- Email: [email protected]
SIOPEL trials using preoperative chemotherapy in hepatoblastoma
Preoperative chemotherapy in hepatoblastoma
Review
SIOPEL trials using preoperative chemotherapy in hepatoblastoma Giorgio Perilongo, Elizabeth Shafford, and Jack Plaschkes
With parental permission
Hepatoblastoma is a rare, malignant liver tumour of childhood. Until the mid 1980s only around 30% of patients were cured, but with modern chemotherapy, and of course surgery, the cure rate is now at least 70%. This dramatic improvement in survival has been achieved by the national and international cooperation of paediatric oncology centres. The International Society of Paediatric Oncology Liver Tumour Group, in contrast to most other groups, has used preoperative chemotherapy in all patients, followed by delayed surgery. The group has also developed a novel staging system, called PRETEXT (PRE Treatment EXTent of disease), based on the anatomy of the liver and radiological findings at diagnosis, to try to predict resectability and outcome. Lancet Oncol 2000; 1: 94–100
Hepatoblastoma, the most common primary hepatic tumour in childhood, is a rare neoplasm, accounting for 0.8 – 2.0 % of all paediatric cancers.1 Hepatoblastoma is an embryonal tumour; its pathogenesis is related to a derangement of the normal mechanism of liver organogenesis.2 This premise is supported by the following: ● hepatoblastoma is a tumour of the first 3 years of life, with congenital cases also described;3 ● there is an association between hepatoblastoma and prematurity ;4,5 ● hepatoblastoma cells produce substances that are normally secreted by hepatic fetal cells during pregnancy. Principally, ␣-fetoprotein (␣-FP), which is the main fetal plasma protein, and interleukin 6, which stimulates megakaryocyte production resulting in thrombocytosis; ● some hereditary syndromes characterised by errors in growth regulation during fetal development, mainly Beckwith-Wiedemann syndrome and isolated hemihypertrophy, are associated with an increased risk of embryonal tumours, including hepatoblastoma .6 An increased risk of hepatoblastoma has also been documented in relatives of families affected by familial polyposis coli, such that hepatoblastoma can be regarded as an extracolonic manifestation of this syndrome .7
Clinical features The classical presentation of hepatoblastoma is an asymptomatic abdominal mass discovered by the mother, or by the physician during a routine examination of a healthy young child. Systemic symptoms, including abdominal pain and weight loss, are uncommon but may be present in children with advanced disease (Figure 1).1 Pseudoprecocious 94
Figure 1. Eleven-month old infant with metastatic hepatoblastoma at diagnosis (a) and after four courses of PLADO (b). The tumour was resected and two more courses of PLADO given. The child is alive and well, aged 16 years.
puberty, due to a -chorionic gonadotropin-secreting hepatoblastoma, is an unusual presentation. The clinical and radiological findings of a hepatic mass in a young child associated with a high ␣-FP value and thrombocytosis are the key elements for making a clinical diagnosis; however, only biopsy can confirm it. Tumour biopsy is considered mandatory in children under 6 months old, because of the wide range of tumours presenting at this age and the possible confounding effect of a high ␣-FP concentration just because of the age of the child. Biopsy is mandatory in children over 3 years of age, to distinguish between hepatoblastoma and hepatocellular carcinoma. For patients between 6 months and 3 years old with unequivocal clinical findings, the need for an Giorgio Perilongo, Elizabeth Shafford, and Jack Plaschkes on behalf of the Liver Tumour Study Group of the International Society of Paediatric Oncology GP is Associate Professor in the Department of Pediatrics, University of Padua, Via Giustiniani 3, 35128 Padua, Italy. ES is a Clinical Research Fellow and Honorary Clinical Assistant in the Department of Paediatric Oncology, Barts and the London NHS Trust, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. JP is a Consultant in Paediatric Surgical Oncology in the Pediatric Surgical Unit, University Children’s Hospital, Inselspital, CH-3010, Berne, Switzerland. Correspondence: Dr Giorgio Perilongo, Division of HaematologyOncology, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Tel: +39 049 8213579. Fax: +39 049 8213510. Email: [email protected] THE LANCET Oncology Vol 1 October 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Review
Preoperative chemotherapy in hepatoblastoma
huge intrahepatic extension of the tumour and/or the presence of extrahepatic disease.1 Data derived from the first cooperative trial on hepatoblastoma run by the Children’s Cancer Study Group (CCSG) in the late 1970s and early 1980s indicated that the use of adjuvant chemotherapy reduced the relapse rate. This highlighted the probable chemosensitivity of this tumour.8 The overall 3-year survival rate reported by this study, and other retrospective national or single institutional series, was about 30%. It was, however, only in the 1980s that significant tumourvolume reduction after cisplatinbased chemotherapy was described in hepatoblastoma patients.9,10 These observations suggested that preoperative chemotherapy could be the best strategy to treat all children with hepatoblastoma, irrespective of the extent of tumour at diagnosis. Within the International Society of Paediatric Oncology (SIOP) this concept had already been well established in trials for children with Wilms’ tumour. Because of the rarity of hepatoblastoma, it was apparent that a meaningful clinical trial could only be attempted through collaboration on a national or international level. The network of paediatric oncology centres participating in SIOP activities was ideally suited to facilitate such international collaboration. After 2 years of preparation and a short, limited-institution, pilot trial11 the SIOP Liver Tumour Study Group Figure 2. Three-year-old child with hepatoblastoma. MRI scan of abdomen (a) before and (b) after four courses of PLADO as part of SIOPEL 1 trial. Subsequent surgical resection and two more launched its first clinical courses of PLADO were given. The child, aged 9 years, is now considered cured. study–SIOPEL 1 (SIOP Epithelial Liver 1).12 This was the first full-scale, initial diagnostic surgical biopsy is a still matter of prospective, multinational clinical study of hepatoblastoma controversy. Around 20% of children with hepatoblastoma ever attempted. present with distant metastases at diagnosis, which are found almost exclusively in the lungs.2 Thus, a chest radiograph and SIOPEL 1 computed tomography, as well as abdominal imaging This study was open to patient registration from January (Figure 2) are essential for completing the staging of a child 1990 to February 1994. Preoperative chemotherapy with a cisplatin-based regimen was the hallmark of this with hepatoblastoma. trial (Table 1). Preoperative chemotherapy with cisplatin and Treatment results In the past two decades significant progress has been doxorubicin (PLADO) for 2 months was the chosen made in the treatment of children diagnosed with therapeutic strategy, because PLADO already had a good hepatoblastoma. ‘track record’ in several pilot studies10,13 and is a relatively Before the 1970s surgery was the only treatment straightforward chemotherapy regimen with easily monitored that offered a real chance of cure to children with toxicity. It also seemed likely that as the tumour became hepatoblastoma. However, more than 50% of patients smaller, delayed surgery could reduce morbidity and were unsuitable for radical surgery at diagnosis owing to mortality from an often difficult liver resection. These factors THE LANCET Oncology Vol 1 October 2000
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Preoperative chemotherapy in hepatoblastoma
Review
