bruce Morland, Derek J. Roebuck, Arthur Zimmerman,
Michela Casanova, Giorgio Perilongo, Veronique Laithier, Rejin Kebudi, Marcelo J. Scopinaro, Albert Shun,
Benedicte Brichard, Beatriz de Camargo, Margaret Childs, Daniel C. Aronson, and Piotr Czauderna
Listen to the podcast by Dr Katzenstein at www.jco.org/podcasts
Maciej Murawski and Piotr Czauderna,

Medical University of Gdansk, Gdansk, A B S T R A C T
Poland; Viola B. Weeda and Daniel C.
Aronson, Emma Children’s Hospital Introduction
Academic Medical Center, Amsterdam, The aim of this article is to present an experience of two prospective studies from the International
the Netherlands; Rudolf Maibach, Childhood Liver Tumor Strategy Group (SIOPEL 2 [S2] and SIOPEL [S3]) trials and to evaluate
International Breast Cancer Study Group
whether modified platinum- and doxorubicin-based chemotherapy is capable of increasing tumor
Coordinating Center; Arthur Zimmerman,
Institute of Pathology, Berne, Switzerland;
resectability and changing patient outcomes.
Bruce Morland, Birmingham Children’s Methods
Hospital, Birmingham; Derek J. Roebuck,
Between 1995 and 2006, 20 patients with hepatocellular carcinoma (HCC) were included in the S2
Great Ormond Street Hospital, London;
Margaret Childs, University of
trial and 70 were included in the S3 trial. Eighty-five patients remained evaluable.
Nottingham, Nottingham, United Results
Kingdom; Michela Casanova, National
Response to preoperative chemotherapy was observed in 29 of 72 patients (40%) who did not have
Cancer Institute, Milan; Giorgio Perilongo,
University of Padova, Padova, Italy;
primary surgery, whereas 13 patients underwent upfront surgery. Thirty-three patients had a
Veronique Laithier, Centre Hospitalier delayed resection. Thirty-nine tumors never became resectable. Complete tumor resection was
Régional et Universitaire de Besançon, achieved in 34 patients (40%), including seven of those treated with liver transplantation (LTX). After
Besançon, France; Rejin Kebudi, İstanbul a median follow-up period of 75 months, 63 patients (74%) had an event (a progression during
University, Oncology Institute, İstanbul,
Turkey; Marcelo J. Scopinaro, Hospital de
treatment, a relapse after treatment, or death from any cause). Sixty patients died. Twenty-three of
Pediatrıá SAMIC J.P. Garrahan, Buenos 46 patients (50%) who underwent tumor resection died. Eighteen of 27 patients (63%) with complete
Aires, Argentina; Albert Shun, Children’s tumor resection (without LTX) and 20 of 34 patients (59%) with LTX survived. Only one of seven
Hospital at Westmead, Sydney, Australia; patients (14%) with microscopically involved margins survived. Overall survival at 5 years was 22%.
Benedicte Brichard, Cliniques
Universitaires Saint Luc, University of Conclusion
Louvain, Brussels, Belgium; and Beatriz Survival in pediatric HCC is more likely when complete tumor resection can be achieved. Inten-
de Camargo, Cancer Hospital A.C. sification of platinum agents in the S2 and S3 trials has not resulted in improved survival. New
Camargo, São Paulo, Brazil.
treatment approaches in pediatric HCC should be postulated.
Published online ahead of print at
www.jco.org on January 25, 2016. J Clin Oncol 34. © 2016 by American Society of Clinical Oncology
Authors’ disclosures of potential conflicts
of interest are found in the article online at
www.jco.org. Author contributions are common pediatric liver malignancy.4 Tradi-
INTRODUCTION
found at the end of this article. tionally, treatment of pediatric HCC has been
Corresponding author: Piotr Czauderna, determined by data derived from its inclusion in
MD, PhD, Department of Surgery and Hepatocellular carcinoma (HCC) continues to trials designed for the treatment of hepato-
Urology for Children and Adolescents,
pose a significant therapeutic challenge. Despite blastoma (HB). The argument for this strategy
Medical University of Gdansk, Ul. Nowe
Ogrody 1-6, 80-803 Gdansk, Poland;
overall progress in pediatric and adult oncology, has been that pediatric HCC seems to behave
e-mail: pczaud@gumed.edu.pl. the cure rates in HCC remain dismal. Hence, differently from its counterpart in adults and
© 2016 by American Society of Clinical HCC, the fifth most common cancer worldwide, usually emerges in noncirrhotic livers; however,
Oncology constitutes the third most common cause of death the question of whether HCC in children and
0732-183X/16/3499-1/$20.00 from cancer.1 Recent statistics show that the adults is the same entity remains unanswered.5
DOI: 10.1200/JCO.2014.60.2250 incidence of HCC is increasing in the Western The policy of HCC treatment with neoadjuvant
world.2,3 Although HCC is much less common chemotherapy has not resulted in improved
in children than in adults, it is the second most survival, which remains in the range of 20% to
© 2016 by American Society of Clinical Oncology 1

