Prognostic stratification for children with hepatoblastoma: The SIOPEL experience

European Journal of Cancer (2012) 48, 1543– 1549

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Prognostic stratification for children with hepatoblastoma: The SIOPEL experience q,qq Rudolf Maibach a,⇑, Derek Roebuck b, Laurence Brugieres c, Michael Capra d, Penelope Brock b, Patrizia Dall’Igna e, Jean-Bernard Otte f, Beatriz De Camargo g, Jozsef Zsiros h, Arthur Zimmermann i, Daniel Aronson j, Margaret Childs k, Marcelo Scopinaro l, Bruce Morland m, Jack Plaschkes n, Piotr Czauderna o, Giorgio Perilongo e a

IBCSG Coordinating Center, Berne, Switzerland Great Ormond Street Hospital, Great Ormond Street, London, United Kingdom c Department of Paediatrics, Institut Gustave Roussy, Villejuif Ce´dex, France d Our Lady’s Children’s Hospital Crumlin, Haematology/Oncology, Dublin, Ireland e Division of Paediatrics, Department of Paediatrics, Padua, Italy f University Clinic Saint-Luc, Department of Paediatric Surgery, Brussels, Belgium g Hospital do Cancer, Department of Research, Sao Paolo, Brazil h Department of Paediatric Oncology, Emma Children’s Hospital, AMC, Amsterdam, The Netherlands i Department of Surgical Pathology, Institute of Pathology, Berne, Switzerland j Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands k CCLG Data Centre, Leicester, United Kingdom l Hospital Prof. Dr. JP Garraham, Servicio de Hemato-Oncologia, Buenos Aires, Argentina m Birmingham Children’s Hospital, Birmingham, United Kingdom n Department of Surgery, University Children’s Hospital, Berne, Switzerland o Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland b

Available online 13 January 2012

KEYWORDS Hepatoblastoma Prognostic factor Metastasis Alpha-fetoprotein Clinical trial Tumour staging

Abstract Purpose: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. Patients and methods: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk

q Presented at the 42nd Annual Meeting of the International Society of Paediatric Oncology SIOP, Oct 21-24, 2010, Boston. Awarded the SIOP Award Clinical Research. qq This research was supported in part by Cancer Research Switzerland/Swiss Cancer League and Cancer Research UK. ⇑ Corresponding author: Address: IBCSG Coordinating Center, Effingerstrasse 40, 3008 Bern, Switzerland. Tel.: +41 31 389 91 96; fax: +41 31 389 92 39. E-mail address: [email protected] (R. Maibach).

0959-8049/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2011.12.011

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R. Maibach et al. / European Journal of Cancer 48 (2012) 1543–1549

(all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). Results: In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16–7.75), AFP P 1.2  106 ng/mL (2.48, 1.47– 4.17), metastatic disease (3.02, 2.05–4.44), PRETEXT IV (2.15, 1.19–3.87), multifocality (1.59, 1.01–2.50), age>5 years (2.76, 1.68–4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91–5.77); but not with PRETEXT III, age 30–60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age > 5 years and/or AFP > 1.2  106 have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3 year EFS of 49%. Conclusion: Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction In oncology, a progressively more accurate definition of a patient’s risk profile has allowed us to tailor therapy better for each individual. Risk stratification is a dynamic process, which is expected to be modified with improvements in therapy and knowledge of the implications for outcome of clinical and tumour biology characteristics. Retrospective analysis of data from clinical trials is critical to investigate characteristics of the tumour or patient which may be relevant for their prognosis. With this purpose in mind the International Childhood Liver Tumor Strategy Group (SIOPEL), has investigated the population of children affected by hepatoblastoma enrolled into two consecutive prospective cooperative trials run from 1995 to 2006, the SIOPEL 2 and 3 trials.1–3 Both trials were approved by the ethics committees of all participating sites and the patients or their parents consented to the trial. The aim of this analysis was to verify if the risk group stratification adopted by the SIOPEL group for these two trials is still applicable at the modern standard of care or if further risk categorisations have to be considered. This paper reports the results obtained. At present the SIOPEL group stratifies patients with hepatoblastoma into two categories: standard risk and high risk.4 The standard risk group encompasses patients with a primary tumour completely confined to the liver and involving at the most three hepatic sections (PRETEXT I, II or III) as defined in the PRETEXT system,5–7 and no other risk factor. Patients are included in the high risk category if they present with a tumour involving all four sections of the liver (PRETEXT IV) and/or the vena porta or both of its right and left branches (P+ in the original PRETEXT system) and/ or the inferior vena cava or all three hepatic veins (V+) and/or intra-abdominal extrahepatic disease (E+)