and delayed surgery of 5% and 8%, respectively. There were three Trial Treatment schedule chemotherapy-related deaths. Two SIOPEL 1 Preoperative chemotherapy—PLADO severely malnourished children died All patients Cisplatin 80 mg/m /24 hours iv continous infusions day 1,22,43,64 Doxorubicin 30 mg/m /24 hours iv continuous infusion day 2,3; 23,24; 44,45; from septicaemia after the first course of 65,66 PLADO. One child, who not only Delayed surgery received an extra course of doxorubicin, Postoperative chemotherapy—PLADO but was also constantly overtreated Cisplatin 80 mg/m /24 hours iv continuous infusion day 1,22 because of a drug dose miscalculation, Doxorubicin 30 mg/m /24 hours iv continuous infusion day 2,3; 23,24 died from cardiomyopathy. These results SIOPEL 2 Standard-risk Preoperative chemotherapy—Cisplatin alone demonstrate that the therapeutic strategy hepatoblastoma Cisplatin 80mg/m /24 hours iv continuous infusion day 1,15,29,44 adopted for the SIOPEL 1 study using Delayed surgery preoperative chemotherapy, based on a Postoperative chemotherapy—Cisplatin alone cisplatin-containing regimen, with Cisplatin 80 mg/m /24 hours iv continuous infusion day 1,15 delayed surgery, is curative in 60 – 70% High-risk Preoperative chemotherapy—Super PLADO therapy of children affected by hepatoblastoma, hepatoblastoma Carboplatin 500 mg/m /1 hour iv day 1,29,57,85 Doxorubicin 30 mg/m /24 hours iv continuous infusion day 1,2; 29,30; 57,58; with acceptable toxicity.12 These data 85,86 double the survival data of the historical Cisplatin 80 mg/m /24 hours iv continuous infusion day 15,43,71 series.1,8 Delayed surgery The preoperative chemotherapy Postoperative chemotherapy—Super PLADO therapy treatment philosophy for childhood Doxorubicin 30 mg/m /24 hours iv continuous infusion day 1,2; 29,30 Cisplatin 80 mg/m /24 hours iv continuous infusion day 15 hepatoblastoma of the SIOPEL studies is not shared by the US or other national childhood liver tumour groups, which seemed crucial because of the large number of centres still recommend primary surgery.14-16 However, even with participating in the study and the different resources and their own strategy, 40 – 60% of patients also receive levels of competence available in the many countries preoperative chemotherapy, with cisplatin-containing represented. Delayed surgery was recommended after four regimens, either because of an unresectable primary tumour courses of PLADO therapy, if considered feasible. For a or because of lung metastases. Therefore, the superiority of responding but still non-resectable tumour, two further one strategy over the other can never be clearly evaluated. The courses were given before resection was attempted. Giving survival data so far produced by the SIOP, the US, and the more than six cycles of PLADO was not recommended. A German tumour study groups are very similar. The SIOP possible argument against the use of preoperative Liver Tumour Study Group believes that for hepatoblastoma, chemotherapy for all children with hepatoblastoma, a chemosensitive tumour in which the response to irrespective of the initial tumour extension, is the concern of chemotherapy can be easily and carefully monitored (by exposing neonates to cytotoxic agents. However, sequential measurements of serum ␣-FP and abdominal accumulating data indicate that neonates may have very ultrasonography) and which requires a sophisticated, aggressive tumours, for which surgery alone would not be potentially difficult operation, it is justifiable to give enough. preoperative chemotherapy in order to make complete An important feature of the SIOPEL 1 study was the resection of tumour more likely and less hazardous. As the worldwide participation of paediatric oncology centres. One tumour becomes smaller in response to preoperative hundred and sixty patients were enrolled in the study from 91 chemotherapy, it usually becomes better demarcated from centres in 30 countries spread over five continents, showing the normal liver parenchyma, less prone to bleeding, and less that through international cooperation it is possible to run a prone to the risk of leaving microscopic residual disease. clinical trial even in rare tumours. Of these 160 patients, 154 The SIOPEL 1 study, apart from aiming to improve the were evaluable for the trial (Table 2). prognosis for children with hepatoblastoma, also attempted The response rate to preoperative PLADO was 82%, as to do the following: shown by a decrease in tumour volume (Figures 1 and 2) and ● determine pretreatment prognostic factors in a group of uniformly treated patients; a fall in ␣-FP concentration. No tumour considered resectable at diagnosis progressed during preoperative ● pilot the value and reproducibility of PRETEXT (PRETreatment EXTent of Disease), a novel staging system, chemotherapy and became unresectable. All treatment in a large group of patients; failures observed were either in patients affected by a large tumour deemed unresectable at diagnosis, or in patients ● evaluate the feasibility of conducting meaningful clinical research on rare tumours on an international scale, and presenting with lung metastases. Complete resection was thereby try and set a standard for the modern approach to possible in 77% of patients, including six who had orthotopic the treatment of hepatoblastoma. liver transplantation after preoperative chemotherapy. For When SIOPEL 1 was designed, only the surgery-based the entire study cohort the 5-year event-free survival (EFS) was 66% (Figure 3), with a 5-year overall survival (OS) of staging system developed by the Children’s Cancer Study 75% (Figure 4). Five-year disease-free survival in the 102 Group (CCSG) was available.14 It defines four categories of patients who achieved complete remission was 81% with a 2- patients based on the absence (stage I) or presence (stage II) year and 5-year relapse rate after preoperative chemotherapy of microscopic residual disease after surgery, measurable Table 1. Treatment details of the SIOPEL trials
2
2
2
2
2
2
2
2
2
2
2
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Review
Preoperative chemotherapy in hepatoblastoma
Table 2. Patient and tumour characteristics of the 154 evaluable patients enrolled into the SIOPEL 1 trial Patient and tumour characteristics Sex male female
97 57
median range
1 0–13
<500 >500
93 61
Yes No
31 123
I II III IV Not known
6 52 45 39 12
Solitary Multifocal Not known
95 22 37
Age (years)
Platelet count (x109/L)
Pulmonary metastases*
PRETEXT category
Tumour focality
*By chest radiography and/or lung computed tomography
The SIOPEL 1 study provides a unique set of data to investigate a large cohort of patients studied and treated homogeneously, for the possible prognostic effect of some pretreatment patient and tumour characteristics.17 Sex, age, ␣-FP concentration, platelet count, histological subtype (obtained from the central review), presence of lung metastases, and radiological evidence of hilar lymph-node enlargement, main vessel invasion (vena cava or vena porta and its main branches), tumour focality, and intrahepatic tumour extent as defined by the PRETEXT system, were analysed for their possible prognostic implications. These variables were first assessed univariately for their association with either OS or EFS. Variables that correlated with survival were then considered for further multivariate analysis. The presence of metastases at diagnosis and PRETEXT category were the only ones identified as independent predictors of EFS. PRETEXT category remained the only independent significant factor for OS. Thus, with current treatment, patients with a PRETEXT IV tumour and/or lung metastases have a significantly worse prognosis than those with nonmetastatic PRETEXT I – III disease.18 SIOPEL 2 (pilot study)
These findings led to the next generation of studies, based on risk group. The ‘standard risk’ group included those patients with tumours involving no more than three hepatic sectors and without evidence of extrahepatic disease, and the ‘high risk’ group (ie those at high risk of treatment failure) included patients with tumours involving all four hepatic sectors and/or with evidence of extrahepatic disease. Therapy was modified according to risk group. As the SIOPEL 1 study progressed, the fundamental role of cisplatin in treating childhood hepatoblastoma became apparent.19,20 So much so that the SIOP Liver Tumour Study Group decided to test the effectiveness (in terms of response and resection rates assumed to be valid surrogates of OS and EFS) of single-agent cisplatin in a pilot study for standard-risk patients.21 There are very few examples in children or adults of a malignant tumour treated with a single drug, therefore conducting a pilot study before going on to a full-scale randomised study was considered wise and even necessary. Furthermore, the pilot study also evaluated the toxicity and the effectiveness of a multiagent, intensive regimen based on the alternating use (every 15 days) of myelotoxic (carboplatin and doxorubicin)