Information downloaded from jco.ascopubs.org and provided by at University of Ca San Diego on January 27, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
132.239.1.230
Copyright 2016 by American Society of Clinical Oncology
Murawski et al
30% in most multicenter trials.5-8 Although all studies have confirmed even without clinical (physical and/or radiologic) evidence of tumor
the importance of complete tumor resection, less than 20% of patients regrowth.
are amenable to surgery at diagnosis. The role of liver transplantation There was no consistent central imaging review throughout the trial;
only rapid radiology review service was offered in questionable cases. No
(LTX) in noncirrhotic HCC remains controversial.6,9,10
strict guidelines were provided for the hepatic resection, but the following
The aim of this article is to present the experience of two recommendations were made: patients should be treated in centers with
recent prospective studies from the International Childhood Liver extensive experience in liver surgery, and radical surgical removal of the
Tumor Strategy Group (SIOPEL 2 [S2] and SIOPEL 3 [S3]) and to tumor was recommended. LTX should be considered in children with
evaluate whether modified platinum- and doxorubicin (DOXO)- tumors completely confined to the liver that remained unresectable. Lung
based chemotherapy is capable of increasing tumor resectability metastasis was a definite LTX contraindication.
and changing patient outcomes. The main objective of both trials was to evaluate whether an intensive
preoperative chemotherapy regimen including CARBO, CDDP, and
DOXO improves the response rate to chemotherapy and the resection rate
METHODS of children affected by HCC, using as a comparison the historical control of
the standard CDDP plus DOXO approach in S1. Cumulative dosages of
chemotherapy agents in S1, S2, and S3 are listed in Table 1. Both protocols
The S2 and S3 treatment protocols were designed primarily for HB. were reviewed and approved by the ethics committees of the participating
However, as with the SIOPEL 1 trial, HCC cases were registered, and institutions.
treatment guidelines for HCC, using the high-risk chemotherapy regimen, Overall survival (OS) was calculated by the Kaplan-Meier method.
were suggested in these protocols. S2 was opened in October 1995 and The S2 and S3 protocols contained no statistical criteria for the number of
closed to recruitment in May 1998. It included two pilot phase II trials: one patients to be included. Accordingly, the evaluation was purely descriptive
for standard-risk HB patients (cisplatin alone) and one for high-risk HB and not comparative. The S2 database was locked on November 25, 2009.
and for patients with HCC (SuperPLADO: carboplatin [CARBO] plus The S3 database was locked on December 1, 2009.
cisplatin [CDDP] plus DOXO). S3, which opened in June 1998, included a
single-arm trial for patients with HCC. The HCC part of the trial was
closed to recruitment on December 31, 2006. Chemotherapy for S2 and S3
patients was mostly identical (in both schedule and doses). Protocol details RESULTS
were presented in previous publications and are briefly summarized below.11-13
Measurement of serum alpha-fetoprotein (AFP) at diagnosis was Twenty patients with HCC were included in the S2 trial, and 70
mandatory. Diagnostic surgical biopsy was strongly recommended. Pri- patients with HCC were included in the S3 trial. Of these, five had
mary HCC resection was encouraged, whenever feasible. The pretreatment inadequately documented treatment and follow-up, and were
assessment of the extent of the primary tumor was performed by abdominal
