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Hepatocellular Carcinoma in Children: Results of the First Prospective Study of the International Society of Pediatric Oncology Group

From the Department of Pediatric Surgery, Medical University of Gdask, Gdask, Poland.

Address reprint requests to Piotr Czauderna, MD, Department of Pediatric Surgery, Medical University of Gdask, Ul, Nowe Ogrody 1-6, 80-803 Gdask, Poland; email: pczaud{at}amg.gda.pl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors.

PATIENTS AND METHODS: Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncology’s first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin).

RESULTS: Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis.

CONCLUSION: Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HEPATOCELLULAR carcinoma (HCC) in childhood is rare and accounts for less than 0.5% of all pediatric malignancies; however, it is the second most common malignant liver neoplasm (after hepatoblastoma [HB]) in children.^1,2 Its relative frequency is 0.5 to 1.0 cases per million children.^2,3 It is more frequently encountered in older children and teenagers than in infants. The most common clinical sign is hepatomegaly, which is sometimes associated with abdominal pain. Unlike HB, HCC often develops in the presence of underlying liver disease and cirrhosis, especially viral hepatitis (mainly hepatitis B) or inborn metabolic errors, such as tyrosinemia.^1,4,5 Compared with HB, the prognosis in HCC is poor.^1,6-9

The Group for Epithelial Liver Tumors of the International Society of Pediatric Oncology (SIOPEL) was formed in 1989 and in 1990 began its first clinical trial devoted to both pediatric HB and HCC. The main clinical aim of the trial was to improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy with a combination of the most effective documented single agents (doxorubicin and cisplatin [PLADO]). The primary scientific objectives were to collect information on the epidemiology and natural history of these tumors and to identify prognostic factors.

The results of the treatment of HB patients in the SIOPEL 1 trial were published in the Journal of Clinical Oncology in 2000.¹⁰ Several reports on the treatment of pediatric HCC have been published, but most of them either present a series less than 10 patients or combine patients treated in different ways^{1,4,6-9,11-13}. The aim of this article is to present the results for patients with HCC treated in SIOPEL 1 and to compare them with the SIOPEL 1 HB patients and other published HCC trials. To the best of our knowledge, ours is the largest series of uniformly treated patients ever reported.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The SIOPEL 1 trial was an international, prospective, cooperative single-arm study. It was open to patient registration between January 1990 and February 1994 and involved 91 centers from 30 countries of the world. Children aged less than 16 years old with a histologically proven, previously untreated HB or HCC were eligible for the study. Central review of the pathology slides was required for each patient entering onto the study. Details of study design, data collection, and statistical methods and packages used have already been published together with the outcome for patients with HB.^10,14

Required Patient Information at Diagnosis and Staging Procedures
The determination of the serum alpha-fetoprotein (AFP) concentration value was mandatory at diagnosis. Open or closed surgical biopsy was strongly recommended for accurate diagnosis before chemotherapy, except in those patients for whom the surgical risk was considered unacceptable in the face of unequivocal clinical findings (hepatic mass and increased AFP). Biopsy was mandatory in children younger than 6 months of age. All material obtained at biopsy and resection was to be centrally reviewed by one pathologist (J.K.).

Staging Procedures and Pretreatment Extent of Disease System (PRETEXT)
The pretreatment assessment of the extent of the primary tumor was by abdominal ultrasound, computed tomography (CT) scan, or magnetic resonance imaging. Metastatic spread was assessed by a chest x-ray (posteroanterior and lateral views) and, where available, lung CT scan. Hepatic angiography was optional. Imaging data sheets were reviewed centrally. Based on the radiologic findings, a Pretreatment Extent of Disease System (PRETEXT) was developed to describe tumor extent at diagnosis, before therapy, and during therapy (Fig 1). Extension of the tumor beyond the liver was indicated with a V for extension into the vena cava and/or all three hepatic veins, P for extension in the main or both left and right branches of the portal vein, E for extrahepatic extension except for P and V, and M for the presence of distant metastases.

View larger version (25K): [in this window] [in a new window]   Fig 1. Schematic representation of the PRETEXT system.