Probability of survival
disease after surgery (stage III), and distant metastases at diagnosis (stage IV). A post-treatment staging system is not appropriate either when giving preoperative chemotherapy nor under any circumstances for evaluating outcome. Therefore, for the SIOPEL 1 trial a novel grouping system called PRETEXT, based on the anatomy of the liver and the radiological findings at diagnosis, was developed to describe the extent of disease before treatment and to try to assess resectability more accurately (Figure 5). In the PRETEXT system, the liver is divided into four sectors: an anterior and a posterior sector on the right, and a medial and lateral sector on the left. In this way, four PRETEXT categories are identified: ● PRETEXT I – three adjoining sectors are free and one is involved by the tumour; ● PRETEXT II – two adjoining sectors are free and two are involved; ● PRETEXT III – just one sector is free and three are involved (or two non-adjoining sectors are free); ● PRETEXT IV – there are no 1·0 tumour-free sectors. 0·9 Extension of the tumour beyond 0·8 the liver is indicated with ‘V’ where 0·7 there is extension of tumour into the 0·6 vena cava and/or all three hepatic 0·5 veins; ‘P’ where there is extension into 0·4 0·3 the main and/or both left and right 0·2 branches of the portal vein; ‘E’ for 0·1 extrahepatic extension except for P 0·0 and V; and M, to indicate the presence 0 6 12 18 24 30 36 42 of distant metastases. Thus, tumour Months since diagnosis extent is expressed in terms of PRETEXT category (I – IV) and Number 154 122 109 104 101 96 88 84 presence/absence of extrahepatic at risk Figure 3. Event-free survival of SIOPEL 1 patients (with 95% CI). disease: V, P, E, or M. THE LANCET Oncology Vol 1 October 2000
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54
60
73
67
56
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Probability of survival
Preoperative chemotherapy in hepatoblastoma
1·0 0·9 0·8 0·7 0·6 0·5 0·4 0·3 0·2 0·1 0·0
Review
The role of orthotopic liver transplantation (OLT) in the treatment of hepatoblastoma
0
Number 154 t risk
6
12
18
137
132
126
24 30 36 Months since diagnosis 118
112
105
42
100
Figure 4. Overall survival of SIOPEL 1 patients (with 95% CI).
and non-myelotoxic agents (cisplatin) for high-risk hepatoblastoma (Table 1). Owing to the participation of a large number of centres throughout the world, 135 children have been enrolled in SIOPEL 2, 76 (57%) with standard-risk hepatoblastoma and 59 high-risk hepatoblastoma. The response rate to cisplatin alone, measured by tumour shrinkage and fall in ␣-FP, was 81.5%, and the complete resection rate was 86.1%. As expected, in the cohort of children considered R high risk, the response and resection rates were significantly lower; 64.7% and 66.3%, respectively. The preliminary analysis of this cohort of children projects a 3-year EFS and OS for the standard-risk patients of 88.1% (95% CI 80 – 96) and 88.5% (95% CI 80 – 97) and for the high-risk group of 39.3% (95% CI 23 – 56) and 49.7% (95% CI 31 – 68), respectively. The results of SIOPEL 2 validate the risk groups identified in the first study. These data are still not mature, owing to the relatively short median follow-up of 23 months for the standard-risk group and 18 months for the high-risk group, but were sufficiently convincing for the SIOP Liver Tumour Study Group to decide to test prospectively, in a randomised study, the hypothesis that cisplatin alone is as effective as PLADO in treating standard-risk hepatoblastoma. The group decided to continue to investigate the role of intensive multiagent chemotherapy for high-risk patients. This is the current trial, SIOPEL 3, which is run by the SIOP Liver Tumour Study Group and opened to registration in June 1998 (Figure 6).
Originally, transplant centres were reluctant to recommend this procedure for hepatoblastoma, because of the data derived mainly from the poor adult experience of OLT in the treatment of hepatocellular carcinoma, and the 48 54 60 relative scarcity of donor organs. However, in the SIOPEL 1 study, five out of six children who 89 80 66 underwent OLT for hepatoblastoma that remained unresectable after preoperative PLADO, are presently alive with no evidence of disease at a median follow-up of over 70 months.12 These favourable results have also been reported by other transplant centres.22,23 OLT is therefore now a realistic option for selected patients. Ideal candidates are children whose tumours, completely confined to the liver, remain unresectable, despite a definite response to chemotherapy. OLT is a worthwhile procedure if used L
Issues for confirmation The SIOPEL studies have raised some interesting issues which need further investigation. 98
Displacement (II)
Invasion (III)
Figure 5. SIOPEL staging system – PRETEXT.
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Review
Preoperative chemotherapy in hepatoblastoma
High-risk hepatoblastoma
Diagnostic and staging procedures
Cisplatin alone x 1
R E G I S T R A T I O N
Standard-risk hepatoblastoma
Cisplatin alone x 1
R A N D O M I S A T I O N
Carboplatin/ doxorubicin/cisplatin Preoperative phase
D E L A Y E D
PLADO Postoperative phase
PLADO Preoperative phase
Cisplatin alone Preoperative phase
Carboplatin/ doxorubicin/cisplatin Postoperative phase
S U R G E R Y
Cisplatin alone Postoperative phase
Figure 6. Treatment plan for SIOPEL 3
early, as part of first-line therapy, and not as a salvage procedure after multiple and prolonged chemotherapy attempts to reduce tumour volume or after tumour recurrence. Furthermore, recent data suggest that children presenting with metastatic hepatoblastoma, whose lung metastases clear with chemotherapy, should also be considered eligible for OLT. Three children among the 31 patients presenting with metastases in the SIOPEL 1 study are presently alive with no evidence of disease at more than 34, 70, and 75 months from transplant.18 Split-liver techniques can partly overcome the scarcity of organs, and transplants from living related donors, applicable only to children, can mitigate some of the ethical problems related to the competition for cadaver donors. Does ␣-FP-negative hepatoblastoma have a poor prognosis?
This uncommon type of hepatoblastoma seems to have an aggressive clinical behaviour. The German Study Group first drew attention to this. They noted that among 71 hepatoblastoma patients they studied prospectively, seven presented with an ␣-FP between 0 and 99 ng/mL, and only three of these were alive with no evidence of disease when last censored. In the SIOPEL 1 and 2 studies, 13 (6·5% of the entire population) had an ␣-FP of less than 100 ng/mL at diagnosis. Only five are alive disease-free with a median follow-up of 5 years 8 months (range 23 months to 7 years); six died 12 days to 8 months from diagnosis, five from progressive disease and one from toxic effects. Two others are alive with evidence of disease at 3 and 19 months. The biological and genetic differences between ␣-FP secreting and the ␣-FP non-secreting tumours are as yet unknown. THE LANCET Oncology Vol 1 October 2000
The treatment of microscopic residual disease
Among the 244 patients registered in the SIOPEL 1 and 2 studies, 28 had microscopic residual disease after surgery. In 26 patients, the microscopic residue consisted of tumour cells at the margin of surgical resection and for two patients, the residue was present in the vessels close to the resection margins. The majority of these patients continued with chemotherapy according to the protocol. Only one patient had further surgery (OLT). Overall, 24 of these 28 children are currently alive with no evidence of disease at follow-up ranging from 1 to 8 years (median 2 years). One died postoperatively and three died from disease. These data indicate that the presence of microscopic residual disease does not necessarily imply a poor prognosis, so heroic chemotherapy or surgical salvage procedures are not called for. However, it is crucial to monitor the ␣-FP concentration closely to ensure a return to normal at the end of treatment.24 These observations need to be confirmed with longer follow-up. What is the role of surgery in treating pulmonary metastases?