excluded. Eighty-five patients (with either fibrolamellar HCC or
ultrasound, computed tomography, or magnetic resonance imaging. A chest
x-ray and lung computed tomography scan were used to determine the conventional HCC) remained evaluable, and their results are
presence of lung metastases. The pretreatment extent of disease system was presented in this article. The flowchart of patients with HCC is
used to describe tumor extent at diagnosis and during therapy. A detailed shown in the Appendix (online only; Fig A1). Patient and tumor
description of the pretreatment extent of disease system has been given in characteristics are listed in Table 2.
other reports.7,14,15 After primary surgery, SuperPLADO chemotherapy was
administered postoperatively up to and including day 85 (four courses of
CDDP, three of CARBO plus DOXO). If the tumor was not resectable or in Response to Preoperative Chemotherapy
case of metastases, or both, children were treated with the high-risk pre- The 72 patients who did not have primary surgery were the
operative and postoperative chemotherapy regimen, including CARBO, basis of the response evaluation. Seven of these 72 patients died
DOXO, and CDDP preoperatively and two courses of CARBO plus DOXO early. Data on response was missing for another seven patients.
and one of CDDP postoperatively. Each course of chemotherapy comprised
first, CDDP 80 mg/m2 in a continuous 24-hour intravenous (IV) infusion
(days 15, 43, and 71 in S2; days 1, 29, 57, and 85 in S3); second, CARBO
500 mg/m2 in a 1-hour IV infusion (days 1, 29, 57, and 85 in S2; days 15, 43,
Table 1. Cumulative Dosages of Chemotherapy Agents
and 71 in S3); and third, DOXO 60 mg/m2 in a continuous 48-hour IV
infusion (days 1, 29, 57, and 85 in S2; days 15, 43, and 71 in S3). If the tumor Maximum
Dose/Course No. of Dosage
was still unresectable after preoperative chemotherapy but showed response Study Agent (mg/m2) Courses (mg/m2)
to chemotherapy, the patient continued with two doses of CARBO plus
DOXO and one of CDDP in the S2 trial, and with two more courses of SIOPEL 1 Cisplatin 80 Maximum 6 480
CARBO plus DOXO in the S3 trial. Doxorubicin 60 Maximum 6 360
SIOPEL 2 Cisplatin 80 3 240
In the S3 trial, if the tumor was then still unresectable, the patient was
Carboplatin 500 4 2,000
considered eligible for LTX. If, after the first three courses of SuperPLADO Doxorubicin 60 4 240
(plus the initial single dose of CDDP), the tumor was unresectable and no Added if response, Cisplatin 80 1 320
longer responded to SuperPLADO, the patient would be eligible for the yet unresectable
phase II chemotherapy trial. Response evaluation was carried out after Carboplatin 500 2 3,000
every second course (based on ultrasound, chest x-ray, and AFP). Com- Doxorubicin 60 2 360
plete response was defined as complete disappearance of tumor and serum SIOPEL 3 Cisplatin 80 4 320
AFP in the normal range. Very good partial response was defined as at least Carboplatin 500 3 1,500
50% tumor volume shrinkage, with a decreasing AFP value. Partial response Doxorubicin 60 3 180
Added if response, Carboplatin 500 2 3,000
was defined as less than 50% tumor volume shrinkage, with a decreasing yet unresectable
AFP value. Stable disease was defined as no change in tumor volume or Doxorubicin 60 2 300
serum AFP value. Progressive disease was an increase in one or more
dimensions or the appearance of a new lesion and/or any increase in the Abbreviations: SIOPEL, International Childhood Liver Tumor Strategy Group.
serum AFP concentration (three successive 1-2 weekly determinations),
2 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