Timing of Tumor Response Evaluation and of Surgery
Tumor response was evaluated after the second and fourth courses of PLADO by repeating the imaging investigations that were positive at diagnosis and monitoring the serum AFP level. If, as defined in the next section, there was evidence of progressive disease at either time point, the patient was switched to alternative chemotherapy. After four courses of PLADO, tumor resectability was assessed. If feasible, partial hepatectomy was then performed, and two more postoperative PLADO courses were given. If the tumor was responding to chemotherapy but was still considered unresectable, two more courses of PLADO were given, and tumor resectability was reassessed.

Tumor Response
Complete response was defined as no evidence of disease and normal serum AFP. Partial response was defined as any tumor volume shrinkage (ie, decrease in at least one dimension with other dimensions decreased or stable) associated with a decreasing AFP value. Stable disease was defined as no change in tumor volume or serum AFP value. Progressive disease was an unequivocal increase in one or more dimensions or the appearance of new lesions.

Surgery
No specific guidelines were provided for resection of the tumor, but to minimize the risk of perioperative deaths, it was recommended that: (1) the nutritional status of the patient be evaluated carefully before surgery, as described by Fan et al,¹⁵ and (2) patients be treated in centers with considerable experience in pediatric liver surgery and anesthesia. Primary surgery was admissible only in those patients in which the tumor was confined to the left lateral or right posterior sector (PRETEXT I).

Orthotopic liver transplantation was considered in patients whose tumor was completely confined to the liver and that, despite a positive response to adequate first line chemotherapy, remained unresectable. Results of orthotopic liver transplantation in the SIOPEL 1 study for HCC and HB will be presented in a separate manuscript. No specific guidelines were provided for patients with lung metastases, except that lung surgery was recommended, if feasible, in cases where pulmonary lesions persisted after PLADO therapy.

Statistical Methods
The results of this trial are expressed in terms of response to PLADO, overall survival, and event-free survival. All calculations are based on intention to treat and include data on patients who died before any treatment could be given or during the first weeks of chemotherapy. To be assessable for response, patients must have received at least two courses of chemotherapy. Overall survival time was defined as the time interval between the date of diagnosis and the date of death (from any cause) or the date of last follow-up. Event-free survival was defined as the time interval from the date of diagnosis to one of the following: (1) date of alternative treatment because of failure of the PLADO regimen, (2) date of relapse, (3) date of death, or (4) date of last follow-up, whichever occurred first. Date of alternative treatment was used as a surrogate for date of progression when the precise date of progression was not recorded. Relapse was identified from unequivocal imaging and serially increasing serum AFP levels or biopsy confirmation. Patients lost to follow-up were censored in these analyses. The Kaplan-Meier method was used to estimate survival curves.⁹ Ninety-five percent confidence intervals (95% CIs) were calculated for the survival estimates using the Greenwood method.¹⁰ Variables at diagnosis were univariately assessed using the log-rank test for association with overall survival or event-free survival. Variables were considered to be statistically correlated at the 10% level of significance. Variables correlated with survival were then considered in a multivariate analysis. The stepwise Cox proportional hazards regression model was used to model the prognostic factors adjusted for the influence of each other. All statistical procedures were carried out using the SAS statistical package (SAS Institute, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient and Tumor Characteristics
Forty patients diagnosed with HCC were registered onto the SIOPEL 1 study, but one was excluded from further analysis because of insufficient data. Male to female ratio was 2.5:1. Age range was from 4 to 15 years (median, 12 years). At diagnosis, lung metastases were identified in 12 (31%) of 39 children, extrahepatic tumor extension was found in seven patients (18%), and major vascular involvement (all three hepatic veins, vena cava, and/or both branches of portal vein) was present in eight cases (21%). Most tumors were classified as the epithelial histologic variant of HCC (29 of 39; 75%), six of 39 tumors were fibrolamellar, and the rest (n = 4) had other histology, ie, poorly differentiated or clear cell.

Tumor staging revealed that a PRETEXT III and IV category were most common (11 and 13 cases, respectively; 61%), whereas PRETEXT I was found in one case and PRETEXT II in 14 patients (36%).