Patients with lung metastases have a poor prognosis. In the SIOPEL 1 study, the 5-year EFS was only 28%, although the OS was 57%.18 Seventeen of 31 patients are alive with no evidence of disease; nine of these had additional treatment, including thoracotomy in four patients. Others have also reported survival of such patients after lung surgery, which in some cases has necessitated multiple thoracotomies .25,26 99
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Preoperative chemotherapy in hepatoblastoma
Search and selection criteria This review includes published and as yet unpublished data from the SIOPEL studies and other relevant articles.
Is histology a prognostic factor?
In the SIOPEL 1 study, histology was not identified as a prognostic factor,17 however, this analysis was done on material obtained at biopsy that may not be representative of the whole tumour. Analysis of material obtained after chemotherapy may also not be representative of the original tumour.27 In a study of 196 patients, Haas and colleagues identified pure fetal histology as a good prognostic factor, but only in patients in whom the tumour was completely resected at diagnosis.28 Undifferentiated hepatoblastoma, which may be associated with a normal or low ␣-FP value, often responds poorly to chemotherapy and has an aggressive behaviour with poor outcome. Further studies are needed to confirm the prognostic significance of histology. The success of the SIOPEL trials, which has been achieved by unparalleled international cooperation, demonstrates that it is possible to conduct clinical trials on rare tumours. This is a model that should be applied to other rare neoplasms. Acknowledgments
We acknowledge funding received from the Bernese Cancer Fund, the Swiss Cancer League, Dr Takedo Takeda (Sapporo, Japan), the UK Liver Tumour Parents Group, especially the Bristow, Marshall, and O’Shea families, and the Cancer Research Campaign, without which the SIOPEL studies could not be conducted. References
1 Exelby PR, Filler RM, Grosfeld YL. Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma. American Academy of Paediatrics Surgical Section Survey – 1974. J Paediat Surg 1975; 10: 329–37. 2 Perilongo G, Shafford EA. Liver Tumours. Eur J Cancer 1999; 35: 953–59. 3 Ammann RA, Plaschkes J, Leibundgut K. Congenital hepatoblastoma: a distinct entity? Med Ped Oncol 1999; 32: 466–68. 4 Ross JA, Gurney JG. Hepatoblastoma incidence in the United States from 1973 to 1992. Med Ped Oncol 1998; 30: 141–42. 5 Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a change? J Pediatrics 1997; 130: 557–60. 6 Debaun MR, Tucker MA. Risk of cancer during the first four years of life in children with the Beckwith-Wiedemann Syndrome. J Pediatrics 1998; 132: 398–400. 7 Li FP, Thurber WA, Seddon J, Holmes GE. Hepatoblastoma in families with polyposis coli. JAMA 1987; 257: 2475–77. 8 Evans AE, Land VJ, Newton WA, Randolph JR et al. Combination chemotherapy in the treatment of children with malignant hepatoma. Cancer 1982; 50: 821–26. 9 Douglass EC, Green AA, Wrenn E, et al. Effective cisplatin (DDP) based chemotherapy in the treatment of hepatoblastoma. Med Ped Oncol 1985; 13: 187–90. 10 Quinn JJ, Altman AJ, Robinson HT, et al. Adriamycin and cisplatin for hepatoblastoma. Cancer 1985; 56: 1926–29.
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11 Ninane J, Perilongo G, Stalens JP, et al. Effectiveness and toxicity of cisplatin and doxorubicin (PLADO) in childhood hepatoblastoma and hepatocellular carcinoma: a SIOP pilot study. Med Ped Oncol 1991; 19: 199–203. 12 Pritchard J, Brown J, Shafford E, et al. Preoperative chemotherapy with cisplatin and doxorubicin for childhood hepatoblastoma: a successful approach. Results of the first prospective study of the International Society of Pediatric Oncology (SIOP) – SIOPEL 1. J Clin Oncol (in press). 13 Pierro A, Langevin AM, Filler RM, et al. Preoperative chemotherapy in ‘unresectable’ hepatoblastoma. J Pediatr Surg 1989; 24: 24–29. 14 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: 2167–72. 15 Douglass EC, Reynolds M, Finegold M, et al. Cisplatin, vincristine and fluorouracil therapy for hepatoblastoma: a Paediatric Oncology Group Study. J Clin Oncol 1993; 11: 96–99. 16 von Schweinitz D, Byrd DJ, Hecker et al. Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Eur J Cancer 1997; 33: 1243–49. 17 Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma – results from the International Society of Pediatric Oncology (SIOP) Study – SIOPEL1. Eur J Cancer 2000; 36: 1418–25. 18 Perilongo G, Brown J, Shafford EA et al. Hepatoblastoma presenting with lung metastases – treatment results of the first cooperaive prospective study of the International Society of Pediatric Oncology (SIOP) on childhood liver tumours (SIOPEL 1). Cancer (in press). 19 Ortega JA, Douglass E, Feusner J, et al. A randomised trial of cisplatin (DDP)/vincristine (VCR)/5-fluorouracil (5FU) vs. DDP/doxorubicin (DOX) iv continuous infusion (CI) for the treatment of hepatoblastoma (HB). Results from the Pediatric Intergroup Hepatoma Study (CCG-8881/POG-8945). Proc Am Soc Clin Oncol 14–17, May 1994. 20 Black CT, Cangir CM, Andrassy RJ. Marked response to preoperative high-dose cis-platinum in children with unresectable hepatoblastoma. J Pediatr Surg 1991; 26: 1070–73. 21 Perilongo G, Brugieres L, Shafford E, et al. Hepatoblastoma – SIOPEL 2 pilot study, preliminary report. Med Ped Oncol 1999; 33: 177 abstract. 22 Koneru B, Flye MW, Busuttil RW, et al. Liver transplantation for hepatoblastoma. The American experience. Ann Surg 1991; 213: 118–21. 23 Al-Qabandi W, Jenkinson HC, Buckels AD, et al. Orthotopic liver transplantation for unresectable hepatoblastoma. J Pediatr Surg 1999; 34: 1261–64. 24 Van Tornout JM, Buckley, Quinn JJ, et al. Timing and magnitud of decline of ␣-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome. A report from the Children’s Cancer Group. J Clin Oncol 1997; 15: 1190–97. 25 Black CT, Luck SR, Musemeche CA, Andrassy RJ. Aggressive excision of pulmonary metastases is warranted in the management of childhood hepatic tumours. J Pediatr Surg 1991; 26: 1082–86. 26 Passmore SJ, Noblett HR, Wisheart JD, Mott MG. Prolonged survival following multiple thoracotomies for metastatic hepatoblastoma. Med Pediatr Oncol 1995; 24: 58–60. 27 Saxena R, Leake JL, Shafford EA, et al. Chemotherapy effects on hepatoblastoma. Am J Surg Pathol 1993; 17: 1266–71. 28 Haas JE, Muczynski KA, Krailo M, et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989; 64: 1082–1095.