132.239.1.230
HCC in Children: Lessons Learned From the SIOPEL 2 and 3 Studies
Table 2. Demographic and Clinical Data of Patients With HCC in SIOPEL 2 and Table 3. Response to Preoperative Chemotherapy
3 Study
SIOPEL 2 SIOPEL 3 Total
Characteristic No. (%) or Mean (Range) Response No. No. No. (%)
Sex Complete response 0 1 1 (1)
Female 37 (44), Partial response 5 23 28 (39)
Male 48 (56) Stable disease 5 10 15 (21)
Median age, years 12.8 (29 months to 17.3 years) Progressive disease 3 11 14 (19)
Median serum AFP level, ng/mL 816 (1-1,831,950) Early death 2 5 7 (10)
, 100 38 (45) No data available 1 6 7 (10)
100-1,000 8 (9)
1,000-10,000 4 (5) NOTE. n = 72.
Abbreviations: SIOPEL, International Childhood Liver Tumor Strategy Group.
10,000-100,000 8 (9)
100,000-1,000,000 23 (27)
. 1,000,000 4 (5)
PRETEXT
I 5 (6)
II 28 (33) microscopic residuals was 34 of 85 patients (40%). The complete
III 20 (24) resection rate (including LTX), with and without microscopic
IV 30 (35) residuals, was 41 of 85 patients (48%; 95% CI, 37% to 59%).
No data 2 (2)
Extrahepatic tumor extension
The following surgical procedures were performed: nine right
V+ hepatectomies, nine extended right hepatectomies, seven left
Yes 12 (14) hepatectomies, four extended left hepatectomies, eight other
No 68 (80) resections, and seven orthotopic LTX. There are no data regarding
No data 5 (6)
P+
the type of resection in one patient. Of the seven patients who
Yes 21 (25) underwent LTX, five died. One patient was alive with no evidence
No 59 (69) of disease at 44 months; the other had a metastatic relapse after
No data 5 (6)
28 months, was treated with five courses of DOXO and thalido-
E+
Yes 19 (22) mide, and was reported as alive without relapse at 71 months.
No 63 (74) Of the 41 patients with macroscopically complete liver tumor
No data 3 (4) resection (including LTX and microscopic residual disease), 11 had
Lung metastases 30 (35)
lung metastases: seven of 27 patients with complete resection, two
Abbreviations: AFP, alpha-fetoprotein; E+, extrahepatic abdominal disease; of seven patients with microscopic residual disease, and two of
HCC, hepatocellular carcinoma; P+, portal vein involvement; PRETEXT, pre-
treatment extent of disease system; SIOPEL, International Childhood Liver
seven patients with liver transplantation. Table 4 lists the resection
Tumor Strategy Group; V+, involvement of the inferior vena cava and/or hepatic results for the liver tumor, regardless of the potential resections of
veins. lung metastases. The response to preoperative chemotherapy,
tumor resectability, and survival after surgery is listed in Table 5.
Postoperative Chemotherapy
A median of six chemotherapy cycles were administered
Twenty-five patients received a median of three postoperative
preoperatively to 63 patients (range, one to 14 cycles). Eighteen
chemotherapy cycles (range, one to 10). Seventeen patients received
patients received exactly seven preoperative cycles, per the pro-
both preoperative and postoperative chemotherapy. The total
tocol. Because the protocol recommended careful monitoring of
median number of preoperative and postoperative chemotherapy
the tumor response, and in the case of stable or progressive disease,
cycles was seven (range, one to 16).
consideration of alternative therapy early, 32 patients received less
than the prescribed number of chemotherapy cycles. Data on the
number of preoperative chemotherapy courses given and response
to chemotherapy are summarized in Table 3. Overall, 29 of 72 Table 4. Tumor Resectability
patients (40%) who started preoperative chemotherapy responded. Surgery No. (%)
The response was assessed at the end of chemotherapy.
Primary surgery 13
Complete resection 12 (92)
Surgery Incomplete resection 1 (8)
Delayed surgery 33
Laparotomy was performed in 46 patients. In 13 patients, Complete resection 15 (46)
tumors were primarily resected. The other 33 patients had received Incomplete resection 10 (30)
a median of seven (range, one to 14) cycles of preoperative che- Microscopic residual disease 7 (21)
Liver transplantation 7
motherapy before they underwent surgery. Another 39 cases never
Postoperative death* 1 (3)
became resectable because of extensive liver involvement. Thirty- Never operable 39 (46)
seven of these patients died; for two patients in the S3 study, the
NOTE. N = 85.
outcome was not documented, and the patients were still alive, Abbreviations: SIOPEL, International Childhood Liver Tumor Strategy Group.
with evidence of disease, at the last follow-up at the time of this *Death within 31 days after surgery (cause of death: hemorrhage).
analysis. The complete resection rate (including LTX) without
www.jco.org © 2016 by American Society of Clinical Oncology 3