Serum AFP concentration at diagnosis ranged from 1 to 1,400,000 ng/mL (median, 9,677 ng/mL). Serum AFP was normal (< 10 ng/mL) in 12 children (31%). All patients with a fibrolamellar HCC variant had low AFP levels (< 25 ng/mL). Tumor diameter varied from 7 to 26 cm (median, 14 cm). Multifocal tumors were present in 22 patients (56%), four of whom liver involvement was diffuse with no healthy hepatic parenchyma seen on the CT.

Thirteen patients (33%) presented with HCC associated with hepatitis B and hepatic cirrhosis. One patient had tyrosinemia, and one patient had biliary cirrhosis.

Tumor biopsy was performed at diagnosis in 34 of 39 cases (open in 12 and closed in 22). In two others, the diagnosis was made on clinical grounds, and in one case, data on biopsy are missing. In all three cases, the clinical diagnosis of HCC was confirmed by the resection specimen. In the remaining two patients, primary tumor resection was performed because of local center decision.

Response to Preoperative Chemotherapy
Thirty-seven patients received preoperative chemotherapy of one to six PLADO courses (median, four courses). Partial response was observed in 18 (49%) of 37 patients. No response was seen in eight (22%) of 37 patients, and disease progressed in six (16%) of 37 patients. For one patient, who was later lost to follow-up, data on response are missing. Four patients received only one PLADO course, therefore their response to chemotherapy could not be judged.

Surgery
Tumor resection was attempted in 19 patients (including 17 [46%] of 37 patients who received preoperative chemotherapy). It was complete in 14 of them, including two total hepatectomies with subsequent liver transplantations, although in one case, the transplant had been performed because of underlying tyrosinemia and not because the tumor itself was unresectable. Thus, the rate of successful tumor excision was 36%. Ten patients with completely resected tumors responded to preoperative chemotherapy, and two had primary tumor surgery. The 13th patient had stable disease after preoperative chemotherapy, whereas data on chemotherapy response of the 14th patient are missing. Partial excision of the tumor (with microscopic residual) was performed in two patients, one of whom had local radiotherapy to residual disease, and in three patients, the tumor was inoperable at laparotomy. The following types of liver resection were performed: (1) eight hemihepatectomies, (2) five extended hemihepatectomies, (3) two total hepatectomies, and (4) one left lateral lobectomy. In 20 cases of HCC (51%), primary tumors never became operable because of extensive liver involvement.

Survival
Eight patients (28%) are alive with no evidence of disease at the median follow-up time of 75 months (from 49 to 90 months). Among them there is one child with fibrolamellar HCC variant. All survivors underwent complete tumor resection. Twenty-seven children (69%) died of progressive disease. One child with progressive disease died of chemotherapy complications after second-line chemotherapy with carboplatin and etoposide. Another child died after complete tumor resection because of surgical complications (septic shock). Two patients were lost to follow-up.

The median survival of the patients who died was 15 months (range, 1 to 65 months). Six relapses occurred (all after complete resections). Three relapses were local, two were distant, and one was combined. Four relapsed patients died of progressive disease, one patient is alive in second remission, and one was lost to follow-up.

The figures for overall survival for HCC patients in the SIOPEL 1 study are 40% (95% CI, 24% to 55%) at 2 years and 28% (95% CI, 14% to 43%) at 5 years (Fig 2). Event-free survival at 2 years was 23% (95% CI, 10% to 37%), whereas it was 17% (95% CI, 6% to 30%) at 5 years (Fig 3).

View larger version (10K): [in this window] [in a new window]   Fig 2. Overall survival of SIOPEL 1 HCC patients.

View larger version (13K): [in this window] [in a new window]   Fig 3. Event-free-survival of SIOPEL 1 HCC patients.

View larger version (10K): [in this window] [in a new window]   Fig 4. Overall survival of SIOPEL 1 HCC patients and presence of metastases.

View larger version (10K): [in this window] [in a new window]   Fig 5. Overall survival of SIOPEL 1 HCC patients and tumor’s multifocality.

View larger version (12K): [in this window] [in a new window]   Fig 6. Overall survival of SIOPEL 1 HCC patients and PRETEXT category.