A list of SIOPEL study participants appears on The Lancet Oncology’s website: http://oncology.thelancet.com
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Review
SIOPEL trials using preoperative chemotherapy in hepatoblastoma Giorgio Perilongo, Elizabeth Shafford, and Jack Plaschkes
With parental permission
Hepatoblastoma is a rare, malignant liver tumour of childhood. Until the mid 1980s only around 30% of patients were cured, but with modern chemotherapy, and of course surgery, the cure rate is now at least 70%. This dramatic improvement in survival has been achieved by the national and international cooperation of paediatric oncology centres. The International Society of Paediatric Oncology Liver Tumour Group, in contrast to most other groups, has used preoperative chemotherapy in all patients, followed by delayed surgery. The group has also developed a novel staging system, called PRETEXT (PRE Treatment EXTent of disease), based on the anatomy of the liver and radiological findings at diagnosis, to try to predict resectability and outcome. Lancet Oncol 2000; 1: 94–100
Hepatoblastoma, the most common primary hepatic tumour in childhood, is a rare neoplasm, accounting for 0.8 – 2.0 % of all paediatric cancers.1 Hepatoblastoma is an embryonal tumour; its pathogenesis is related to a derangement of the normal mechanism of liver organogenesis.2 This premise is supported by the following: ● hepatoblastoma is a tumour of the first 3 years of life, with congenital cases also described;3 ● there is an association between hepatoblastoma and prematurity ;4,5 ● hepatoblastoma cells produce substances that are normally secreted by hepatic fetal cells during pregnancy. Principally, ␣-fetoprotein (␣-FP), which is the main fetal plasma protein, and interleukin 6, which stimulates megakaryocyte production resulting in thrombocytosis; ● some hereditary syndromes characterised by errors in growth regulation during fetal development, mainly Beckwith-Wiedemann syndrome and isolated hemihypertrophy, are associated with an increased risk of embryonal tumours, including hepatoblastoma .6 An increased risk of hepatoblastoma has also been documented in relatives of families affected by familial polyposis coli, such that hepatoblastoma can be regarded as an extracolonic manifestation of this syndrome .7
Clinical features The classical presentation of hepatoblastoma is an asymptomatic abdominal mass discovered by the mother, or by the physician during a routine examination of a healthy young child. Systemic symptoms, including abdominal pain and weight loss, are uncommon but may be present in children with advanced disease (Figure 1).1 Pseudoprecocious 94
Figure 1. Eleven-month old infant with metastatic hepatoblastoma at diagnosis (a) and after four courses of PLADO (b). The tumour was resected and two more courses of PLADO given. The child is alive and well, aged 16 years.
puberty, due to a -chorionic gonadotropin-secreting hepatoblastoma, is an unusual presentation. The clinical and radiological findings of a hepatic mass in a young child associated with a high ␣-FP value and thrombocytosis are the key elements for making a clinical diagnosis; however, only biopsy can confirm it. Tumour biopsy is considered mandatory in children under 6 months old, because of the wide range of tumours presenting at this age and the possible confounding effect of a high ␣-FP concentration just because of the age of the child. Biopsy is mandatory in children over 3 years of age, to distinguish between hepatoblastoma and hepatocellular carcinoma. For patients between 6 months and 3 years old with unequivocal clinical findings, the need for an Giorgio Perilongo, Elizabeth Shafford, and Jack Plaschkes on behalf of the Liver Tumour Study Group of the International Society of Paediatric Oncology GP is Associate Professor in the Department of Pediatrics, University of Padua, Via Giustiniani 3, 35128 Padua, Italy. ES is a Clinical Research Fellow and Honorary Clinical Assistant in the Department of Paediatric Oncology, Barts and the London NHS Trust, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. JP is a Consultant in Paediatric Surgical Oncology in the Pediatric Surgical Unit, University Children’s Hospital, Inselspital, CH-3010, Berne, Switzerland. Correspondence: Dr Giorgio Perilongo, Division of HaematologyOncology, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Tel: +39 049 8213579. Fax: +39 049 8213510. Email: [email protected] THE LANCET Oncology Vol 1 October 2000
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huge intrahepatic extension of the tumour and/or the presence of extrahepatic disease.1 Data derived from the first cooperative trial on hepatoblastoma run by the Children’s Cancer Study Group (CCSG) in the late 1970s and early 1980s indicated that the use of adjuvant chemotherapy reduced the relapse rate. This highlighted the probable chemosensitivity of this tumour.8 The overall 3-year survival rate reported by this study, and other retrospective national or single institutional series, was about 30%. It was, however, only in the 1980s that significant tumourvolume reduction after cisplatinbased chemotherapy was described in hepatoblastoma patients.9,10 These observations suggested that preoperative chemotherapy could be the best strategy to treat all children with hepatoblastoma, irrespective of the extent of tumour at diagnosis. Within the International Society of Paediatric Oncology (SIOP) this concept had already been well established in trials for children with Wilms’ tumour. Because of the rarity of hepatoblastoma, it was apparent that a meaningful clinical trial could only be attempted through collaboration on a national or international level. The network of paediatric oncology centres participating in SIOP activities was ideally suited to facilitate such international collaboration. After 2 years of preparation and a short, limited-institution, pilot trial11 the SIOP Liver Tumour Study Group Figure 2. Three-year-old child with hepatoblastoma. MRI scan of abdomen (a) before and (b) after four courses of PLADO as part of SIOPEL 1 trial. Subsequent surgical resection and two more launched its first clinical courses of PLADO were given. The child, aged 9 years, is now considered cured. study–SIOPEL 1 (SIOP Epithelial Liver 1).12 This was the first full-scale, initial diagnostic surgical biopsy is a still matter of prospective, multinational clinical study of hepatoblastoma controversy. Around 20% of children with hepatoblastoma ever attempted. present with distant metastases at diagnosis, which are found almost exclusively in the lungs.2 Thus, a chest radiograph and SIOPEL 1 computed tomography, as well as abdominal imaging This study was open to patient registration from January (Figure 2) are essential for completing the staging of a child 1990 to February 1994. Preoperative chemotherapy with a cisplatin-based regimen was the hallmark of this with hepatoblastoma. trial (Table 1). Preoperative chemotherapy with cisplatin and Treatment results In the past two decades significant progress has been doxorubicin (PLADO) for 2 months was the chosen made in the treatment of children diagnosed with therapeutic strategy, because PLADO already had a good hepatoblastoma. ‘track record’ in several pilot studies10,13 and is a relatively Before the 1970s surgery was the only treatment straightforward chemotherapy regimen with easily monitored that offered a real chance of cure to children with toxicity. It also seemed likely that as the tumour became hepatoblastoma. However, more than 50% of patients smaller, delayed surgery could reduce morbidity and were unsuitable for radical surgery at diagnosis owing to mortality from an often difficult liver resection. These factors THE LANCET Oncology Vol 1 October 2000