132.239.1.230
Murawski et al
Table 5. Response to Preoperative Chemotherapy, Tumor Resectability, and Survival After Surgery
Outcome
Surgery Response to Chemotherapy Tumor Resectability Alive Dead
Primary surgery — Complete (n = 12) 8 4
Incomplete (n = 1) 1 0
Delayed surgery Complete remission* (n = 1) Inoperable (n = 1) 0 1
Partial remission (n = 28) Complete (n = 7) 4 3
Microscopic residual disease (n = 4) 1 3
Macroscopic residual disease (n = 3) 1 2
Liver transplantation (n = 5) 2 3
Inoperable (n = 9) 1 8
Stable disease (n = 15) Complete (n = 3) 3 0
Macroscopic residual disease (n = 1) 0 1
Liver transplantation (n = 2) 0 2
Progressive disease (n = 14) Complete (n = 2) 1 1
Early death† (n = 7) Inoperable (n = 7) 0 7
No data (n = 7) Complete (n = 3) 2 1
NOTE. N = 85.
*The single complete response is questionable and was counted as a partial response.
†Death within 31 days after surgery.
Survival (95% CI, 14% to 43%) in the first SIOPEL trial.7 In S1, 37 patients
After a median follow-up period of 75 months, 63 patients received preoperative chemotherapy. A partial response was
(74%) had an event, that is, a progression during treatment, a observed in 18 of 37 patients (49%) versus 29 of 72 patients (40%)
relapse after treatment, or death from any cause. Sixty patients in the reported S2 and S3 studies. Delayed tumor resection was
died. The outcome of three relapsed patients without docu- attempted in the S1 trial in 17 of 37 patients (46%) who received
mented death is unknown. In seven cases, no cause of death was preoperative chemotherapy versus 33 of 72 (40%) in the S2 and S3
given in the database. trials. Tumor resection was complete in 14 (including two with
Table 5 lists the outcomes of patients who underwent an LTX) of S1 patients (82%) versus 34 of 85 patients (40%) in the S2
attempt at resection at any time. Twenty-three of 46 patients (50%) and S3 trials.7 The results of surgery and the outcome of patients
who underwent tumor resection died. Twenty-one of 41 patients treated with preoperative chemotherapy from the three trials are
(51%) with complete tumor resection (including LTX and micro- summarized in Table 6.
scopic residual disease) survived. Complete resection with tumor- Although no formally randomized comparison was per-
free margins was predictive of a survival advantage. Eighteen of 27 formed, analysis of SIOPEL 2 and 3 trials suggests by historical
patients (63%) with complete tumor resection (without LTX) and comparison with the SIOPEL 1 study that, despite the increased
20 of 34 (59%) with LTX survived. Only one of seven patients intensity of preoperative and postoperative chemotherapy (Table 1),
(14%) with microscopically involved margins survived (P = .035, there was no improvement in survival in pediatric HCC. Overall,
Fisher’s exact test). Thus, long-term outcome was strongly correlated the results of HCC treatment remained dismal in children, with
with completeness of resection. OS rates of less than 30%.5,7,8 Figure 2 seems to show that patients
The Kaplan-Meier estimate of the 5-year OS was 22% (95% who had delayed resection did poorly compared with those who
CI, 12% to 32%). The results according to OS and event-free had upfront surgery, especially as early outcome was concerned.
survival of S2 and S3 patients were identical. The OS results of S2 However, after a prolonged follow-up period, survival was com-
and S3 patients were superposable, as shown by Kaplan-Meier parable. This must be interpreted as selection bias, because those
curves (Fig 1). Survival depending on the timing of surgery is shown who presented with resectable tumors probably usually had pri-
in Fig 2. mary surgery. Despite this apparent difference in initial survival
between primarily resected and neoadjuvantly treated patients in
this study (Fig 2), OS rates were equal to the North American
DISCUSSION Intergroup Hepatoma Study (N = 46 patients), in which primary
resection was the guideline.15 After initial surgery or biopsy, 46
No change in outcome of pediatric HCC has occurred since 1990, patients were randomly assigned to receive CDDP with either
when SIOPEL began its first clinical trial devoted to pediatric HB DOXO or fluorouracil and vincristine. There was no difference in
and HCC. The 5-year OS for children with HCC in the S2 and S3 response or survival rate between the two treatment regimens.
trials was only 22% (95%, CI 12% to 32%) compared with 28% Seven of eight patients (88%) with complete tumor excision at the