For event-free survival, metastases and vascular invasion were significant at the 10% level in the univariate analysis (P = .0001 and P = .08, respectively; Table 2). In the multivariate analysis, the only predictor of event-free survival was metastases (hazard ratio, 0.167 [95% CI, 0.04 to 0.6]).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In our series, 33% had underlying liver disease. This observation confirms that the majority of pediatric hepatocarcinomas are de novo cases, usually not related to hepatic cirrhosis, in contrast to the adult experience.^1,5,17-19

We could not confirm earlier adult observations on better outcome associated with fibrolamellar variant of HCC, although there were only a few such patients in the reported group (six of 39; one is alive with no evidence of disease, one was lost to follow-up, and four of them died).^1,20,21 However, median survival of patients with fibrolamellar HCC was much longer (25 months v 11 months) than that for the rest of HCC group.

Optimal therapy for pediatric HCC patients is yet to be determined. The advanced stage of most tumors at diagnosis (as far as local PRETEXT grouping, presence of metastases, and multifocality are concerned) and the relative insensitivity of HCC to current chemotherapy mean that the rate of complete excision is low (36% in the reported study compared with 87% for HB in the same SIOPEL 1 study), which is in line with other reports.^1,4 All authors agree that complete tumor excision remains a cornerstone of therapy (in our series, eight of 14 patients who had complete resection are alive, and they are the only survivors).^1,4,16 In our series, multifocal tumors strongly influenced the possibility of surgical resection (10% complete resections in multifocal tumors v 61% in unifocal tumors). This is probably why multifocality of the tumor was one of the identified prognostic factors. Presence of vascular invasion on imaging was another one, and a similar observation was made by Tagge et al.¹⁶ Both multifocality and vascular invasion could be an explanation for the much higher relapse rate and lower survival in completely resected HCC patients in comparison with HB patients (5-year disease-free survival in SIOPEL 1 was 92% for completely resected HB v 54% for HCC). It is also possible that multifocality is even more frequent, but small lesions are not picked up on imaging and remain undetected and hence unresected. If this hypothesis is true, these unidentified lesions may be to blame for the higher proportion of relapses in HCC. It is difficult to analyze separately the patients who relapsed because they are a small subset of children. Their median age, tumor size, and frequency of liver cirrhosis were similar to the whole group. The majority of them were unifocal (five of six) and in the PRETEXT II group (five of six), but that was probably because most multifocal and more advanced tumors were unresectable (90%). It is worth noting that five (83%) of six relapsed HCC patients had low AFP levels (< 100 ng/mL) compared with three (33%) of nine who did not relapse. Half of the relapsed children (three of six) apart from the low AFP levels had fibrolamellar HCC variant.

Other reports indicate even lower survival rates in completely excised cases of approximately 30% to 40%.^1,4,6 The role of liver transplantation in pediatric HCC is still very much a matter for debate; however, in adults, transplantation criteria for HCC are strict, including disease confined to the liver with no more than three tumor foci of a maximum diameter of 3 cm.^16,22 In general, orthotopic liver transplantation is not an option for most HCC patients because of advanced disease at diagnosis and the much higher proportion of recurrences in comparison with HB.¹⁶ This issue will be discussed in detail in a separate article devoted to transplantation in SIOPEL 1.

Chemotherapy is only partially effective for HCC (approximately 50% partial responses in the reported series). Although the response to PLADO chemotherapy in this study constitutes a significant improvement in response rate in comparison with historical controls, our experience has been that observed responses are not sufficient to render the majority of patients resectable, which is in parallel with other reports.^4,23 Nevertheless, resectability rate and survival were much higher among patients who responded to preoperative chemotherapy (61% v 5% and 33% v 0%, respectively). The response to chemotherapy achieved in this trial seems to be a significant improvement in comparison with other reports.^4,16 However, it has to be mentioned that the response definition used in this protocol was different (ie, any tumor shrinkage and decrease of AFP) to that used by many adult studies (usually 50% decrease in the sum of the products of the tumor’s longest dimension).^24-26 None of the patients who did not respond to preoperative chemotherapy survived. Thus, it seems that chemotherapy response in HCC may be used as an additional indicator of the chance of cure. The relative chemoresistance of HCC is also reflected by the fact that metastatic patients had the worst prognosis, and the presence of metastases was the most potent adverse prognostic factor. This finding was confirmed by Chen et al.⁴ It is speculated that refractoriness of HCC to chemotherapy results from the presence of multidrug resistance genes, including p53 gene.²⁷