and/or metastases (M+) and/or serum alpha-fetoprotein (AFP) less than 100 ng/mL. In addition, children suffering from tumour rupture at diagnosis were allocated to the high risk category starting from 2004. The fundamental treatment philosophy adopted by the SIOPEL group, as adopted in the SIOPEL 2 and 3 trials, is based on the use of pre-operative chemotherapy in all patients before definitive surgery regardless of initial tumour extension. All the clinical and tumour characteristics which are taken into consideration for their possible prognostic implications were available at diagnosis before any therapeutic act. 2. Patients The SIOPEL 2 trial enrolled 76 standard risk and 59 high risk patients from 1995 to 1998.1 Between 1998 and 2006, 251 patients were randomised into the standard risk part of SIOPEL 3,2 whereas 155 were enrolled into the high risk study.3 The total of 541 children affected by hepatoblastoma form the analysis population for the present evaluation. Main patient and tumour characteristics are reported in Table 1. The treatment strategy was in both trials based on the use of pre-operative chemotherapy and both of them included a patient stratification based on the two risk groups as defined above. SIOPEL 2 was a combination of two pilot trials, one aiming to investigate the role of Cisplatin alone in standard risk patients and the other introducing a three-drug regimen for the high risk group consisting of Cisplatin alternating with the combination of Carboplatin/ Doxorubicin. SIOPEL 3 encompassed a randomised trial directed to standard risk patients, comparing the cisplatin monotherapy regimen piloted in the SIOPEL 2 trial with the combination of Cisplatin/Doxorubicin. For high risk patients SIOPEL 3 continued the investigation into the three-drug regimen introduced by SIOPEL 2 but

R. Maibach et al. / European Journal of Cancer 48 (2012) 1543–1549 Table 1 Patient and tumour characteristics. Patient characteristics

Median

Range

Age in months Alpha fetoprotein at diagnosis (ng/ mL) Platelets (106 L)

17 116,574

0–185 1–10,980,000

601,500

94,000– 1,791,000

Gender F M Tumour characteristics PRETEXT I II III IV Tumour Unifocal Multifocal Involvement of Vena cava Portal vein Extrahepatic intra-abdominal structures Metastases Small cell undifferentiated histology

215 326

39.7% 60.3%

26 198 210 107

4.8% 36.6% 38.8% 19.8%

449 92

83.0% 17.0%

47 60 26

8.7% 11.1% 4.8%

94 8

17.4% 1.5%

starting with the first dose of Cisplatin alone and administering the combination of Carboplatin/Doxorubicin two weeks later. This approach provided a two-week staging window to allow sufficient time to allocate patients to the correct risk group in doubtful cases.

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patients’ age, with cut-off values of 6, 12, 18, 24, 30, 36, 48 and 60 months; (b) platelet count less than versus greater than or equal to 500,000/mL as done in the previous pretreatment prognostic factor analysis4; (c) PRETEXT categories I or II versus III versus IV (PRETEXT I and II were lumped together due to the low number of PRETEXT I: 26 patients with 2 EFS events); (d) evidence of vascular involvement or intra-abdominal extra-hepatic disease (V+ and/or P+ and/or E+)5; (e) presence versus absence of metastases (M+); (f) tumour focality (unifocal versus multifocal); (g) small cell undifferentiated histology versus any other histology as documented by the local pathologist at initial biopsy; (h) AFP. AFP values at diagnosis were divided into categories using the cut-offs 102, 103, 104, 105, 3  105, 6  105, 9  105, 1.2  106 and 2  106 ng/mL. In SIOPEL trials, any patient with a ruptured tumour at the time of diagnosis was considered high risk from 2004. Tumour rupture was however not taken into the current analysis because only three patients presented with it and a statistical evaluation would not have been appropriate. Radiologic findings from participating sites were used; rapid central radiology review at diagnosis was offered to help classify difficult cases, but was not mandatory. Factors were analysed both univariately with one factor taken at a time, and then in a multivariate model combining all factors. A total of 125 EFS events were observed. The median follow-time for the patients enrolled into the SIOPEL 2 study was 7.4 years and for SIOPEL 3 was 5.0 years. The median follow-up time of the entire cohort of patients was 5.6 years.