132.239.1.230
1.0
0.8
Overall Survival (probability)
0.6
Fig 1. Overall survival of hepatocellular car-

cinoma patients in the International Childhood
0.4 Liver Tumor Strategy Group (SIOPEL) 2 and 3
trials.
0.2
SIOPEL 2
SIOPEL 3
0.0
0 12 24 36 48 60 72 84 96 108 120
Months
time of diagnosis (stage I) followed by adjuvant cisplatin-based In the cooperative studies of the German Society of Pediatric
chemotherapy survived. In contrast, the outcome was poor for Oncology and Hematology, HCC was also treated with the same
patients with advanced-stage unresectable disease, with a 5-year OS regimens as HB, with surgery recommended as a primary approach
for stage III and IV patients of 23% and 10%, respectively. The in all patients. Chemotherapy in the HB-89 study consisted of
5-year event-free survival for patients with stage III and IV disease conventional dosed ifosfamide, CDDP, and DOXO, whereas in the
was 8% and 0%, respectively. Tumor resection after neoadjuvant HB-94 study, carboplatin and etoposide were added to ifosfamide,
chemotherapy was only feasible in two patients, and although they CDDP, and DOXO.16,17 The results were equally dismal. The OS
did have prolonged survival, they eventually died of recurrent rate was 33% in HB-89 (four of 12 patients from 1988 to 1992) and
disease. This study suggests that only children with initially 32% in HB-94 (eight of 25 patients from 1994 to 1998).17 Results
resectable HCC have a chance for cure. were poor in all studies of pediatric HCC because of the advanced
1.0
0.8
Survival (probability)
0.6
Fig 2. Survival of the International Childhood

Liver Tumor Strategy Group (SIOPEL) S2 and S3
0.4 patients according to the timing and feasibility of
surgery.
0.2
Delayed
Primary
Unresectable
0.0
0 12 24 36 48 60 72 84 96 108 120
Months