Overall survival in pediatric HCC is far from satisfactory, and the relative resistance of this neoplasm to present therapeutic regimens indicates that new treatment approaches are required. It could well be that the whole strategy of treatment should be redesigned. Some new chemotherapeutic agents (for example, paclitaxel or anti-AFP monoclonal antibodies) have already been tested in children and adults but with contradictory results.^28-30 Other new treatment strategies that are being investigated are transarterial chemoembolization, cryosurgery, thermotherapy, or large-dose intra-arterial chemotherapy under conditions of hepatic venous isolation and hemoperfusion.^24-26,30-33 However, many of these treatments, at least in adults, are only palliative or at best prolong life rather than achieve cure. Others, like chemoembolization, are more promising but difficult to test in the framework of multicenter, international trials.

Survival for pediatric HCC patients is significantly inferior to that for children with HB despite similar multidisciplinary treatment. At present, complete tumor excision remains the only realistic chance of cure. However, in many cases it cannot be achieved because of advanced disease at diagnosis and refractoriness of HCC to standard chemotherapy. Because pediatric HCC is relatively rare in the Western world, most groups incorporate these patients into HB trials. In light of the above observations, this approach should now be questioned. It is probably more appropriate to encourage a prospective worldwide cooperation in the field of pediatric HCC to look for and test new treatment approaches and novel therapeutic concepts.

APPENDIX
The present study could only be conducted with the participation of the following lead clinicians and centers:T. Acha, Hospital Materno Infantil, Malaga, Spain; F. Breatnach, Our Lady’s Hospital Sick Children, Dublin, Ireland; M. Buyukpamukcu, Hacettepe University, Ankara, Turkey; B. de Camargo, AC Camargo Hospital, Sao Paulo, Brazil; M-H Chang, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; M.P. Gerard, Children’s Hospital Sheffield, United Kingdom; P. Hartley, Red Cross CH, Cape Town, South Africa; M. Heikinheimo, Children’s Hospital, Helsinki, Finland; H. Hertz and M. Yssing, University Hospital, Copenhagen, Denmark; P.B. Hesseling, Faculty of Medicine, Tygerberg, South Africa; A. Kilby, Middlesex Hospital, London, United Kingdom; J.A. Kohler and M. Radford, Southampton General Hospital, Southampton, United Kingdom; D.E. Koliouskas, Ippokration Hospital, Thessaloniki, Greece; L. Lashford, Royal Manchester Children’s Hospital, United Kingdom; J.R. Mann, M.C.G. Stevens, and D. Kelly, Children’s Hospital, Birmingham, United Kingdom; J. Marky, A. Rubensen, and B. Lannering, University of Goteborg, Goteborg, Sweden; V. Martinez Ibanez, Hospital Infantil Valle Hebron, Barcelona, Spain; D.C. Mauger and J. Skeen, Auckland Children’s Hospital, Auckland, New Zealand; G. Mieli-Vergani, King’s College Hospital, London, United Kingdom; J. Ninane, Cliniques Universitaires St Luc, Brussels, Belgium; G. Perilongo and G. Cecchetto, Chirurgica Pediatrica, Padova, Italy; C.R. Pinkerton, Royal Marsden Hospital, London, United Kingdom; A.A. Marques da Silva and S. Vianna, Domingos A Bolini, Sao Paulo, Brazil; Takeo Takeda, Sapporo National Hospital, Sapporo, Japan; K. Tiedeman, Royal Children’s Hospital, Victoria, Australia; and D. Walker, Queen’s Medical Centre, Nottingham, United Kingdom.

	ACKNOWLEDGMENTS

 
Supported by the Swiss Cancer League, Bernese Cancer League, Berno, Switzerland, and the United Kingdom Liver Tumor Parents Group.

We thank Claire Dicks-Mireaux, MD, for her invaluable work with imaging in SIOPEL 1 study.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted June 18, 2001; accepted March 4, 2002.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Czauderna, P. Articles by Otte, J.B. Search for Related Content PubMed PubMed Citation Articles by Czauderna, P. Articles by Otte, J.B. Social Bookmarking                            What's this?