3. Statistical methods The data from the two trials were pooled into a single sample for the analysis of prognostic factors. Survival curves were estimated according to Kaplan Meier, the Greenwood formula was used for the standard deviation. A Cox proportional hazards regression approach was chosen for the evaluation with event-free survival (EFS) as the primary end-point. Results are expressed as hazard ratios (HR) and their 95% confidence intervals (CI) and graphically presented as forest plots on a log scale. A HR > 1 indicates an elevated risk with respect to the reference category. A confidence interval which does not include the value 1 indicates statistical significance at the 5% level. It should be noted that this is a retrospective evaluation and therefore statistical significance should be interpreted with caution. All statistical evaluations were done with SAS version 9.1 (SAS Institute, Cary, NC). EFS was calculated as time from definitive clinical diagnosis to progression, recurrence or death from any cause, whichever occurred first, counting as censored at last follow-up all patients without such an event. Overall survival (OS) was calculated as time from diagnosis to death from any cause. The following factors, with their value determined at the time of diagnosis, were taken into the analysis: (a)

4. Results In a first step, we evaluated the correlation of the age and AFP categories with EFS. For age, the category below 6 months was chosen as reference. There was a clear trend of worsening prognosis with increasing age at diagnosis (Fig. 1A). Three subgroups were chosen for further analysis: Age between 30 and 60 months correlated with a slightly elevated risk, and patients aged 5 years or above showed a clearly higher risk for an EFS event. AFP values were not corrected for age since only 1 patient would have been reclassified as low AFP for age. The graphical evaluation of AFP suggested that the categories AFP < 100 ng/mL and P1.2  106 ng/mL were associated with an impaired prognosis (Fig. 1B). These results prompted us to categorise age and AFP into three groups each for further analysis. Table 2 gives an overview of the correlations between potential risk factors and EFS. The univariate results suggest that the following characteristics carry a worse prognosis: tumours invading all 4 sections of the liver (PRETEXT IV); AFP either less than 100 ng/mL or above 1.2  106 ng/mL; the presence of distant metastases; more than one tumour lesion in the liver; age above

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analysis gives additional information by weighing the relative impact of one factor, taking into account the influence of all other factors. The hazard ratios and their 95% confidence intervals change to various degrees with respect to the univariate analysis. PRETEXT III tumours, platelet count below 500,000/mL and small cell undifferentiated histology do not confer a significantly higher risk. Multifocality remains only borderline significant. PRETEXT IV tumours, AFP less than 100 ng/ml or above 1.2  106 ng/ml, metastatic disease, and age above 5 years are confirmed as conferring an increased risk of an EFS event (Fig. 1C). We decided to investigate a potential new risk stratification for the next generation of clinical trials in hepatoblastoma, taking into account these statistical findings and medical reasoning:

Fig. 1. Forest plots for potential prognostic factors. (A) Age categories. (B) Alpha-fetoprotein (AFP) categories. (C) All potential prognostic factors, multivariate results.

2.5 years; a platelet count of 6500,000/mL; and small cell undifferentiated histology. Some of these factors may be intercorrelated, and therefore the multivariate

Stratum 1 defined by: hepatoblastoma completely confined to the liver AND involving at the most three hepatic sections (PRETEXT I,II and III) AND none of the other risk factors considered below Stratum 2 including patients with one or more of the following factors: age more than 5 years PRETEXT IV tumour multifocal tumour AFP value at diagnosis above 1.2  106 ng/mL none of the risk factors considered for stratum 3 Stratum 3 of patients presenting with one or more of the following factors: metastases AFP less than 100 ng/mL small cell undifferentiated histology Fig. 2 provides a graphical summary of the stratification. A further exploration in stratum 1 showed that the 3 year EFS in PRETEXT I and II was 90.4% versus

Table 2 Correlation of potential prognostic factors with event free survival. Factor

PRETEXT III PRETEXT IV AFP < 100 ng/ml AFP P 1.2  106 ng/ml V/P/E: Vascular or extrahepatic involvement Metastases Multi focal Age 30 to 60 months Age over 5 years Platelet count 6 500,000/mL Small cell undifferentiated