132.239.1.230
Murawski et al
Table 6. Patients Treated With Preoperative Chemotherapy From the Three Trials: Results of Surgery and Outcome
S1 S2/S3
Alive Dead Alive Dead
Results of Surgery n = 19 No. (%) No. (%) n = 33 No. (%) No. (%)
Complete resection 14 8 (57.1) 6 (42.9) 15 10 (66.7) 5 (33.3)
Incomplete resection 2 0 2 (100) 7 1 (14.3) 6 (85.7)
Microscopic residual disease
Incomplete resection — — — 3 1 (33.3) 2 (66.7)
Macroscopic residual disease
Liver transplantation — — — 7 2 (28.6) 5 (71.4)
Postoperative death* — — — 1 0 1 (100)
Inoperable 3 0 3 (100) — — —
*Death within 31 days after surgery (cause of death: hemorrhage).
stage of most tumors at diagnosis, the lack of tumor response to Milan criteria, with a recent trend toward their slight expansion.24-27
chemotherapy, and thus the low rate of complete resection. The Milan criteria are likely not applicable in children because they
Observed responses to chemotherapy in pediatric HCC are are derived from experience in adults with cirrhosis, whereas the
generally better compared with adult reports, where they con- majority of children with HCC do not have an underlying liver
sistently remain below 10% to 20%.5,18,19 This may be due to the disease.6,28 Little is known about the role of LTX in noncirrhotic
inclusion in HCC of a subgroup of transitional tumors that HCC.28 Some published data suggest that LTX may be a useful
consist of both HB and HCC tumor types,18 of which the HB treatment option in selected unresectable or even conventionally
component may show tumor response, or to biologic differences resectable, but advanced, pediatric HCC cases.28,29 Although our
between pediatric and adult HCC.5 Relative insensitivity of HCC results show that survival after LTX in pediatric HCC is dismal, this
to chemotherapy contributes to a low resectability rate. is not reflected by the recent literature.23,29 In the study by Ismail
Although in our studies (SIOPEL 1-3) approximately 40% of et al,29 eight of 11 patients exceeding the Milan criteria (72%) were
patients responded to preoperative chemotherapy, these responses alive, with a follow-up ranging from 32 to 85 months. Eight of 11
were insufficient to render tumor operability. Complete resection tumors were large (. 5 cm) and/or multifocal, and in some cases,
was achieved in 40% of cases (in 48%, including microscopically angioinvasion and even local extrahepatic extension were also
incomplete excisions and LTX). A pediatric HCC study by Chen present. Our data on LTX may be difficult to interpret because of
et al20 reported a complete resection rate of 18%. In SIOPEL 1, the low number of patients and multicenter nature of the trial, with
complete tumor resection was possible in 36% of HCC cases.7 limited information available. Hence, probably in future trials,
Complete tumor resection remains the only treatment modality LTX should be encouraged and its criteria in children should be
leading to long-term survival.7,8,21,22 Current and previously modified, allowing transplantation of any unifocal unresectable
reported SIOPEL studies clearly showed that the long-term out- HCC confined to a noncirrhotic liver, without an upper limit for
come of HCC was related to completeness of resection. Results the tumor size.28,29
from the Pediatric Oncology Group and the Children’s Cancer In conclusion, the intensification of platinum- and doxorubicin-
Group Intergroup Study showed that tumor resection was possible based chemotherapy assessed in the S2 and S3 studies (Table 1) did
in two of the 20 children (10%) with advanced stage disease (stage not result in an improvement in HCC survival. Thus, new
III or IV) after chemotherapy. OS for the group of patients strategies are required for the management of HCC in children.
with unresectable disease was extremely poor; however, the Two key issues should be addressed by these new approaches. First,
two patients who did undergo delayed complete resection better tumor shrinkage is needed to facilitate surgery. Second,
experienced prolonged survival.15 According to the previously tumor recurrence, after apparently complete resection, needs to
described experiences, as well as our studies, use of adjuvant and be prevented. The role of adjuvant chemotherapy in completely
neoadjuvant chemotherapy in pediatric HCC does not seem to resected tumors remains controversial and needs to be inves-
improve ultimate outcome. Hence, in future studies, only post- tigated. Our experience may indicate that these strategies should
operative chemotherapy after complete HCC resection should be not rely only on conventional chemotherapy. Because of the rarity
investigated. of pediatric HCC, future research strategies should include a large
It is interesting that in our study, only 41% of patients with multinational cooperative trial including patients with HCC of all
complete tumor resection (including LTX) survived. Similarly, in age groups, including children, teenagers, and possibly even
SIOPEL 1, eight of 14 patients (57%) who had a complete resection young adults.
survived.7 Although we are aware that these results may be slightly
different from those of other studies, we still believe that every effort
(including LTX) should be directed at achieving complete tumor AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
resection, either primary or delayed.23 OF INTEREST
The role of orthotopic LTX in pediatric HCC remains
debatable, and experience in this field remains limited.6,9,10 In Disclosures provided by the authors are available with this article at
adults, transplantation guidelines are strictly on the basis of the www.jco.org