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and delayed surgery of 5% and 8%, respectively. There were three Trial Treatment schedule chemotherapy-related deaths. Two SIOPEL 1 Preoperative chemotherapy—PLADO severely malnourished children died All patients Cisplatin 80 mg/m /24 hours iv continous infusions day 1,22,43,64 Doxorubicin 30 mg/m /24 hours iv continuous infusion day 2,3; 23,24; 44,45; from septicaemia after the first course of 65,66 PLADO. One child, who not only Delayed surgery received an extra course of doxorubicin, Postoperative chemotherapy—PLADO but was also constantly overtreated Cisplatin 80 mg/m /24 hours iv continuous infusion day 1,22 because of a drug dose miscalculation, Doxorubicin 30 mg/m /24 hours iv continuous infusion day 2,3; 23,24 died from cardiomyopathy. These results SIOPEL 2 Standard-risk Preoperative chemotherapy—Cisplatin alone demonstrate that the therapeutic strategy hepatoblastoma Cisplatin 80mg/m /24 hours iv continuous infusion day 1,15,29,44 adopted for the SIOPEL 1 study using Delayed surgery preoperative chemotherapy, based on a Postoperative chemotherapy—Cisplatin alone cisplatin-containing regimen, with Cisplatin 80 mg/m /24 hours iv continuous infusion day 1,15 delayed surgery, is curative in 60 – 70% High-risk Preoperative chemotherapy—Super PLADO therapy of children affected by hepatoblastoma, hepatoblastoma Carboplatin 500 mg/m /1 hour iv day 1,29,57,85 Doxorubicin 30 mg/m /24 hours iv continuous infusion day 1,2; 29,30; 57,58; with acceptable toxicity.12 These data 85,86 double the survival data of the historical Cisplatin 80 mg/m /24 hours iv continuous infusion day 15,43,71 series.1,8 Delayed surgery The preoperative chemotherapy Postoperative chemotherapy—Super PLADO therapy treatment philosophy for childhood Doxorubicin 30 mg/m /24 hours iv continuous infusion day 1,2; 29,30 Cisplatin 80 mg/m /24 hours iv continuous infusion day 15 hepatoblastoma of the SIOPEL studies is not shared by the US or other national childhood liver tumour groups, which seemed crucial because of the large number of centres still recommend primary surgery.14-16 However, even with participating in the study and the different resources and their own strategy, 40 – 60% of patients also receive levels of competence available in the many countries preoperative chemotherapy, with cisplatin-containing represented. Delayed surgery was recommended after four regimens, either because of an unresectable primary tumour courses of PLADO therapy, if considered feasible. For a or because of lung metastases. Therefore, the superiority of responding but still non-resectable tumour, two further one strategy over the other can never be clearly evaluated. The courses were given before resection was attempted. Giving survival data so far produced by the SIOP, the US, and the more than six cycles of PLADO was not recommended. A German tumour study groups are very similar. The SIOP possible argument against the use of preoperative Liver Tumour Study Group believes that for hepatoblastoma, chemotherapy for all children with hepatoblastoma, a chemosensitive tumour in which the response to irrespective of the initial tumour extension, is the concern of chemotherapy can be easily and carefully monitored (by exposing neonates to cytotoxic agents. However, sequential measurements of serum ␣-FP and abdominal accumulating data indicate that neonates may have very ultrasonography) and which requires a sophisticated, aggressive tumours, for which surgery alone would not be potentially difficult operation, it is justifiable to give enough. preoperative chemotherapy in order to make complete An important feature of the SIOPEL 1 study was the resection of tumour more likely and less hazardous. As the worldwide participation of paediatric oncology centres. One tumour becomes smaller in response to preoperative hundred and sixty patients were enrolled in the study from 91 chemotherapy, it usually becomes better demarcated from centres in 30 countries spread over five continents, showing the normal liver parenchyma, less prone to bleeding, and less that through international cooperation it is possible to run a prone to the risk of leaving microscopic residual disease. clinical trial even in rare tumours. Of these 160 patients, 154 The SIOPEL 1 study, apart from aiming to improve the were evaluable for the trial (Table 2). prognosis for children with hepatoblastoma, also attempted The response rate to preoperative PLADO was 82%, as to do the following: shown by a decrease in tumour volume (Figures 1 and 2) and ● determine pretreatment prognostic factors in a group of uniformly treated patients; a fall in ␣-FP concentration. No tumour considered resectable at diagnosis progressed during preoperative ● pilot the value and reproducibility of PRETEXT (PRETreatment EXTent of Disease), a novel staging system, chemotherapy and became unresectable. All treatment in a large group of patients; failures observed were either in patients affected by a large tumour deemed unresectable at diagnosis, or in patients ● evaluate the feasibility of conducting meaningful clinical research on rare tumours on an international scale, and presenting with lung metastases. Complete resection was thereby try and set a standard for the modern approach to possible in 77% of patients, including six who had orthotopic the treatment of hepatoblastoma. liver transplantation after preoperative chemotherapy. For When SIOPEL 1 was designed, only the surgery-based the entire study cohort the 5-year event-free survival (EFS) was 66% (Figure 3), with a 5-year overall survival (OS) of staging system developed by the Children’s Cancer Study 75% (Figure 4). Five-year disease-free survival in the 102 Group (CCSG) was available.14 It defines four categories of patients who achieved complete remission was 81% with a 2- patients based on the absence (stage I) or presence (stage II) year and 5-year relapse rate after preoperative chemotherapy of microscopic residual disease after surgery, measurable Table 1. Treatment details of the SIOPEL trials
2
2
2
2
2
2
2
2
2
2
2
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Table 2. Patient and tumour characteristics of the 154 evaluable patients enrolled into the SIOPEL 1 trial Patient and tumour characteristics Sex male female
97 57
median range
1 0–13
<500 >500
93 61
Yes No
31 123
I II III IV Not known
6 52 45 39 12
Solitary Multifocal Not known
95 22 37
Age (years)
Platelet count (x109/L)
Pulmonary metastases*
PRETEXT category
Tumour focality
*By chest radiography and/or lung computed tomography
The SIOPEL 1 study provides a unique set of data to investigate a large cohort of patients studied and treated homogeneously, for the possible prognostic effect of some pretreatment patient and tumour characteristics.17 Sex, age, ␣-FP concentration, platelet count, histological subtype (obtained from the central review), presence of lung metastases, and radiological evidence of hilar lymph-node enlargement, main vessel invasion (vena cava or vena porta and its main branches), tumour focality, and intrahepatic tumour extent as defined by the PRETEXT system, were analysed for their possible prognostic implications. These variables were first assessed univariately for their association with either OS or EFS. Variables that correlated with survival were then considered for further multivariate analysis. The presence of metastases at diagnosis and PRETEXT category were the only ones identified as independent predictors of EFS. PRETEXT category remained the only independent significant factor for OS. Thus, with current treatment, patients with a PRETEXT IV tumour and/or lung metastases have a significantly worse prognosis than those with nonmetastatic PRETEXT I – III disease.18 SIOPEL 2 (pilot study)
These findings led to the next generation of studies, based on risk group. The ‘standard risk’ group included those patients with tumours involving no more than three hepatic sectors and without evidence of extrahepatic disease, and the ‘high risk’ group (ie those at high risk of treatment failure) included patients with tumours involving all four hepatic sectors and/or with evidence of extrahepatic disease. Therapy was modified according to risk group. As the SIOPEL 1 study progressed, the fundamental role of cisplatin in treating childhood hepatoblastoma became apparent.19,20 So much so that the SIOP Liver Tumour Study Group decided to test the effectiveness (in terms of response and resection rates assumed to be valid surrogates of OS and EFS) of single-agent cisplatin in a pilot study for standard-risk patients.21 There are very few examples in children or adults of a malignant tumour treated with a single drug, therefore conducting a pilot study before going on to a full-scale randomised study was considered wise and even necessary. Furthermore, the pilot study also evaluated the toxicity and the effectiveness of a multiagent, intensive regimen based on the alternating use (every 15 days) of myelotoxic (carboplatin and doxorubicin)