N

210 107 20 42 89 94 92 78 44 179 8

Univariate Cox regression

Multivariate Cox regression

HR

95% CI*

HR

95% CI*

1.25 2.37 6.18 2.32 1.51 3.57 2.85 1.57 3.21 1.46 6.19

0.88–1.78 1.64–3.43 3.53–10.8 1.41–3.82 0.99–2.31 2.48–5.14 1.96–4.15 1.01–2.44 2.08–4.98 1.02–2.09 2.72–14.1

1.54 2.15 4.09 2.48 0.87 3.02 1.59 1.51 2.76 1.30 2.29

0.95–2.51 1.19–3.87 2.16–7.75 1.47–4.17 0.55–1.37 2.05–4.44 1.01–2.50 0.93–2.44 1.68–4.53 0.86–1.95 0.91–5.77

AFP = alpha-fetoprotein. HR = hazard ratio. CI = confidence interval. * A 95% CI which does not include the value 1 indicates statistical significance at the 5% level.

R. Maibach et al. / European Journal of Cancer 48 (2012) 1543–1549

Fig. 2. Prognostic factors and prognostic strata. +, factor must be present.

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, factor must be absent. +/ , factor may be present or absent

73–87%) and 54% (95% CI 44–63%) (Fig. 3 B). The differences between strata were statistically significant for both EFS and OS.

0.4

0.6

5. Discussion

Stratum 1 Stratum 2 Stratum 3

n=295 n=135 n=111

0.0

0.2

% event free

0.8

1.0

(A) Event-free survival stratified by three risk groups

12

24

36

48

60

72

84

72

84

months

0.6 0.4

Stratum 1 Stratum 2 Stratum 3

n=295 n=135 n=111

0.0

0.2

% survival

0.8

1.0

(B) Overall survival stratified by three risk groups

12

24

36

48

60

months

Fig. 3. (A) Event-free survival stratified by three risk groups. (B) Overall survival stratified by three risk groups.

88.7% for PRETEXT III, and the logrank test showed a non-significant p-value of 0.61. Based on this observation, PRETEXT III was kept in this stratum. In stratum 2, the 32 patients with an AFP above 1.2  106 ng/mL had a 3 year EFS of 69%, compared to 72% in the other 103 patients (logrank p = 0.47), a result which justified keeping the group in this stratum. The resulting strata encompassed 295 (stratum 1), 135 (stratum 2) and 111 (stratum 3) patients. The 3-year EFS was 90% (95% CI 86–93%), 71% (95% CI 63–79%) and 49% (95% CI 40–58%) for strata 1, 2 and 3, respectively (Fig. 3A). The corresponding 3-year overall survival rates were 94% (95% CI 92–97%), 80% (95% CI

There is clear evidence that children with hepatoblastoma enrolled in the SIOPEL 2 and 3 trials can be stratified into three well-defined risk groups. The factors which contribute substantially to this are PRETEXT, age, AFP level, presence of metastases, multifocality and small cell undifferentiated histology. The latter factor was kept although not statistically significant in the multivariate model, but highly significant univariately. The three groups show major differences in EFS and OS. This stratification is not merely derived from a statistical analysis. It is rather a critical reading of the data by experts in the field and an in-depth elaboration of observations of different study groups who have conducted therapeutic clinical trials on hepatoblastoma in the past three decades. The presence of metastases (mostly in the lung) has been acknowledged as a negative prognostic factor by all study groups. The event free survival of these children is around 25%.8,9 Similarly, all study groups accept that a normal (for age) or low level (<100 ng/mL) of AFP is a hallmark of quite negative prognosis. In the SIOPEL experience the 3-year OS of children presenting with low or normal AFP was 24%.10 A similar outcome has been reported by the North American groups for children with hepatoblastoma with a small cell undifferentiated component.11 An association between small cell undifferentiated hepatoblastoma and low or normal for age AFP has been proposed, however cases of otherwise classical hepatoblastoma presenting with low AFP have been documented.10 Thus, the fact that each of these three characteristics herald a dismal prognosis is a consolidated finding, even more so if they are present concurrently in the same patients. The PRETEXT system has been shown to have a prognostic value by both SIOPEL and the North American investigators in their retrospective review of the Intergroup CCG/POG study INT-0098.12 The involvement at diagnosis of all four sections of the liver by the tumour – PRETEXT IV – has always been consid-