132.239.1.230
Collection and assembly of data: Maciej Murawski, Michela Casanova,

AUTHOR CONTRIBUTIONS Giorgio Perilongo, Veronique Laithier, Rejin Kebudi, Marcelo J. Scopinaro,
Albert Shun, Benedicte Brichard, Beatriz de Camargo, Margaret Childs
Conception and design: Maciej Murawski, Rudolf Maibach, Derek Data analysis and interpretation: Maciej Murawski, Vı́ola B. Weeda,
J. Roebuck, Arthur Zimmerman, Michela Casanova, Giorgio Rudolf Maibach, Bruce Morland, Daniel C. Aronson, Piotr Czauderna
Perilongo, Margaret Childs, Daniel C. Aronson, Piotr Manuscript writing: All authors
Czauderna Final approval of manuscript: All authors
of Paediatric Oncology: SIOPEL trials using pre- 19. Pircher A, Medinger M, Drevs J: Liver cancer:
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n n n

132.239.1.230
Murawski et al
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Changes
Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Maciej Murawski Rejin Kebudi
No relationship to disclose No relationship to disclose
Vı́ola B. Weeda Marcelo J. Scopinaro
Rudolf Maibach Albert Shun
Bruce Morland Benedicte Brichard
Honoraria: Takeda Pharmaceuticals No relationship to disclose
Travel, Accommodations, Expenses: Takeda Pharmaceuticals
Beatriz de Camargo
Derek J. Roebuck No relationship to disclose
No relationship to disclose
Margaret Childs
Arthur Zimmerman No relationship to disclose
Daniel C. Aronson
Michela Casanova No relationship to disclose
Consulting or Advisory Role: Genentech, Boehringer Ingelheim
Piotr Czauderna
Giorgio Perilongo No relationship to disclose
Veronique Laithier
© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

132.239.1.230
Appendix
Total,
N = 90
Evaluated, Excluded,
N = 85 n=5
Neoadjuvant chemotherapy,
Primary surgery, Never resectable,
then surgery,
n = 13 n = 39
n = 33
Alive, Dead, Alive, Dead, Alive with disease, Death,

n = 9 (69.2%) n = 4 (30.8%) n = 14 (42.4%) n = 19 (57.6%) n = 2 (2.6%) n = 37 (97.4%)
Fig A1. Flowchart of hepatocellular carcinoma patients.
www.jco.org © 2016 by American Society of Clinical Oncology

132.239.1.230

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Published Ahead of Print on January 25, 2016 as 10.1200/JCO.2014.60.

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Hepatocellular Carcinoma in Children: Does Modiﬁed

Maciej Murawski and Piotr Czauderna,

© 2016 by American Society of Clinical Oncology 1

2 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

www.jco.org © 2016 by American Society of Clinical Oncology 3

4 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Fig 1. Overall survival of hepatocellular car-

Fig 2. Survival of the International Childhood

www.jco.org © 2016 by American Society of Clinical Oncology 5

*Death within 31 days after surgery (cause of death: hemorrhage).

6 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Collection and assembly of data: Maciej Murawski, Michela Casanova,

www.jco.org © 2016 by American Society of Clinical Oncology 7

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Alive, Dead, Alive, Dead, Alive with disease, Death,

Fig A1. Flowchart of hepatocellular carcinoma patients.

www.jco.org © 2016 by American Society of Clinical Oncology

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