Probability of survival
disease after surgery (stage III), and distant metastases at diagnosis (stage IV). A post-treatment staging system is not appropriate either when giving preoperative chemotherapy nor under any circumstances for evaluating outcome. Therefore, for the SIOPEL 1 trial a novel grouping system called PRETEXT, based on the anatomy of the liver and the radiological findings at diagnosis, was developed to describe the extent of disease before treatment and to try to assess resectability more accurately (Figure 5). In the PRETEXT system, the liver is divided into four sectors: an anterior and a posterior sector on the right, and a medial and lateral sector on the left. In this way, four PRETEXT categories are identified: ● PRETEXT I – three adjoining sectors are free and one is involved by the tumour; ● PRETEXT II – two adjoining sectors are free and two are involved; ● PRETEXT III – just one sector is free and three are involved (or two non-adjoining sectors are free); ● PRETEXT IV – there are no 1·0 tumour-free sectors. 0·9 Extension of the tumour beyond 0·8 the liver is indicated with ‘V’ where 0·7 there is extension of tumour into the 0·6 vena cava and/or all three hepatic 0·5 veins; ‘P’ where there is extension into 0·4 0·3 the main and/or both left and right 0·2 branches of the portal vein; ‘E’ for 0·1 extrahepatic extension except for P 0·0 and V; and M, to indicate the presence 0 6 12 18 24 30 36 42 of distant metastases. Thus, tumour Months since diagnosis extent is expressed in terms of PRETEXT category (I – IV) and Number 154 122 109 104 101 96 88 84 presence/absence of extrahepatic at risk Figure 3. Event-free survival of SIOPEL 1 patients (with 95% CI). disease: V, P, E, or M. THE LANCET Oncology Vol 1 October 2000
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54
60
73
67
56
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1·0 0·9 0·8 0·7 0·6 0·5 0·4 0·3 0·2 0·1 0·0
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The role of orthotopic liver transplantation (OLT) in the treatment of hepatoblastoma
0
Number 154 t risk
6
12
18
137
132
126
24 30 36 Months since diagnosis 118
112
105
42
100
Figure 4. Overall survival of SIOPEL 1 patients (with 95% CI).
and non-myelotoxic agents (cisplatin) for high-risk hepatoblastoma (Table 1). Owing to the participation of a large number of centres throughout the world, 135 children have been enrolled in SIOPEL 2, 76 (57%) with standard-risk hepatoblastoma and 59 high-risk hepatoblastoma. The response rate to cisplatin alone, measured by tumour shrinkage and fall in ␣-FP, was 81.5%, and the complete resection rate was 86.1%. As expected, in the cohort of children considered R high risk, the response and resection rates were significantly lower; 64.7% and 66.3%, respectively. The preliminary analysis of this cohort of children projects a 3-year EFS and OS for the standard-risk patients of 88.1% (95% CI 80 – 96) and 88.5% (95% CI 80 – 97) and for the high-risk group of 39.3% (95% CI 23 – 56) and 49.7% (95% CI 31 – 68), respectively. The results of SIOPEL 2 validate the risk groups identified in the first study. These data are still not mature, owing to the relatively short median follow-up of 23 months for the standard-risk group and 18 months for the high-risk group, but were sufficiently convincing for the SIOP Liver Tumour Study Group to decide to test prospectively, in a randomised study, the hypothesis that cisplatin alone is as effective as PLADO in treating standard-risk hepatoblastoma. The group decided to continue to investigate the role of intensive multiagent chemotherapy for high-risk patients. This is the current trial, SIOPEL 3, which is run by the SIOP Liver Tumour Study Group and opened to registration in June 1998 (Figure 6).
Originally, transplant centres were reluctant to recommend this procedure for hepatoblastoma, because of the data derived mainly from the poor adult experience of OLT in the treatment of hepatocellular carcinoma, and the 48 54 60 relative scarcity of donor organs. However, in the SIOPEL 1 study, five out of six children who 89 80 66 underwent OLT for hepatoblastoma that remained unresectable after preoperative PLADO, are presently alive with no evidence of disease at a median follow-up of over 70 months.12 These favourable results have also been reported by other transplant centres.22,23 OLT is therefore now a realistic option for selected patients. Ideal candidates are children whose tumours, completely confined to the liver, remain unresectable, despite a definite response to chemotherapy. OLT is a worthwhile procedure if used L
Issues for confirmation The SIOPEL studies have raised some interesting issues which need further investigation. 98
Displacement (II)
Invasion (III)
Figure 5. SIOPEL staging system – PRETEXT.
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Preoperative chemotherapy in hepatoblastoma
High-risk hepatoblastoma
Diagnostic and staging procedures
Cisplatin alone x 1
R E G I S T R A T I O N
Standard-risk hepatoblastoma
Cisplatin alone x 1
R A N D O M I S A T I O N
Carboplatin/ doxorubicin/cisplatin Preoperative phase
D E L A Y E D
PLADO Postoperative phase
PLADO Preoperative phase
Cisplatin alone Preoperative phase
Carboplatin/ doxorubicin/cisplatin Postoperative phase
S U R G E R Y
Cisplatin alone Postoperative phase
Figure 6. Treatment plan for SIOPEL 3
early, as part of first-line therapy, and not as a salvage procedure after multiple and prolonged chemotherapy attempts to reduce tumour volume or after tumour recurrence. Furthermore, recent data suggest that children presenting with metastatic hepatoblastoma, whose lung metastases clear with chemotherapy, should also be considered eligible for OLT. Three children among the 31 patients presenting with metastases in the SIOPEL 1 study are presently alive with no evidence of disease at more than 34, 70, and 75 months from transplant.18 Split-liver techniques can partly overcome the scarcity of organs, and transplants from living related donors, applicable only to children, can mitigate some of the ethical problems related to the competition for cadaver donors. Does ␣-FP-negative hepatoblastoma have a poor prognosis?
This uncommon type of hepatoblastoma seems to have an aggressive clinical behaviour. The German Study Group first drew attention to this. They noted that among 71 hepatoblastoma patients they studied prospectively, seven presented with an ␣-FP between 0 and 99 ng/mL, and only three of these were alive with no evidence of disease when last censored. In the SIOPEL 1 and 2 studies, 13 (6·5% of the entire population) had an ␣-FP of less than 100 ng/mL at diagnosis. Only five are alive disease-free with a median follow-up of 5 years 8 months (range 23 months to 7 years); six died 12 days to 8 months from diagnosis, five from progressive disease and one from toxic effects. Two others are alive with evidence of disease at 3 and 19 months. The biological and genetic differences between ␣-FP secreting and the ␣-FP non-secreting tumours are as yet unknown. THE LANCET Oncology Vol 1 October 2000
The treatment of microscopic residual disease
Among the 244 patients registered in the SIOPEL 1 and 2 studies, 28 had microscopic residual disease after surgery. In 26 patients, the microscopic residue consisted of tumour cells at the margin of surgical resection and for two patients, the residue was present in the vessels close to the resection margins. The majority of these patients continued with chemotherapy according to the protocol. Only one patient had further surgery (OLT). Overall, 24 of these 28 children are currently alive with no evidence of disease at follow-up ranging from 1 to 8 years (median 2 years). One died postoperatively and three died from disease. These data indicate that the presence of microscopic residual disease does not necessarily imply a poor prognosis, so heroic chemotherapy or surgical salvage procedures are not called for. However, it is crucial to monitor the ␣-FP concentration closely to ensure a return to normal at the end of treatment.24 These observations need to be confirmed with longer follow-up. What is the role of surgery in treating pulmonary metastases?