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ered an intuitively unfavourable clinical characteristic due to the limitation that this extensive tumour involvement implies for radical surgical resection. However, the negative impact on prognosis of the PRETEXT IV category is reduced because some of these large tumours can be resected conventionally after preoperative chemotherapy,13 and orthotopic liver transplantation has become a valid therapeutic option for many others.14 There is less evidence in the literature on the possible negative role of a very high AFP level and of older age. The liver tumour study group of the German Society for Paediatric Oncology and Haematology (Gesellschaft fu¨r Pa¨diatrische Onkologie und Ha¨matologie, GPOH) highlighted the possible negative influence on outcome of an AFP15 level above 106ng/mL but no other report has supported this original observation. Age over 5 years has never been claimed as a negative prognostic factor. It is known that adolescents and young adults can suffer from a particular subtype of hepatoblastoma, called transitional liver cell tumour, which by itself seems to bring a poor outcome.16 It is commonly accepted that the lack of all the clinical and tumour characteristics listed above identify a group of children with very favourable outcome. Vascular involvement or intra-abdominal extra-hepatic disease (V+ and/or P+ and/or E+) showed a marginal correlation with outcome in the univariate, but not in the multivariate analysis. This can be explained by the strong correlation of such involvement with higher PRETEXT stage, multifocality of the tumour and presence of metastases. A potential drawback of this evaluation is that it is based on two sequential clinical trials conducted over a period of 12 years. The follow-up time of SIOPEL 2 is longer than for SIOPEL 3. In SIOPEL 2, 28% of patients had an EFS event, and in SIOPEL 3 only 21% of patients. However, both median follow-up periods went well into the range where the survival curves show a plateau (Fig 2). Central radiologic review of diagnostic imaging was not mandatory. Instead, rapid radiologic review was offered to participating sites for difficult cases. Our previously used risk stratification into standard and high risk patients, relying mainly on radiologic findings and AFP value, resulted in striking EFS and OS differences; this may serve as evidence that the stratification based on imaging was done correctly in the vast majority of cases (1, 2, 3). Any risk allocation at the time of diagnosis of hepatoblastoma needs to serve the purpose of selecting the appropriate treatment strategy for the patient. With this in mind, the treatment effects seen in the patients were not evaluated as prognostic factors, although they will have influenced long-term outcome as well. EFS and OS observed in our cohort differ considerably between the three proposed risk groups. A broad stratification into few groups is of primary importance for the planning of future therapeutic trials, which need to be

conducted with a reasonably high sample size and evaluated early enough to lead to rapid advances. The detailed discussion on how to refine the therapy according to the three groups and on how to adapt it according to the tumour response to therapy goes beyond the scope of this paper. However the results strongly support modulating the treatment according to this new categorisation. The stratification currently used by the North American group also encompasses three categories.17 However their categorisation and the one we are proposing overlap only partially. The discrepancy between the two systems stems mostly from the difference in treatment philosophy the groups use to approach hepatoblastoma (primary chemotherapy versus primary surgery).6,18 There is a need to arrive at a more comprehensive risk stratification system taking into account all relevant factors. With this in mind, a combined retrospective analysis looking for prognostic factors is being planned combining data from clinical trials from the SIOPEL group, the Children’s Oncology Group, the GPOH and the Japanese Paediatric Liver Tumour Group. This will allow more definitive conclusions about factors which we have not been able to evaluate due to small numbers (i.e. tumour rupture, rare histological subtypes) or which reached at most borderline significance (i.e. platelet count, vascular or extrahepatic intra-abdominal invasion). This should be complemented by investigations of the underlying biological mechanisms driving the prognostic factors described here. In summary this report shows that within the concept of treating hepatoblastoma patients with preoperative chemotherapy, at the present standard of care, three well defined prognostic categories can be identified exclusively based on diagnostic findings. These results should be taken into consideration when designing future trials. Conflict of interest statement None declared. References 1. Perilongo G, Shafford E, Maibach R, et al. Risk-adapted treatment for childhood hepatoblastoma. Final report of the second study of the International Society of Paediatric Oncology – SIOPEL 2. Eur J Cancer 2004;40:411–21. 2. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard risk hepatoblastoma. N Engl J Med 2009;361(17):1662–70. 3. Zsı´ros J, Maibach R, Shafford E, et al. Successful treatment of childhood high risk hepatoblastoma with dose intensive multiagent chemotherapy and surgery – final results of the SIOPEL3HR study of the childhood Liver tumor strategy group. J Clin Oncol 2010;28(15):2584–90. 4. Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma – results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 2000;36(11):1418–25.

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