Patients with lung metastases have a poor prognosis. In the SIOPEL 1 study, the 5-year EFS was only 28%, although the OS was 57%.18 Seventeen of 31 patients are alive with no evidence of disease; nine of these had additional treatment, including thoracotomy in four patients. Others have also reported survival of such patients after lung surgery, which in some cases has necessitated multiple thoracotomies .25,26 99
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Search and selection criteria This review includes published and as yet unpublished data from the SIOPEL studies and other relevant articles.
Is histology a prognostic factor?
In the SIOPEL 1 study, histology was not identified as a prognostic factor,17 however, this analysis was done on material obtained at biopsy that may not be representative of the whole tumour. Analysis of material obtained after chemotherapy may also not be representative of the original tumour.27 In a study of 196 patients, Haas and colleagues identified pure fetal histology as a good prognostic factor, but only in patients in whom the tumour was completely resected at diagnosis.28 Undifferentiated hepatoblastoma, which may be associated with a normal or low ␣-FP value, often responds poorly to chemotherapy and has an aggressive behaviour with poor outcome. Further studies are needed to confirm the prognostic significance of histology. The success of the SIOPEL trials, which has been achieved by unparalleled international cooperation, demonstrates that it is possible to conduct clinical trials on rare tumours. This is a model that should be applied to other rare neoplasms. Acknowledgments
We acknowledge funding received from the Bernese Cancer Fund, the Swiss Cancer League, Dr Takedo Takeda (Sapporo, Japan), the UK Liver Tumour Parents Group, especially the Bristow, Marshall, and O’Shea families, and the Cancer Research Campaign, without which the SIOPEL studies could not be conducted. References
1 Exelby PR, Filler RM, Grosfeld YL. Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma. American Academy of Paediatrics Surgical Section Survey – 1974. J Paediat Surg 1975; 10: 329–37. 2 Perilongo G, Shafford EA. Liver Tumours. Eur J Cancer 1999; 35: 953–59. 3 Ammann RA, Plaschkes J, Leibundgut K. Congenital hepatoblastoma: a distinct entity? Med Ped Oncol 1999; 32: 466–68. 4 Ross JA, Gurney JG. Hepatoblastoma incidence in the United States from 1973 to 1992. Med Ped Oncol 1998; 30: 141–42. 5 Ikeda H, Matsuyama S, Tanimura M. Association between hepatoblastoma and very low birth weight: a trend or a change? J Pediatrics 1997; 130: 557–60. 6 Debaun MR, Tucker MA. Risk of cancer during the first four years of life in children with the Beckwith-Wiedemann Syndrome. J Pediatrics 1998; 132: 398–400. 7 Li FP, Thurber WA, Seddon J, Holmes GE. Hepatoblastoma in families with polyposis coli. JAMA 1987; 257: 2475–77. 8 Evans AE, Land VJ, Newton WA, Randolph JR et al. Combination chemotherapy in the treatment of children with malignant hepatoma. Cancer 1982; 50: 821–26. 9 Douglass EC, Green AA, Wrenn E, et al. Effective cisplatin (DDP) based chemotherapy in the treatment of hepatoblastoma. Med Ped Oncol 1985; 13: 187–90. 10 Quinn JJ, Altman AJ, Robinson HT, et al. Adriamycin and cisplatin for hepatoblastoma. Cancer 1985; 56: 1926–29.
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11 Ninane J, Perilongo G, Stalens JP, et al. Effectiveness and toxicity of cisplatin and doxorubicin (PLADO) in childhood hepatoblastoma and hepatocellular carcinoma: a SIOP pilot study. Med Ped Oncol 1991; 19: 199–203. 12 Pritchard J, Brown J, Shafford E, et al. Preoperative chemotherapy with cisplatin and doxorubicin for childhood hepatoblastoma: a successful approach. Results of the first prospective study of the International Society of Pediatric Oncology (SIOP) – SIOPEL 1. J Clin Oncol (in press). 13 Pierro A, Langevin AM, Filler RM, et al. Preoperative chemotherapy in ‘unresectable’ hepatoblastoma. J Pediatr Surg 1989; 24: 24–29. 14 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: 2167–72. 15 Douglass EC, Reynolds M, Finegold M, et al. Cisplatin, vincristine and fluorouracil therapy for hepatoblastoma: a Paediatric Oncology Group Study. J Clin Oncol 1993; 11: 96–99. 16 von Schweinitz D, Byrd DJ, Hecker et al. Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Eur J Cancer 1997; 33: 1243–49. 17 Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma – results from the International Society of Pediatric Oncology (SIOP) Study – SIOPEL1. Eur J Cancer 2000; 36: 1418–25. 18 Perilongo G, Brown J, Shafford EA et al. Hepatoblastoma presenting with lung metastases – treatment results of the first cooperaive prospective study of the International Society of Pediatric Oncology (SIOP) on childhood liver tumours (SIOPEL 1). Cancer (in press). 19 Ortega JA, Douglass E, Feusner J, et al. A randomised trial of cisplatin (DDP)/vincristine (VCR)/5-fluorouracil (5FU) vs. DDP/doxorubicin (DOX) iv continuous infusion (CI) for the treatment of hepatoblastoma (HB). Results from the Pediatric Intergroup Hepatoma Study (CCG-8881/POG-8945). Proc Am Soc Clin Oncol 14–17, May 1994. 20 Black CT, Cangir CM, Andrassy RJ. Marked response to preoperative high-dose cis-platinum in children with unresectable hepatoblastoma. J Pediatr Surg 1991; 26: 1070–73. 21 Perilongo G, Brugieres L, Shafford E, et al. Hepatoblastoma – SIOPEL 2 pilot study, preliminary report. Med Ped Oncol 1999; 33: 177 abstract. 22 Koneru B, Flye MW, Busuttil RW, et al. Liver transplantation for hepatoblastoma. The American experience. Ann Surg 1991; 213: 118–21. 23 Al-Qabandi W, Jenkinson HC, Buckels AD, et al. Orthotopic liver transplantation for unresectable hepatoblastoma. J Pediatr Surg 1999; 34: 1261–64. 24 Van Tornout JM, Buckley, Quinn JJ, et al. Timing and magnitud of decline of ␣-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome. A report from the Children’s Cancer Group. J Clin Oncol 1997; 15: 1190–97. 25 Black CT, Luck SR, Musemeche CA, Andrassy RJ. Aggressive excision of pulmonary metastases is warranted in the management of childhood hepatic tumours. J Pediatr Surg 1991; 26: 1082–86. 26 Passmore SJ, Noblett HR, Wisheart JD, Mott MG. Prolonged survival following multiple thoracotomies for metastatic hepatoblastoma. Med Pediatr Oncol 1995; 24: 58–60. 27 Saxena R, Leake JL, Shafford EA, et al. Chemotherapy effects on hepatoblastoma. Am J Surg Pathol 1993; 17: 1266–71. 28 Haas JE, Muczynski KA, Krailo M, et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989; 64: 1082–1095.
A list of SIOPEL study participants appears on The Lancet Oncology’s website: http://oncology.thelancet.com
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